27693404 true Agent for recovery: the opportunity for enhancing social inclusion afforded by prolonged-release buprenorphine formulations PROP Does Buvidal provide the opportunity for an individual to gain a greater sense of belonging to a community through social identity change? Background and study aims A body of literature describes the experience of stigma and shame that people who use drugs (PWUD) are subjected to, within both the wider community and in healthcare settings. PWUD are often considered to live outside of the everyday social norms of society. As a result they can be described as having tainted identities and regarded as second class citizens. One consequence of this is that PWUD are deprived of choice, options and inclusion. The use of pharmacological approaches has been a mainstay of UK treatment for opiate dependency for many years. The use of opiate substitution therapy (OST) is well evidenced, and for the vast majority of patients prescribed on a daily dispensing (supervised or unsupervised) basis. However, OST is often criticised for oppressive and "normalising" effects, with very little change happening for those prescribed. A body of work describes the mechanics of the delivery of OST as a factor in producing an environment in which change is difficult to achieve. The “methadone queue” is often perceived as stigmatising and in which the behaviours experienced and the obligatory social relationships negotiated make it difficult to make the desired identity change. A new OST option is now available. Prolonged-release subcutaneous buprenorphine can be administered at weekly or monthly intervals. The introduction of prolonged-release subcutaneous buprenorphine products provides an opportunity to deliver OST in an alternate way, allowing greater flexibility for both clinician and patient. This study will investigate if prolonged-release buprenorphine can be the catalyst for change over an 18-month period. It will investigate if it allows those receiving this type of OST to create a new identity, strengthen or make new relationships and mobilise new resources such as increased wellbeing, employment and education opportunities and social inclusion to aid a recovery journey. Who can participate? Patients aged 18 years or over who are receiving buprenorphine from Drug and Alcohol Recovery Services in Tayside. Up to 10 staff participants from these services can also participate What does the study involve? This study involves three appointments with researchers from the University of Dundee over the course of 18 months. These appointments will be face-to-face or by telephone call. The researchers will collect information about patient participants' lives, including their living arrangements, employment, and financial situation. They will also record information about their medical history, including past and current drug use. Patient participants will be asked to complete some questionnaires about how they are feeling and how much they are in control of what happens in their lives. The researcher will also interview patient participants about being prescribed buprenorphine and how it affects their lives. The interviews will be recorded, which will then be typed up and analysed for themes. The second appointment will be 3-15 months after the first one and the final appointment will be 1-2 years after the first. Staff participants will be recruited from the teams caring for people prescribed prolonged-release buprenorphine (Buvidal). Their views and experiences with Buvidal will be captured using semi-structured interviews and/or focus groups. What are the possible benefits and risks of participating? The study may not benefit participants directly but it is hoped that it will give a better understanding of the effect of different types of OST on people's lives and help determine the right type for people in the future. It is possible that some of the questions in the questionnaires or in the interview may cause participants distress or discomfort. Participants can stop the interview at any time and the researcher will be trained to support participants. In thanks and compensation for their time they will be offered a supermarket voucher. A £10 voucher will be offered after visit 1 and 2 and £20 voucher after visit 3. Where is the study run from? Drug and Alcohol Recovery Services in NHS Tayside, conducted by researchers based in NHS Tayside and the University of Dundee (UK) When is the study starting and how long is it expected to run for? June 2021 to January 2025 Who is funding the study? Camurus (Sweden) Who is the main contact? Sarah Donaldson SDonaldson001@dundee.ac.uk The thematic narrative of semi-structured interviews describing the views, meanings and values of participants at baseline (visit 1), visit 2 and visit 3 Measured at baseline (visit 1), visit 2 and visit 3: 1. Wellbeing of the population described using the Short Warwick Edinburgh Mental Wellbeing Scale (SWEMWBS) 2. Social and financial characteristics of the population described using financial inclusion data from Scottish Core Survey Questions (captured on Case Report Form) 3. Shifts in social networks described using social Identity mapping 4. Social inclusion of the population described using the 5R’s of citizenship tool Ethics approval required North West- Greater Manchester East Research Ethics Committee

3rd Floor, Barlow House, 4 Minshull Street

Manchester United Kingdom M1 3DZ 21/NW/0358 10.1186/ISRCTN27693404 305675 CPMS: 52198, Sponsor 3.08.21, Protocol 3.08.21 305675 52198 Sponsor 3.08.21, Protocol 3.08.21 Mixed methods ethnographic case study Observational Cohort study Other 2025-01-31T00:00:00.000Z United Kingdom Scotland NHS Tayside

Ninewells Hospital

Dundee Scotland DD1 9SY Mixed 1. Adult (aged 18 years or over) males and females 2. History of problematic substance abuse 3. Treated in NHS Tayside with either Buvidal (prolonged-release buprenorphine) or sublingual/oral lyophilisate buprenorphine OR 4. A member of the multidisciplinary alcohol and drug recovery service team in NHS Tayside (staff participant only) AND 5. People of any ethnic origin who are able to speak English and are willing to talk about and reflect on their experiences with the phenomenon under study 6. Willing to have the semi-structured interviews audio recorded 7. Able to give informed consent Mixed 18 Years 120 Years All 70 57 1. Individuals will not be enrolled on the study if they are participating in the clinical phase of another interventional study or have done so within the last 30 days 2. Individuals who are participating in the follow-up phase of another interventional trial/study, or who are enrolled in an observational study, will be co-enrolled where the CIs of each study agree that it is appropriate 2022-04-19T00:00:00.000Z 2024-01-31T00:00:00.000Z Patient participants prescribed a buprenorphine formulation by NHS Tayside Drug and Alcohol Recovery Services for their opioid dependence Mental and Behavioural Disorders Mental and behavioural disorders due to use of opioids Up to 60 patient participants will be recruited from drug and alcohol recovery services in Tayside, Scotland. Patient participants will be recruited from patients receiving prolonged-release subcutaneous buprenorphine, weekly or monthly, as per standard pathway of care (up to n=30) and a control arm (up to n=30) of those currently prescribed oral buprenorphine formulations as per the standard pathway of care. This study has no influence on the prescribing choices of the drug and alcohol recovery services or patients. An estimated 10 staff participants will be recruited from the multidisciplinary drug and alcohol recovery service teams providing care to the patients receiving prolonged-release subcutaneous buprenorphine to capture their views and experiences through semi-structured interviews and/or focus groups. Patient participants will be followed up over an 18-month period and interviewed at three timepoints (visit 1 [baseline], visit 2 [9 months (+/- 6 months)], visit 3 [18 months (+/- 6 months)]) by the researchers to provide a long-term view on the individual and societal benefits of prolonged-release buprenorphine. Semi-structured interviews will be used to describe the views, meanings and values for individuals of their OST treatment at three timepoints over an 18-month period. A study topic guide will be used as the baseline for the semi-structured interviews. The interviews will be audio-recorded and transcribed verbatim. The resulting transcripts will be thematically analysed with themes coded. A number of questionnaires will also be used to capture patient experience, wellbeing and social identity: 1. Social Identity Mapping: The participants will be asked to place their social networks on a mapping tool that will provide a graphic representation of the social network at that point in time. The participant's name will not be recorded on the map, only the participant ID number. The map will demonstrate the number of social contacts within the network, a measure of the relationship (inner circle, outer circle and influence) and the substance use status of the members of the network. Participants will be asked to assign pseudo identities for their social network members as the participant needs to be able to classify the individuals within their own network and document how this may change over time. The pseudo-identity is known only to the participant and will be insufficient for the researcher to identify an actual person. The participant will rate the importance of their social network members (indicated by placing them in the inner or outer circle) and indicate their status as user, non-user or in recovery. Social contact pseudo identities will be assigned coloured dots to indicate their status: red for active user, green for non-user and blue for individuals in recovery. This tool provides a quantitative measure of their social network and will be mapped at each interview stage so that longitudinal insights into the change in social influences may be clearly described. 2. Short Warwick Edinburgh Mental Wellbeing Scale (SWEMWS): Patient participants will be asked to complete the self-reported short Warwick-Edinburgh Mental Wellbeing Scale (SWEMWBS) with assistance from the researcher if required. The measure is a list of seven positive mental health statements with five response categories assigned scores and the total scores calculated. Movements in the total wellbeing score have been evaluated using the wellbeing valuation method and represent the additional money the average individual would need to improve their wellbeing, which is the same as the improvement in their SWEMWBS score. This measurement can then be used to calculate a social value impact. 3. Financial Inclusion Data: Participant data will be collected at visit 1 (baseline), 2nd visit and 3rd visit to record age, gender, ethnic background, financial inclusion, household income and employment data, current and/or previous treatment for problematic substance use. The questions included are part of the Scottish Survey Core Questions and are recommended for use in other surveys as they have been extensively tested. 4. Citizenship Measure: A measure of citizenship (Yale University’s 5R’s of citizenship tool) will provide a description of how these participants are able to reclaim citizenship. Citizenship is similar, yet distinct from quality of life and wellbeing. This tool measures the ability of people to reclaim citizenship, defined by Rowe as the 5R’s of citizenship: Relationships, Resources, Responsibilities, Rights and Roles. The measure is a 46 item tool that measures demographic factors, sense of community, and social capital as predictors of citizenship, recovery, and well-being. 5. Observational field notes: Observational notes will be maintained by the researcher during the time period under investigation to allow for description and understanding of the order of events and actions. The researcher will record participant observations to provide rich verbatim descriptions of the specific situations, events and behaviours of the participants. These observations will be included in the thematic analysis of the data and clearly reported as observations differentiated from participant descriptions. Explicit description of the researchers’ analytical thinking will be maintained using field notes with a clear description of the decision-making process while developing initial and final themes. Other The datasets generated during and/or analysed during the current study will be available on request from SDonaldson001@dundee.ac.uk Available on request Results Basic results see attached file ISRCTN27693404 BasicResults 10.02.26.pdf (added 10/02/2026)

Added from spreadsheet

29ba8cd0-65f9-473a-ba9a-03b80641f50f 31cb9f82-ab24-4334-9ad6-1157ee45fe6a fb59ac75-ef36-4e2a-9638-56ae9b0274e9 9db2bcd7-3700-4faf-a135-bfb93d159c63 Yes Participant information sheet 41533_PIS_Staff_V2.0_07Jan22.pdf 8680bb5c-5bfd-4531-be38-d69734c35ce1 true application/pdf 801622 21677783ab94d99f3e441d459e086174 Participant information sheet 41533_PIS_V2.0_07Jan22.pdf 520ac677-b50d-49ef-b61c-075d90a15dd1 true application/pdf 167755 0aa0e30e943835dcdffd09d76952fda8 Basic results ISRCTN27693404 BasicResults 10.02.26.pdf 290b9111-583c-4935-abb3-5484e6b7293a true application/pdf 73348 a021eed86c048593393e221c1afb6ab2 Andrew Radley https://orcid.org/0000-0003-4772-2388 Scientific

School of Health Sciences City campus 11 Airlie Place University of Dundee

Dundee United Kingdom DD1 4HJ - a.radley@dundee.ac.uk Public Sarah Donaldson https://orcid.org/0000-0003-2816-3293 Public

Directorate of Public Health Kings Cross Hospital

Dundee United Kingdom DD3 8AE +44 (0)7967323195 SDonaldson001@dundee.ac.uk Public NHS Tayside Hospital/treatment centre https://ror.org/000ywep40 Non-commercial Camurus AB 87895237 true CANnabidiol for Parkinson’s Disease Psychosis (CAN-PDP) CAN-PDP For Part I of the proposed study, it is predicted that: 1. Cannabidiol at doses between 200-800 mg/day will be safe for short-term (6 weeks) use as a treatment in patients with Parkinson’s disease psychosis 2. A dose of 800 mg/day of cannabidiol will be the maximum tolerated dose in patients with Parkinson’s disease psychosis 3. There will be a minimal effect of short-term (6 weeks) cannabidiol treatment (at doses between 200 to 800 mg/day) on levels of medications such as quetiapine and donepezil in peripheral blood (drug-drug interaction) Based on the results of Part I, the researchers will identify a safe and tolerated dose of cannabidiol to test in Part II of the study. For Part II of the proposed study, it is predicted that: 1. The dose of cannabidiol chosen based on Part I of the study will be safe over a 12-week period of treatment in patients with Parkinson’s disease psychosis 2. The dose of cannabidiol chosen based on Part I of the study will show evidence of activity on measures of psychosis in patients with Parkinson’s disease psychosis (pharmacodynamic signal) For the mechanistic sub-study, it is predicted that: 1. Presence of psychosis in Parkinson’s disease patients would be associated with altered brain function in the striatum and medial temporal, prefrontal and visual cortices and functional connectivity between those regions as measured using MRI 2. 12-week treatment with cannabidiol would normalise those brain functional and connectivity alterations present at baseline (pre-treatment) in Parkinson’s disease patients with psychosis Background and study aims People with Parkinson’s disease often suffer from unusual experiences such as hallucinations (e.g. seeing things or hearing voices that are not there) or develop delusions (i.e. false beliefs, for example, that someone may be trying to harm them) as part of their illness. These experiences are also known as psychotic symptoms and are distressing both to patients and those caring for them. More than half of all patients with Parkinson's eventually develop these symptoms over the course of their disorder. These problems can be difficult to manage and can impact quality of life. Currently, existing medications to treat these symptoms are either not very effective or have significant side effects. The aim of this study is to test a new treatment called cannabidiol (CBD). CBD is a non-addictive substance present in the extract from the cannabis plant that is not responsible for the effects typically produced by cannabis, such as ‘feeling high’. Previous studies not only suggest that CBD may be useful in treating symptoms of psychosis, they also suggest that it is safe to use in older adults. Although CBD may be a promising treatment for symptoms of psychosis, it is not known whether this treatment will be tolerated well in patients with Parkinson’s-related psychosis, whether it will provide relief from psychotic symptoms, and what doses may work best for people with Parkinson’s-related psychosis. The aim of this study is to address all of these questions. Who can participate? Patients aged 40 or older with Parkinson’s disease who are experiencing symptoms of psychosis (such as hallucinations e.g. seeing things or hearing voices that are not there or delusions e.g. false beliefs, for example, that someone may be trying to harm them) for at least 1 month before the first study visit What does the study involve? The study will be carried out in two parts. In Part I, the researchers want to know whether cannabidiol is safe for people with Parkinson’s-related psychosis and find the dose that may work best. For this, groups of participants (three participants per group) will receive different doses of CBD for 6 weeks, starting with a small dose i.e., 200 mg per day of CBD, to determine if that dose is safe and tolerated well. If the treatment that the first three participants receive does not cause side effects, the dose of CBD will slowly be increased to the next dose i.e., 400 mg per day, as the researchers enrol the rest of the participants into the study. A minimum of three and a maximum of 24 participants will be treated with CBD in this part of the study to find the best-tolerated dose. In the second part of the study, the researchers will assess the usefulness of CBD on symptoms of Parkinson’s-related psychosis. For this, they will study 120 eligible and willing participants. Half of the participants will receive CBD and the other half will receive a placebo (an inactive substance) in addition to their regular treatment. Participants will have a 50/50 chance of receiving either CBD or placebo (dummy) capsules. Neither the participants nor researchers will know which treatment is being given to each individual. The researchers will monitor participants as in the first stage and compare CBD’s effects with that of placebo. Participants will be asked to take the study medicine for 12 weeks (84 days). There will also be an opportunity to take part in an optional sub-study that aims to understand how CBD may work. For this, a smaller group of participants from part II of the study will have two brain scans using functional magnetic resonance imaging (MRI). One brain scan will take place before they start treatment and the second scan after they complete treatment with the study medicine. In each part of the study, participants will be expected to attend between five and six study visits of varying length (two of the visits will be about 1 to 2 hours, one visit will be 2 to 3 hours and two visits will be 3 to 5 hours), where the researchers will carry out the following assessments. Not all of the assessments will be carried out at every visit. The researchers will explain the study procedures and obtain the participant’s consent to take part in the study, ask about any relevant past medical history and current medications, and collect general information such as the participant’s age, gender, and education. They will carry out a physical examination (blood pressure, heart rate, temperature, heart trace (ECG) and neurological examination), take a blood sample to test for underlying medical problems and measure levels of medications and collect a urine sample to test for pregnancy (where appropriate). The researchers will use paper-pencil questionnaires to assess a range of neurological (e.g. motor symptoms of Parkinson’s disease) and psychological symptoms (e.g. non-motor symptoms of Parkinson’s disease such as psychosis, sleep, mood), quality of life, memory and the burden on caregivers. They will check for any side effects that participants may be experiencing and give participants study medication to take home and also check how many capsules they have taken or may have missed during follow-up visits. Where possible, the researchers will conduct assessments and questionnaires remotely (i.e. over the telephone, video call or email). For study procedures that need to be carried out in person, i.e. blood samples and psychical examinations, there will be an option for these visits to take place at the participant’s home. What are the possible benefits and risks of participating? Participants may or may not receive any benefits from taking CBD as part of the study. CBD might improve some of the symptoms of Parkinson’s disease psychosis. The information obtained in this study may help doctors to treat Parkinson’s disease patients with psychosis more effectively in the future, reducing both patient and caregiver distress. Previous research has shown that the effects of CBD are very subtle. Nevertheless, like all medicines, the active medication may cause side effects in some people, including mild sleepiness or tiredness, gastrointestinal (digestive) problems, headache or nausea. The physical risks and discomforts of giving the blood samples are the same as those for any other blood sample taken from a vein. There may be minor bruising or irritation. Some of the questionnaires and rating scales may involve the participants answering questions that are sensitive and of a personal nature. MRI scans can sometimes feel uncomfortable because of the noise and may cause temporary dizziness. People who are claustrophobic or have any metallic foreign bodies in the body or eyes or metal implants in the body, such as intra-cranial aneurysm clips, pacemakers or defibrillators, cannot take part in this study. Where is the study run from? King’s College London and South London and Maudsley NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? January 2019 to December 2025 Who is funding the study? Parkinson’s UK Who is the main contact? CAN-PDP Trial Manager canpdp.trialoffice@kcl.ac.uk Part I: 1. Maximum tolerated dose of CBD determined by the number of dose-limiting toxicities occurring throughout the study 2. Safety and tolerability of CBD assessed by evaluating treatment-emergent adverse events, UKU side effect rating scale for psychotropic drugs, physical examination (vital signs, ECG and neurological assessment) and laboratory tests at every visit Part II: Safety and tolerability of CBD assessed by evaluating treatment-emergent adverse events, UKU side effect rating scale for psychotropic drugs, physical examination (vital signs, ECG and neurological assessment) and laboratory tests at every visit Part I: 1. Drug-drug interaction with any of the safe and tolerated doses of CBD, assessed by measuring the change in CBD and quetiapine and its metabolite and/ or donepezil levels in the blood at baseline (pre-treatment) and weeks 2 and 6 2. Evidence of neuropsychiatric drug activity (pharmacodynamic signal) measured using Parkinson’s disease-adapted scale for assessment of positive symptoms of psychosis (SAPS-PD) and Neuropsychiatric Inventory (NPI) at baseline (pre-treatment) and week 6 3. Non-motor symptoms of Parkinson’s Disease measured using the non-motor assessment scale for PD (NMSS) at baseline (pre-treatment) and week 6 4. Quality of life measured using the Parkinson’s disease questionnaire-39 (PDQ-39) at baseline (pre-treatment) and week 6 5. Sleep measured using SCOPA-Sleep at baseline (pre-treatment) and week 6 6. Cognition measured using SCOPA-COG and MoCA at baseline (pre-treatment) and week 6 7. Global improvement/change measured using the Clinical Global Impression of Change at baseline (pre-treatment) and week 6 8. Caregiver burden measured using the Zarit Burden Interview at baseline (pre-treatment) and week 6 9. Motor symptoms of Parkinson’s disease measured using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline (pre-treatment) and week 6. Part II: 1. Drug-drug interaction with any of the safe and tolerated doses of CBD, assessed by measuring the change in CBD and quetiapine and its metabolite and/or donepezil levels in the blood at baseline (pre-treatment) and weeks 2, 6 and 12 2. Evidence of neuropsychiatric drug activity (pharmacodynamic signal) measured using Parkinson’s disease-adapted scale for assessment of positive symptoms of psychosis (SAPS-PD) and Neuropsychiatric Inventory (NPI) at baseline (pre-treatment) and week 12 3. Non-motor symptoms of Parkinson’s Disease measured using the non-motor assessment scale for PD (NMSS) at baseline (pre-treatment) and week 12 4. Quality of life measured using the Parkinson’s disease questionnaire-39 (PDQ-39) at baseline (pre-treatment) and week 12 5. Sleep measured using SCOPA-Sleep at baseline (pre-treatment) and week 12 6. Cognition measured using SCOPA-COG and MoCA at baseline (pre-treatment) and week 12 7. Global improvement/change measured using the Clinical Global Impression of Change at baseline (pre-treatment) and week 12 8. Caregiver burden measured using the Zarit Burden Interview at baseline (pre-treatment) and week 12 9. Motor symptoms of Parkinson’s disease measured using the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) at baseline (pre-treatment) and week 12 Mechanistic sub-study: Neurophysiological mechanisms underlying the antipsychotic effects of CBD in PDP measured using: 1. Within-subject change in medial temporal, prefrontal, and striatal activation (as estimated from the blood oxygen level-dependent haemodynamic response signal measured using fMRI; BOLD signal) in the MRI scanner at baseline (pre-treatment) and week 12 2. Within-subject change in functional connectivity between the medial temporal, prefrontal, striatal and visual cortical regions of interest (as estimated from the BOLD signal) and between these regions and the rest of the brain using both resting state and task-based fMRI data in the MRI scanner at baseline (pre-treatment) and week 12 Old ethics approval format Approved 20/01/2020, London - Hampstead Research Ethics Committee (Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8104, +44 (0)207 104 8134; hampstead.rec@hra.nhs.uk), REC ref: 19/LO/1967 10.1186/ISRCTN87895237 2019-003623-37 271052 CPMS: 43972 2019-003623-37 271052 43972 Randomized; Interventional; Design type: Treatment, Drug Interventional Randomised controlled trial Treatment 2025-12-19T00:00:00.000Z United Kingdom England Scotland Wales King's College Hospital NHS Foundation Trust (lead centre)

-

London England SE5 9RS South London and Maudsley NHS Foundation Trust

-

London England SE5 8AZ St George's Healthcare Nhst

Blackshaw Road

London England SW17 0QT RAX63@2.16.840.1.113883.2.1.3.2.4.18.48 Royal United Hospitals Bath NHS Foundation Trust

Combe Park

Bath England BA1 3NG RD1@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Hallamshire Hospital

Glossop Road

Sheffield England S10 2JF 5EQHH@2.16.840.1.113883.2.1.3.2.4.18.48 St Peters Hospital

Guildford Road

Chertsey England KT16 0PZ RVRA3@2.16.840.1.113883.2.1.3.2.4.18.48 Derbyshire Healthcare NHS Foundation Trust

Trust Headquarters Kingsway Hospital Kingsway

Derby England DE22 3LZ RXM@2.16.840.1.113883.2.1.3.2.4.18.48 Cornwall Partnership NHS Foundation Trust

Carew House Beacon Technology Park Dunmere Road

Bodmin England PL31 2QN RJ8@2.16.840.1.113883.2.1.3.2.4.18.48 Sunderland Royal Hospital

Kayll Road

Sunderland England SR4 7TP RTDCT@2.16.840.1.113883.2.1.3.2.4.18.48 Gateshead Health NHS Foundation Trust

Queen Elizabeth Hospital Sheriff Hill

Gateshead England NE9 6SX RR7@2.16.840.1.113883.2.1.3.2.4.18.48 Royal Gwent Hospital

Cardiff Road

Newport Wales NP20 2UB RVFAR@2.16.840.1.113883.2.1.3.2.4.18.48 Prince Philip Hospital

Bryngwynmawr Dafen

Llanelli Wales SA14 8QF RKSAL@2.16.840.1.113883.2.1.3.2.4.18.48 Wrexham Maelor Hospital

Croesnewydd Road Wrexham Technology Park

Wrexham Wales LL13 7TD R1DD4@2.16.840.1.113883.2.1.3.2.4.18.48 Withybush General Hospital

Fishguard Road

Haverfordwest Wales SA61 2PZ RR6BL@2.16.840.1.113883.2.1.3.2.4.18.48 NHS Grampian

Summerfield House 2 Eday Road

Aberdeen Scotland AB15 6RE SN999@2.16.840.1.113883.2.1.3.8.2.16.1 NHS Tayside

Kings Croos Clepington Road

Dundee Scotland DD3 8EA ST999@2.16.840.1.113883.2.1.3.8.2.16.1 NHS Lothian

Waverley Gate 2-4 Waterloo Place

Edinburgh Scotland EH1 3EG SS999@2.16.840.1.113883.2.1.3.8.2.16.1 Patient 1. Satisfy established diagnostic criteria (NINDS-NIMH criteria for the diagnosis of Parkinson’s disease psychosis) and UK Brian Bank criteria for idiopathic Parkinson’s disease 2. Age 40 years or older 3. For psychotic symptoms, they should have developed after the PD diagnosis and should have been present for at least 1 month, occurring at least weekly over the month before screening and should have a combined score of at least 6 or an individual score of at least 4 on the neuropsychiatric inventory (NPI) A (delusions) and/or B (hallucinations) subscale in the month before screening 4. Parkinson’s disease dementia would not be an exclusion criterion 5. Participants with score greater than 18 on the Montreal Cognitive Assessment scale 6. Treatment as usual will include patients on quetiapine and/ or cholinesterase inhibitors (rivastigmine/ donepezil) as well as standard antiparkinsonian treatments with dosage stable for at least 1 month 7. At least 6 months post stereotaxic surgery (deep brain stimulation) and stimulator settings stable for at least 1 month prior to baseline and must remain stable during the trial 8. Ability to participate in study evaluation and ingest oral medication 9. Reliable informant/caregiver 10. Written informed consent to participate Mixed 40 Years 99 Years All 144 100 1. Insufficient understanding of trial 2. History of significant psychotic disorders prior to or concomitantly with the diagnosis of Parkinson’s disease including, but not limited to, schizophrenia or bipolar disorder 3. Psychotic symptoms secondary to other toxic or metabolic disorders 4. Psychosis onset after ablative stereotaxic surgery 5. Diagnosis of dementia made concurrent with or prior to a PD diagnosis 6. Patients on clozapine due to the requirement of special safety monitoring required for clozapine, which will unblind the safety 7. Patients taking part in another intervention trial concurrently. However, those withdrawn from another study or who have recently completed another intervention study will be eligible for inclusion if they satisfy study inclusion/ exclusion criteria. For pharmacological intervention, they will be eligible only after a sufficient period of washout (~ 5 times half-life of other study drug) 8. Participant no longer able to report symptoms as a result of cognitive impairment 9. Presence of depressive symptoms would not be an exclusion criterion. However, we would exclude those participants who may have severe depression 10. Participants who answer "yes" on the C-SSRS Suicidal Ideation Item 4 or Item 5 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan, or Active Suicidal Ideation with Specific Plan and Intent) and whose most recent episode meeting the criteria for C-SSRS Item 4 or Item 5 occurred within the last 6 months, OR Participants who answer "yes" on any of the 5 C-SSRS Suicidal Behavior Items (actual attempt, interrupted attempt, aborted attempt, preparatory acts, or behaviour) and whose most recent episode meeting the criteria for any of these 5 C-SSRS Suicidal Behavior items occurred within the last 2 years, OR Participants who, in the opinion of the investigator, present a serious risk of suicide 11. Any medical or psychological condition or social circumstances which may impair their ability to participate reliably in the study, or who may increase the risk to themselves or others by participating in the study 12. Significant ocular pathology 13. Concomitant medication that has a clinically relevant interaction with the CYP2C19 or CYP3A classes of liver enzymes will not be permitted from two weeks before inclusion until the end of the study. Examples of co-medication that will be not allowed will include CYP3A4 inhibitors (such as itraconazole, ketoconazole, posaconazole, fluconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, telaprevir, boceprevir, imatinib, ticagrelor, voriconazole), CYP3A4 inducers (such as carbamazepine, efavirenz, nevirapin, etravirin) and CYP2C19 inhibitors (such as moclobemine, fluvoxamine, chloramphenicol, fluoxetine) 14. Female patients who are pregnant or lactating 15. Female patients of childbearing potential who are not willing to use a highly effective method of contraception for the duration of the trial to prevent pregnancy, or abstain from heterosexual activity *Females of childbearing potential are females who have experienced menarche and are not surgically sterilised (e.g. by hysterectomy, bilateral salpingectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period). ** Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, e.g. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable; intrauterine device (IUD), intrauterine hormone-releasing system (IUS); vasectomised partner Sexual abstinence is considered to be highly effective method only if defined as refraining from heterosexual activity from the date of consent until end of treatment and for 2 weeks after. The reliability of this method should be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant 16. Known hypersensitivity to CBD, gelatine or micro-crystalline cellulose 17. Mechanistic sub-study only: Patients who have any contraindications to MRI, including: pacemakers, metallic foreign body in the eye, aneurysm clip in their brain, severe claustrophobia where patients would not be able to tolerate the scan etc 2020-10-19T00:00:00.000Z 2025-03-02T00:00:00.000Z Parkinson’s disease psychosis Mental and Behavioural Disorders Parkinson disease The first phase is a multi-centre, open-label, safety, tolerability and dose-finding study of cannabidiol (CBD). CBD will be given orally, once per day for 6 weeks in different doses as per dosing protocol in up to 24 participants. To identify the maximum tolerated dose (MTD) of orally administered CBD, the researchers will employ a variation of the traditional 3+3 design, with subjects assigned in groups of 3 to each dose. For the purposes of this study, MTD will be determined by toxicity and defined as the highest dose at which 2 or more out of 6 patients at a specified dose level experience a drug-related dose-limiting toxicity. The second phase is a multi-centre, randomised, double-blind, placebo-controlled trial of CBD versus placebo. Up to 120 eligible patients will be randomly assigned at the baseline visit to receive CBD or matching placebo capsules for 12 weeks. Within the CBD arm, a single daily dose of CBD (dosage as identified from Phase I study) given in capsule form to be taken orally. For both phases of the study, CBD or placebo will be added as an adjunct to treatment as usual (TAU). TAU corresponds to the typical package of care offered to PDP patients and may include antiparkinsonian medications, quetiapine or cholinesterase inhibitors (rivastigmine/ donepezil) in line with existing clinical practice. Drug Phase II Cannabidiol (CBD) Data sharing statement to be made available at a later date

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afecdb32-dcd0-401a-ac7b-de56c9136884 3a7376a4-dce7-447f-8124-e6d8084b8ff0 5fc4131b-f141-4882-b52f-39778b69b1e2 7b4588f2-ca5b-4993-ac1b-3093914b7b8e No Sagnik Bhattacharyya https://orcid.org/0000-0002-8688-8025 Scientific

Department of Psychosis Studies Box P067 Institute of Psychiatry, Psychology & Neuroscience King’s College London 16 De Crespigny Park

London United Kingdom SE5 8AF +44 (0)7936545178 canpdp.trialoffice@kcl.ac.uk Public Katie McGoohan Public

Department of Old Age Psychiatry Institute of Psychiatry, Psychology & Neuroscience King’s College London 16 De Crespigny Park

London United Kingdom SE5 8AF +44 (0)2078486997 canpdp.trialoffice@kcl.ac.uk Public King’s College London and South London & Maudsley NHS Foundation Trust Hospital/treatment centre https://ror.org/015803449 Non-commercial Parkinson's UK; Grant Codes: G-1901 http://dx.doi.org/10.13039/501100000304 32474552 true Establishing alpha-synuclein Real Time - Quaking Induced Conversion (RT-QuIC) assay as a diagnostic technique in REM sleep behaviour disorder (RBD) RTQUIC&RBD The researchers hypothesise that a real-time quaking induced conversion assay for the detection of pathological alpha-synuclein (α -syn RTQuIC) can be used to differentiate between cases of idiopathic REM-sleep behaviour disorder (RBD) and RBD that is symptomatic of prodromal α-synucleinopathies. With a patient sample size of n=125, this multicentre study will be the largest analysis of CSF α-synuclein in RBD patients to date. In line with The National CJD Research & Surveillance Unit (NCJDRSU)’s recent inclusion of a positive RT-QuIC for pathological prion protein in the diagnostic criteria for Creutzfeldt-Jakob Disease (CJD), the researchers aim to deploy this novel method to establish it as an accurate research and diagnostic resource in the assessment and prognosis of RBD. This research is transformative and has the potential to change practice. Currently, there is no simple method with high sensitivity and specificity available which can identify patients who will go on to develop an α - synucleinopathy. Clinical assessment of a panel of markers (e.g. Postuma et al. 2015) are time-consuming and impractical in normal clinical settings, with the majority of patients presenting to sleep physicians, geriatricians, and non-specialised neurology clinics, both publicly and privately. This has a major impact on counselling strategies for RBD patients, appropriate follow-up, trials of novel neuroprotective agents in alpha-synucleinopathies before full-blown phenotype is manifest and enhancing understanding of pathways involved in RBD out-with the dopaminergic system. RBD is a common, sometimes fatal disease (through injury to self/others) and treatments are indiscriminate regarding aetiology with limited evidence-base. A simple test using CSF (analogous to measuring CSF-orexin levels to diagnose narcolepsy+cataplexy) with high sensitivity and specificity is ideal. Thus, the researchers believe that the central thesis of their work will not only inform subsequent behavioural, genetic and neuroimaging characterisation of their established RBD cohort, but will also translate the α-syn RT-QuIC concept into evidence-based and effective clinical practice. Background and study aims Rapid Eye Movement Sleep Behaviour Disorder (RBD) is a sleep disorder in which people act out their dreams. Previous studies have found a high conversion rate from RBD to subsequent neurodegenerative disease, with the majority of patients developing one of the α-synucleinopathies (Parkinson’s disease, multiple system atrophy, Lewy body dementia). As not all RBD patients go on to develop a neurodegenerative disease (40 - 80.8% in 16 to 25 years of follow-up), and RBD only presents as a comorbidity in a percentage of patients with α-synucleinopathies (30% of Parkinson’s disease patients have RBD), it is important to identify factors which robustly provide prognostic data on the clinical course of RBD. The aim of this study is to develop and validate a test for the detection of pathological protein (α-syn RT-QuIC) that can be used to differentiate between cases of RBD that subsequently progress to a neurodegenerative disorder such as Parkinson's disease and those that do not. Who can participate? Patients aged over 18 with a diagnosis of RBD What does the study involve? All data is collected in one 90-minute appointment, which takes place at the Wellcome Trust Clinical Research Facility (WTCRF) at either Royal Infirmary of Edinburgh or Western General Hospital Edinburgh. The appointment involves a clinical examination and interview, blood sampling and cerebrospinal fluid (CSF) sampling via lumbar puncture. Participants are interviewed with regards to their lifestyle, medical history and comorbidities. Participants are asked to fill out sleep diaries and questionnaires relating to their sleep. All patients are examined clinically regarding motor function and anosmia. Markers of autonomic dysfunction are also tested for using simple techniques such as an orthostatic standing test. Any individuals who have already developed PD are interviewed with regards to their neurodegenerative presentation, e.g. response to drug treatment. What are the possible benefits and risks of participating? Whilst there is no direct benefit to the individual participant, their participation in the study will help to develop a test which may benefit many other patients with RBD in the future. Time burden to the patient is minimal, with only a single 90-minute study visit required. Blood sampling is generally well-tolerated. Minor discomfort and bruising may occur at the needle site but should self-resolve quickly. Some individuals may feel dizzy or faint, and can lie down during the procedure. A lumbar puncture is generally a safe procedure and serious side effects are uncommon. The most common side effects include headaches, which can last for up to a week and can be relieved using over-the-counter painkillers, and swelling and lower back pain where the needle was inserted, which should get better after a few days and is normally nothing to worry about. The questionnaires used contain personal questions which some individuals may find intrusive or uncomfortable to answer, though all information is required purely to make a complete clinical assessment. Where is the study run from? University of Edinburgh/NHS Lothian Royal Infirmary (UK) When is the study starting and how long is it expected to run for? January 2020 to September 2023 (updated 21/04/2020, previously: June 2023) Who is funding the study? Weston Brain Institute (UK) Who is the main contact? Dr Renata Riha rriha1@staffmail.ed.ac.uk Positive/negative (binary) result from the α-syn RT-QuIC assay. A positive output confirms the presence of pathological α-synuclein within the CSF. Measured using lumbar puncture to obtain CSF at a single trial visit. All measures will take place at the patient's only trial visit: 1. Screening for co-morbidities using a medical history questionnaire 2. Screening for REM Behavioural disorder with the RBDQ-HK questionnaire 3. Excessive daytime sleepiness assessed using the Epworth Sleepiness Scale 4. Sleep pattern assessed using a sleep diary 5. Stressful events that might cause illnesses assessed using the Holmes and Rahe stress scale 6. Orthostatic hypotension assessed using the Orthostatic Standing Test 7. Clinical rating scale for Parkinson's disease using the MDS-UPDRS questionnaire 8. Venepuncture to obtain 9 ml of blood for future genetic testing in follow-up study Old ethics approval format Approved 23/03/2020, South East Scotland Research Ethics Committee 1 (NHS Lothian, Waverley Gate, 2 - 4 Waterloo Place, Edinburgh, EH1 3EG, UK; +44 (0)131 465 5473; Sandra.Wyllie@nhslothian.scot.nhs.uk), ref: DL/20/ES/0032 10.1186/ISRCTN32474552 Funder's Reference Number - 16021036.1 Funder's Reference Number - 16021036.1 Cross-sectional multicentre study Observational Cross sectional study Screening Stopped Lack of staff/facilities/resources 2023-09-01T00:00:00.000Z United Kingdom Scotland NHS Lothian

Waverley Gate 2-4 Waterloo Place

Edinburgh United Kingdom EH1 3EG NHS Tayside

Ninewells Hosptial and Medical School James Arrott Drive

Dundee United Kingdom DD1 9SY The University of Edinburgh

The National Creutzfeldt-Jakob Disease Research and Surveillance Unit Brian Matthews Building Western General Hospital

Edinburgh United Kingdom EH4 2XU Patient 1. Diagnosis of RBD based on International Classification of Sleep Disorders 3rd Edition (ICSD-3) criteria 2. Aged 18 years or over 3. Willing and able to give written informed consent and comply with protocol Adult 18 Years All 125 1. RBD secondary to medication or withdrawal state 2. <18 years old 3. Unwilling or unable to give written informed consent or comply with protocol 4. Contraindication to lumbar puncture procedure (e.g. patients taking Warfarin) 2021-10-01T00:00:00.000Z 2022-12-01T00:00:00.000Z Stopped REM behavioural disorder and Parkinson's disease Mental and Behavioural Disorders This is a cross-sectional, multi-centre study using the CSF of patients with RBD which may or may not develop into a neurodegenerative disease, as well as patients with RBD who have already developed an α-synucleinopathy. The proposed study length is 3 years (36 months). Participant involvement will be approximately 30 months from receipt of invitation letter to dissemination of results. The researchers envisage ongoing follow-up of this group of patients into the future to assess for development of a α-synucleinopathy to further confirm the utility of this technique in day-to-day clinical practice. Participants will be recruited from sleep clinics and existing RBD patient cohort databases under the care of the Department of Sleep Medicine, Royal Infirmary of Edinburgh and the Behavioural Sleep Medicine Department, Ninewells Hospital, Dundee. Together, these departments have an unselected RBD cohort of approximately 250 patients, from which the researchers aim for a sample size of 125 patients. Participants who consent to participate will be invited to a single, 90 minute, appointment at the clinical research facility (CRF) at either the Royal Infirmary of Edinburgh or Western General Hospital, Edinburgh. Participants will be interviewed with regards to their lifestyle and medical history. They will be asked to fill out sleep diaries and questionnaires relating to their sleep and will be examined clinically for possible symptoms of PD and, in individuals who have already been diagnosed with PD, their response to drug treatment. A 9 ml blood sample will be collected as part of clinical evaluation. During the lumbar puncture, 1.5 ml of CSF will be collected. The samples will be stored at -80C prior to analysis. Participants will be observed for the duration of the trial (36 months), and further funding sought to continue long-term follow-up of RBD cohort participants. Other The data sharing plans for the current study are unknown and will be made available at a later date Data sharing statement to be made available at a later date

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b78be046-2500-43b8-99ec-1281d7777fdb 90149816-8e06-4ee8-b09b-847a5808ba08 672fffc8-930d-47b0-90c0-c7b35e3ddbd8 fe97c64e-838f-494d-ad38-73e48e0c6d5a No Steven Williams Public

Chancellors Building Room 305 49 Little France Crescent

Edinburgh United Kingdom EH16 4SB +44 (0)7903029892 picklish@hotmail.com Public Renata Riha Scientific

Chancellors Building Room 305 49 Little France Crescent

Edinburgh United Kingdom EH16 4SB +44 (0)131 242 3882 rriha1@staffmail.ed.ac.uk Public ACCORD Research organisation Non-commercial Weston Brain Institute 43958304 true RECALL – REducing Cognitive decline and dementiA by Lowering bLood pressure - Pilot I RECALL Complex interventions aiming to slow cognitive decline have been disappointing, are time-consuming and labour intensive and require extensive commitment on behalf of the health services, individual therapist, and participant. Mounting evidence supports the beneficial effects of reducing blood pressure to ameliorate cognitive decline and to prevent dementia. We intend to conduct a large online study of blood pressure-lowering medication to lower blood pressure and prevent dementia. Although elements of the proposed study methodology have been used in other studies, they have not yet been tested in the target population. We therefore plan a pilot study to assess the feasibility of several aspects of the proposed method. Background and study aims Ahead of a large online clinical trial to determine whether reducing blood pressure can prevent dementia, this pilot study will determine the feasibility of recruiting participants aged ≥60 years into an online study. Participants will be recruited via general practice. This study will determine whether participants can complete online registration and consent, measure and enter their home blood pressure online and complete an online cognitive function (thinking and reasoning) questionnaire. This information will inform the design of the larger study. The feasibility of using a portable device to perform study blood tests will be determined by asking participants to attend their GP practice for a blood test using the device (iSTAT). Who can participate? Individuals over 60 years old, with a valid email address and access to the internet What does the study involve? This is a pilot study to determine the feasibility of performing a large secure online study of blood pressure lowering to prevent dementia, by testing several aspects of trial methodology (including recruitment and baseline data collection). What are the possible benefits and risks of participating? Risks- Blood sampling may cause bruising and discomfort. There may be inconvenience to participants attending GP/MEMO research/Community Hubs for blood sampling. Online cognitive function questionnaires can take up to 45 minutes to complete. Participants may find asking the alternative contacts to act in this capacity for them in the study uncomfortable. Benefits- There are no direct benefits however, participants will be able to keep the OMRON home blood pressure monitor. Where is the study run from? MEMO Research, Ninewells Hospital, Dundee, UK When is the study starting and how long is it expected to run for? November 2019 to June 2021 Who is funding the study? Investigator initiated and funded Who is the main contact? Prof. Thomas MacDonald (scientific), t.m.macdonald@dundee.ac.uk Dr Evelien Rooke (public), e.rooke@dundee.ac.uk 1. Recruitment numbers 2. Protocol adherence Timepoint: End of pilot 1. Assess suitability of online cognitive testing for study cohort Outcome measures: Proportion of participants who complete a baseline test 2. Assess baseline cognitive function Outcomes measures: Proportion of study population completing online screening cognitive function test, and scores obtained 3. Assess feasibility of requiring each participant to identify two individuals who agree to act as alternative contacts Outcome measures: Proportion of participants who have two consenting alternative contacts 4. Assess feasibility of home blood pressure monitoring using study supplied HBPM machine Outcome measures: Proportion of participants submitting a complete set of home BP measurements 5. Assess baseline blood pressure suitability of study cohort Outcome measures: Proportion of participants with a home BP submission averaging 140mmHg or below systolic 6. Assess feasibility of using portable i-STAT Alinity device for providing blood results Outcome measures: Proportion of blood results obtained using portable system 7. Assess the likely number of eligible patients signing up Outcome measures: Proportion of those invited who meet proposed formal study entry criteria Old ethics approval format Approved 14/05/2019, NHS HRA North East- York Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS; +44 (0) 207 104 8079; nrescommittee.northeast-york@nhs.net), ref: 19/NE/0172 10.1186/ISRCTN43958304 1-020-18 1-020-18 Feasibility study Other Not applicable Other 2021-06-18T00:00:00.000Z United Kingdom Scotland MEMO Research

Level 7 Mailbox 2 Ninewells Hospital

Dundee Scotland DD1 9SY Other 1. Over 60 years old 2. Valid email address (per participant) 3. Able to access the internet Senior All 110 251 1. GPs may exclude participants who they deem unsuitable to participate 2. Clinical diagnosis of dementia, treatment with medication for dementia or cognitively unable to follow the protocol (investigator opinion) 2019-11-01T00:00:00.000Z 2021-05-20T00:00:00.000Z Cognitive decline Mental and Behavioural Disorders Cognitive decline Potential participants will be invited to visit a study web page by letter of invitation. On this study webpage they can read the participant information documentation and then complete an electronic informed consent form. Participants will then be asked to complete questions on their demographics, medical history, and lifestyle. Consenting participants will be supplied with a home blood pressure monitor (HBPM) and detailed instructions on how to use it. They will then be asked to submit a set of readings (modified version of NICE guidance) to the website. Following consent participants will be asked to complete an online cognitive function assessment hosted by Cambridge Brain Sciences (CANADA) and attend either their GP, the MEMO Research Unit in Dundee or Community Hubs to have a blood sample taken. They will also be asked to provide two alternative contact details. The participant will be asked to get the permission of their alternative contacts before entering their details into the RECALL secure website. The alternative contacts will be asked by email if they are willing to act in this capacity. Once this information has been submitted the participants will be asked to complete feedback questionnaires on the study/website. All aspects of the study are voluntary and so the participants may still proceed to the next section whether they have completed the previous section of the study or not. Once the participant has submitted their information then their participation is the study is complete. Participants will be asked to complete the tasks within 4 weeks if possible. There will be no follow up. Other Data sharing statement to be made available at a later date Thesis results in https://discovery.dundee.ac.uk/ws/portalfiles/portal/108320793/Evelien_Rooke_MD_Thesis-Final.pdf (added 26/05/2026) Results

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Study website Migrated from study website field

8b764b52-0933-452c-b3fc-cc3a563177de c774828d-6e48-4368-bf4e-1081ddbe2fd4 38026e2d-fefd-4558-8aca-01626eed4605 6a96d246-8b66-4cb7-8af7-309885d13f2c No Protocol file ISRCTN43958304 _Protocol_V5_26Apr2021.pdf 5d052497-b5a8-49f0-b415-60e0047b474d true application/pdf 434341 7cb756cba8af04e1a8d7faab00ddbb46 Statistical Analysis Plan ISRCTN43958304_SAP_V1_14Jul2021.pdf 8b140689-0982-4095-a653-105e79176590 true application/pdf 353859 dbe6ffaf0d0cd1ec4530ef6212d051b2 Thomas MacDonald https://orcid.org/0000-0001-5189-6669 Scientific

MEMO Research Level 7 Ninewells Hospital & Medical School

Dundee United Kingdom DD1 9SY +44 (0) 1382 383119 t.m.macdonald@dundee.ac.uk Public Evelien Rooke Public

MEMO Research Level 7 Ninewells Hospital & Medical School

Dundee United Kingdom DD1 9SY +44 (0) 1382 383119 e.rooke@dundee.ac.uk Public University of Dundee/NHS Tayside University/education https://ror.org/03h2bxq36 Non-commercial Investigator initiated and funded 72151939 true A randomised, double-blind, placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression PAX-BD The PAX-BD trial is a multi-centre, randomised, controlled trial of pramipexole versus placebo, and will elicit whether pramipexole, co-prescribed with a mood stabiliser (lithium, valproate, carbamazepine and/or lamotrigine), is an efficient treatment for treatment-resistant bipolar depression. Background and study aims The aim of this study is to find out whether pramipexole, co-prescribed with a mood stabiliser (lithium, valproate, carbamazepine and/or lamotrigine), is an efficient treatment for treatment-resistant bipolar depression. Who can participate? Patients aged 18 years or over with treatment-resistant bipolar depression What does the study involve? If participants are on an antipsychotic it is gradually withdrawn, as it may block the effect of pramipexole. Additionally, if participants are not on a ‘mood stabiliser’, one is started. Once this is done, participants are randomly allocated to receive either pramipexole or placebo (dummy drug), in addition to an ongoing mood stabiliser. The trial team, participants and their treating mental health team do not know whether the participant receives pramipexole or placebo. The effectiveness of pramipexole after 12 weeks is assessed, and participants continue to be monitored by trial researchers for 48 weeks, even if they discontinue the initial treatment, giving real-life information on the use of this treatment. The effect on depressive symptoms and quality of life are assessed, along with side-effects and whether any other treatments are needed. Assessments are self-reported using an online system completed by participants, who are supported by email prompts. These methods have worked well in previous studies and participants approve of their use. The system allows more frequent (weekly) self-ratings of bipolar depression symptoms and thus gives a more complete picture of long-term symptom control. Paper versions are provided where necessary. Participants are telephoned monthly to assess other medication use and side effects. What are the possible benefits and risks of participating? Possible risks include adverse effects of pramipexole and/or carbamazepine, lamotrigine, lithium and/or valproate, distress from stopping their usual medication and/or starting a new medication, intrusion and/or inconvenience and/or change to lifestyle of completing online or paper questionnaires, weekly, and taking part in telephone calls with Research Assistants (RAs) and home visits by Clinical Studies Officers or similar. The mitigations to these risks include increased monitoring of the participants than would normally be conducted as part of standard care, including additional support from a wider team (local research team, clinical treating team if separate and RAs). For the participants’ convenience and to reduce burden, the study visits can be conducted in the clinic or in their own home, based on their preference. The eligibility criteria for the trial have been carefully considered to ensure that patients that are suitable to take part can be identified. Additionally, safety will be closely monitored and all participants will be given a safety card to keep on them at all times. This card will include details of the CNTW (Sponsor) out of hours service, which will be available for emergency clinical queries. Participants will also be provided with a participant diary, which will used as an aid to the participant to ensure that they take their medication correctly according to the schedule. Participants will also receive a personalised medication schedule with each prescription, to help with the changes to the medication dose across different periods of the study. The medication labels have been designed so that they are different colours for the two different strengths of tablets, which are also different shapes. This has been incorporated in the patient diary with colour coding and pictures. Where is the study run from? Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust (UK) When is the study starting and how long is it expected to run for? September 2019 to March 2023 Who is funding the study? NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) (UK) Who is the main contact? 1. Zoë Walmsley (public) PAX.BD@newcastle.ac.uk 2. Andrew Swain (public) PAX.BD@newcastle.ac.uk 3. Nicola Goudie (public) PAX.BD@newcastle.ac.uk Depression symptoms measured using QIDS-SR questionnaire (Quick Inventory of Depressive Symptomatology) at 12 weeks Current secondary outcome measures as of 12/10/2020: 1. Mood and anxiety symptoms over 48 weeks, and pleasure symptoms over 12 weeks, measured using the QIDS-SR questionnaire weekly to week 48, the Generalised Anxiety Disorder 7 (GAD-7) weekly to week 48 and the Snaith Hamilton Pleasure Scale (SHAPS) at weeks 0, 6 and 12 2. Psychosocial function measured using the Work and Social Adjustment Scale (WSAS) at weeks 0, 6, 12, 24, 36 and 48 3. Tolerability of pramipexole assessed using rates of AEs, SAEs and SUSARs reported describing severity, seriousness, causality and expectedness 4. Risk of switching to mania and occurrence of psychosis or impulse control disorders, which are known possible side-effects of pramipexole, measured using the Altman Self Rating Scale of Mania (ASRM) questionnaire completed weekly to week 48 5. Rates of impulsivity during treatment with pramipexole, measured using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale (QUIP-RS) at weeks 0, 6, 12 and then 4-weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48) 6. Side effects and overall acceptability of pramipexole treatment measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) at Weeks 6, 12 and then 4-weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48) and collection of Adverse Events - reported weekly to week 12 and then 4-weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48) 7. Adherence to medication to which patients are randomised via participant reported dose taken during RA phone calls and from central trial medication accountability and reconciliation records 8. Quality of life assessed using EuroQoL 5 Dimension 5 Level (EQ-5D-5L) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 9. Capability assessed using the ICEpop CAPability measure for Adults (ICECAP-A) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 10. Capability in people with mental health problems assessed using the Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 11. Societal cost assessed uising the Health Economics Questionnaire (HEQ) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 12. Mania and depression assessed using Young Mania Self-Rating Scale (YMRS) at weeks 0 and 12, Montgomery Asberg Depression Rating Scale (MADRS) at weeks 0 and 12 and Quick Inventory of Depressive Symptomatology – Clinician Rated (QIDS-C) at weeks 0 and 12 _____ Previous secondary outcome measures: 1. Mood and anxiety symptoms over 48 weeks, and pleasure symptoms over 12 weeks, measured using the QIDS-SR questionnaire weekly to week 48, the Generalised Anxiety Disorder 7 (GAD-7) weekly to week 48 and the Snaith Hamilton Pleasure Scale (SHAPS) at week 0, 6 and 12 2. Psychosocial function measured using the Work and Social Adjustment Scale (WSAS) at weeks 0, 6, 12, 24, 36 and 48 3. Cardiovascular side effects of pramipexole via pulse and blood pressure measurements taken at weeks 0, 2, 6, 12, 24, 36 and 48 4. Risk of switching to mania and occurrence of psychosis or impulse control disorders, which are known possible side-effects of pramipexole, measured using the Altman Self Rating Scale of Mania (ASRM) questionnaire completed weekly to week 48 5. Rates of impulsivity during treatment with pramipexole, measured using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale (QUIP-RS) at weeks 0, 6, 12 and then 4 weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48) 6. Side effects and overall acceptability of pramipexole treatment measured using the Treatment Satisfaction Questionnaire for Medication (TSQM) at Weeks 6, 12 and then 4 weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48) and collection of Adverse Events - reported weekly to week 12 and then 4 weekly to week 48 (weeks 16, 20, 24, 28, 32, 36, 40, 44 and 48 7. Adherence to medication to which patients are randomised via participant reported dose taken during RA phone calls and from central trial medication accountability and reconciliation records 8. Quality of life, wellbeing, health and social care and broader societal costs of patients randomised to either pramipexole or placebo. The incremental cost-effectiveness of pramipexole in comparison to placebo over 48 weeks measured using EuroQoL 5 Dimension 5 Level (EQ-5D-5L) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48, ICEpop CAPability measure for Adults (ICECAP-A) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48, Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 and the Health Economics Questionnaire (HEQ) at start of pre-randomisation and weeks 0, 6, 12, 24, 36 and 48 9. Mania and depression assessed using Young Mania Self-Rating Scale (YMRS) at weeks 0 and 12, Montgomery Asberg Depression Rating Scale (MADRS) at weeks 0 and 12 and Quick Inventory of Depressive Symptomatology – Clinician Rated (QIDS-C) at weeks 0 and 12 Old ethics approval format Approved 04/09/2019, North East - Newcastle & North Tyneside 2 Research Ethics Committee (NHS BT Blood Donor Centre, Holland Drive, Newcastle upon Tyne, Tyne and Wear, NE2 4NQ, UK; Tel: +44 (0)207 1048091; Email: nrescommittee.northeast-newcastleandnorthtyneside2@nhs.net), REC ref: 19/NE/0233 10.1186/ISRCTN72151939 2018-002869-18 239794 39561 2018-002869-18 239794 39561 Randomized; Both; Design type: Treatment, Drug, Health Economic Interventional Randomised controlled trial Treatment 2023-03-01T00:00:00.000Z United Kingdom England Scotland Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust

St. Nicholas Hospital Jubilee Road Gosforth

Newcastle Upon Tyne United Kingdom NE3 3XT Nottinghamshire Healthcare NHS Foundation Trust

The Resource, Trust HQ Duncan Macmillan House Porchester Road

Nottingham United Kingdom NG3 6AA Surrey and Borders Partnership NHS Foundation Trust

18 Mole Business Park Randalls Road

Leatherhead United Kingdom KT22 7AD Avon And Wiltshire Mental Health Partnership NHS Trust

Jenner House Avon Way Langley Park

Chippenham United Kingdom SN15 1GG Derbyshire Healthcare NHS Foundation Trust

Trust Headquarters Kingsway Hospital Kingsway

Derby United Kingdom DE22 3LZ Oxford Health NHS Foundation Trust

Warneford Hospital Warneford Lane Headington

Oxford United Kingdom OX3 7JX Cheshire and Wirral Partnership NHS Foundation Trust

Trust Board Offices Upton Lea Resource Centre The Countess Of Chester Health Park

Chester United Kingdom CH2 1BQ Devon Partnership NHS Trust

Wonford House Hospital Dryden Road

Exeter United Kingdom EX2 5AF Leicestershire Partnership NHS Trust

Riverside House Bridge Park Plaza Bridge Park Road Thurmaston

Leicester United Kingdom LE4 8PQ Lincolnshire Partnership NHS Foundation Trust

Unit's 8 & 9 The Point Lions Way

Sleaford United Kingdom NG34 8GG South West Yorkshire Partnership NHS Foundation Trust

Trust Headquarters Fieldhead Ouchthorpe Lane

Wakefield United Kingdom WF1 3SP Sheffield Health & Social Care NHS Foundation Trust

Fulwood House Old Fulwood Road

Sheffield United Kingdom S10 3TH South London and Maudsley NHS Foundation Trust

Maudsley Hospital Denmark Hill

London United Kingdom SE5 8AZ Essex Partnership University NHS Foundation Trust

The Lodge Runwell Chase Runwell

Wickford United Kingdom SS11 7XX NHS Tayside

Ninewells Hospital and Medical School James Arrott Drive

Dundee United Kingdom DD1 9SY NHS Lothian

Waverley Gate 2-4 Waterloo Place

Edinburgh United Kingdom EH1 3EG NHS Greater Glasgow and Clyde

J B Russell House Gartnavel Royal Hospital 1055 Great Western Road

Glasgow United Kingdom G12 0XH Tees, Esk and Wear Valleys NHS Foundation Trust

West Park Hospital

Darlington United Kingdom DL2 2TS Lancashire & South Cumbria NHS Foundation Trust

Unit 5 Sceptre Point Sceptre Way

Preston United Kingdom PR5 6AW Kent and Medway NHS and Social Care Partnership Trust

Canada House Barnsole Road

Gillingham United Kingdom ME7 4JL Patient Current inclusion criteria as of 29/07/2022: Stage 1/ pre-randomisation: 1. Currently under the care of secondary care mental health services at screening with a plan for the patient to remain in secondary care throughout the period of the trial 2. A decision made by the patient’s clinical team that a change in medication is indicated 3. A current diagnosis of Bipolar Disorder (type I or II), defined as in DSM-5, which is supported by the use of the Mini-International Neuropsychiatric Interview (MINI) 4. Currently depressed, i.e. meeting DSM-5 criteria for a Major Depressive Episode assessed via MINI and with a current QIDS-SR >10 5. Current episode of depression failed to have responded to adequate trials, or lack of tolerability or patient declined/clinically inappropriate, of two different NICE recommended medications (quetiapine, olanzapine (with or without fluoxetine), lamotrigine) or lurasidone. Adequacy of treatment trial defined using a custom-designed 'Bipolar Demographics and Treatment Questionnaire' (BDTQ). 6. Aged 18 years or over at the point of consent 7. Willing and able to provide written informed consent prior to any trial procedures taking place 8. In the opinion of the investigator, is able to follow the trial prescription instructions and is able to manage 8 weeks supply of trial medication without risk of overdose 9. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] 10. Women of child-bearing potential are required to use a highly effective contraceptive method during the pre-randomisation and post-randomisation phase of the trial. Highly effective methods of contraception include: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) - progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) - bilateral tubal occlusion - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) Stage 2/ at randomisation: 1. Been in Stage 1 (pre-randomisation) for a minimum of 23 calendar days. 2. Currently depressed, i.e. meeting DSM-5 (78) criteria for a Major Depressive Episode and with a current QIDS-SR >10. 3. A minimum of two telephone/teleconference or videoconference calls with a trial RA and two on-line weekly symptom ratings have been completed during the pre-randomisation phase 4. On mood stabilising medication (lithium, valproate, carbamazepine, lamotrigine) 5. If on an antipsychotic this must be one listed, and at a dose of no more than the maximum stated, in the table in section 4.1. 6. All regular psychotropic medication, including antipsychotics and mood stabilisers, at a stable dose for a minimum of four weeks. Additionally, if a participant is on lamotrigine, quetiapine, olanzapine or lurasidone then this must have been at the current dose or higher for a minimum of three months. 7. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)]*. 8. Women of child-bearing potential are required to use a highly effective contraceptive method during the post-randomisation phase of the trial. Highly effective methods of contraception include: 8.1. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) 8.2. progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 8.3. intrauterine device (IUD) 8.4. intrauterine hormone-releasing system (IUS) 8.5. vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) 8.6. bilateral tubal occlusion 8.7. sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) 9. Willing and able to confirm written informed consent at the point of randomisation, after the pre-randomisation period. _____ Previous inclusion criteria as of 12/10/2020: Stage 1/ pre-randomisation: 1. Currently under the care of secondary care mental health services at screening with a plan for the patient to remain in secondary care throughout the period of the trial 2. A decision made by the patient’s clinical team that a change in medication is indicated 3. A current diagnosis of Bipolar Disorder (type I or II), defined as in DSM-5, which is supported by the use of the Mini-International Neuropsychiatric Interview (MINI) 4. Currently depressed, i.e. meeting DSM-5 criteria for a Major Depressive Episode assessed via MINI and with a current QIDS-SR >10 5. Current episode of depression failed to have responded to adequate trials, or lack of tolerability or patient declined/clinically inappropriate, of two different NICE recommended medications (quetiapine, olanzapine (with or without fluoxetine), lamotrigine) or lurasidone. Adequacy of treatment trial defined using a custom-designed 'Bipolar Demographics and Treatment Questionnaire' (BDTQ). 6. Aged 18 years or over at the point of consent 7. Willing and able to provide written informed consent prior to any trial procedures taking place 8. In the opinion of the investigator, is able to follow the trial prescription instructions and is able to manage 8 weeks supply of trial medication without risk of overdose 9. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] 10. Women of child-bearing potential are required to use a highly effective contraceptive method during the pre-randomisation and post-randomisation phase of the trial. Highly effective methods of contraception include: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) - progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) - bilateral tubal occlusion - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) Stage 2/ at randomisation: 1. Currently depressed, i.e. meeting DSM-5 (56) criteria for a Major Depressive Episode and with a current QIDS-SR >10. 2. A minimum of two telephone phone calls with a trial RA and two on-line weekly symptom ratings have been completed during the pre-randomisation phase 3. On mood stabilising medication (lithium, valproate, carbamazepine, lamotrigine) 4. All regular psychotropic medication, including mood stabilisers, at a stable dose for a minimum of four weeks 5. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)]. 6. Women of child-bearing potential are required to use a highly effective contraceptive method during the post-randomisation phase of the trial. Highly effective methods of contraception include: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) - progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) - bilateral tubal occlusion - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) 7. Willing and able to confirm written informed consent at the point of randomisation, after the pre-randomisation period. _____ Previous inclusion criteria as of 20/05/2020: Stage 1/ pre-randomisation: 1. Currently under the care of secondary care mental health services at screening with a plan for the patient to remain in secondary care throughout the period of the trial. 2. A decision made by the patient’s clinical team that a change in medication is indicated. 3. A current diagnosis of Bipolar Disorder (type I or II), defined as in DSM-5, which is supported by the use of the Mini-International Neuropsychiatric Interview (MINI) (55). 4. Currently depressed, i.e. meeting DSM-5 criteria for a Major Depressive Episode assessed via MINI and with a current QIDS-SR >10. 5. Current episode of depression failed to have responded to adequate trials, or lack of tolerability or patient declined/clinically inappropriate, of two different NICE recommended medications (quetiapine, olanzapine + fluoxetine, lamotrigine) or lurasidone. Adequacy of treatment trial defined using a custom designed ‘Bipolar Demographics and Treatment Questionnaire’ (BDTQ). 6. Aged 18 or over at the point of consent. 7. Willing and able to provide written informed consent prior to any trial procedures taking place. 8. In the opinion of the investigator, is able to follow the trial prescription instructions and is able to manage 8 weeks supply of trial medication without risk of overdose. 9. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)]. 10. Women of child-bearing potential are required to use a highly effective contraceptive method during the pre-randomisation and post-randomisation phase of the trial. Highly effective methods of contraception include: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) - progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) - bilateral tubal occlusion - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) Stage 2/ at randomisation: 1. Currently depressed, i.e. meeting DSM-5 (56) criteria for a Major Depressive Episode and with a current QIDS-SR >10. 2. A minimum of two telephone phone calls with a trial RA and two on-line weekly symptom ratings have been completed during the pre-randomisation phase 3. On mood stabilising medication (lithium, valproate, carbamazepine, lamotrigine) 4. All regular psychotropic medication, including mood stabilisers, at a stable dose for a minimum of four weeks 5. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)]. 6. Women of child-bearing potential are required to use a highly effective contraceptive method during the post-randomisation phase of the trial. Highly effective methods of contraception include: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) - progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) - intrauterine device (IUD) - intrauterine hormone-releasing system (IUS) - vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) - bilateral tubal occlusion - sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) 7. Willing and able to confirm written informed consent at the point of randomisation, after the pre-randomisation period. _____ Previous inclusion criteria: Stage 1/ pre-randomisation: 1. Currently under the care of secondary care mental health services at screening with a plan for the patient to remain in secondary care throughout the period of the trial 2. A decision made by the patient’s clinical team that a change in medication is indicated 3. A current diagnosis of Bipolar Disorder (type I or II), defined as in DSM-5, which is supported by the use of the Mini-International Neuropsychiatric Interview (MINI) 4. Currently depressed, i.e. meeting DSM-5 criteria for a Major Depressive Episode assessed via MINI and with a current QIDS-SR > 10 5. Current episode of depression failed to have responded to adequate trials, or lack of tolerability or patient refusal, of two different NICE recommended medications (quetiapine, olanzapine + fluoxetine, lamotrigine) or lurasidone. Adequacy of treatment trial defined using a custom designed ‘Bipolar Depression Treatment Questionnaire’ (BDTQ) 6. Aged 18 or over at the point of consent 7. Willing and able to provide written informed consent prior to any trial procedures taking place 8. In the opinion of the investigator, is able to follow the trial prescription instructions and is able to manage 8 weeks supply of trial medication without risk of overdose 9. The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] 10. Women of child-bearing potential are required to use a highly effective contraceptive method during the pre-randomisation and post-randomisation phase of the trial. Highly effective methods of contraception include: 10.1 Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) 10.2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 10.3. Intrauterine device (IUD) 10.4 Intrauterine hormone-releasing system (IUS) 10.5. Vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) 10.6. Bilateral tubal occlusion 10.7. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) Stage 2/ at randomisation: 1. Currently depressed, i.e. meeting DSM-5 (53) criteria for a Major Depressive Episode and with a current QIDS-SR > 10 2. A minimum of two telephone phone calls with a trial RA and two on-line weekly symptom ratings have been completed during the pre-randomisation phase 3. On mood stabilising medication (lithium, valproate, carbamazepine, lamotrigine) 4. All regular psychotropic medication, including mood stabilisers, at a stable dose for a minimum of four weeks 5. The patient, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG) 6. Women of child-bearing potential are required to use a highly effective contraceptive method during the post-randomisation phase of the trial. Highly effective methods of contraception include: 6.1. Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal) 6.2. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) 6.3. Intrauterine device (IUD) 6.4. Intrauterine hormone-releasing system (IUS) 6.5. Vasectomised partner (provided that partner is the sole sexual partner of the trial participant and that the vasectomised partner has received medical assessment of the surgical success) 6.6. Bilateral tubal occlusion 6.7. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject) 7. Willing and able to confirm written informed consent at the point of randomisation, after the pre-randomisation period Qualitative interviews A sample of participants who opt to consent to qualitative interviews will be contacted. For staff interviews, a sample of PIs at sites that have been open to recruitment for at least 4 months, and are willing to be interviewed, will be contacted. Adult 18 Years All 290 90 Current exclusion criteria as of 29/07/2022: Stage 1/ pre-randomisation: 1. DSM-5 defined severe substance use disorder. 2. Current psychotic symptoms as assessed using the MINI. 3. History of retinal disease. 4. Current cardiovascular symptoms or significant concerns around cardiovascular disease. 5. History of significant renal disease (for example within the last 6 months eGFR is less than 50ml/min/1.73m2 or there is a concern that eGFR is deteriorating and may be expected to fall below 50 during the course of the study). 6. Any known sensitivity to trial drug including its excipients. 7. Current pregnancy or planned pregnancy during the trial period, or breastfeeding. 8. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation. 9. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt). 10. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome (where restless legs syndrome has been formally diagnosed by a sleep clinic). 11. Significant clinical concern regarding impulse control behaviours Stage 2/ at randomisation: 1. Psychotic symptoms over the preceding 4 weeks. 2. Any known sensitivity to trial drug including its excipients 3. Any deterioration in physical or mental health since pre-randomisation that means there is a clinical concern to proceed with the study. 4. Current or planned pregnancy during the trial period, or breast feeding. 5. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation. 6. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt). 7. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome (where restless legs syndrome has been formally diagnosed by a sleep clinic). 8. Significant clinical concern regarding impulse control behaviours 9. Electroconvulsive therapy (ECT) in the last 28 days. 10. Any study team’s concern regarding the patient’s ability to remain engaged in the study collecting self-ratings of their symptoms and undertake all study procedures. _____ Previous exclusion criteria as of 20/05/2020: Stage 1/ pre-randomisation: 1. DSM-5 defined severe substance use disorder. 2. Current psychotic symptoms as assessed using the MINI. 3. History of retinal disease. 4. Current cardiovascular symptoms or significant concerns around cardiovascular disease. 5. History of significant renal disease (for example within the last 6 months eGFR is less than 50ml/min/1.73m2 or there is a concern that eGFR is deteriorating and may be expected to fall below 50 during the course of the study). 6. Any known sensitivity to trial drug including its excipients. 7. Current pregnancy or planned pregnancy during the trial period, or breastfeeding. 8. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation. 9. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt). 10. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome (where restless legs syndrome has been formally diagnosed by a sleep clinic). 11. Significant clinical concern regarding impulse control behaviours Stage 2/ at randomisation: 1. Psychotic symptoms over the preceding 4 weeks. 2. Any known sensitivity to trial drug including its excipients 3. Any deterioration in physical or mental health since pre-randomisation that means there is a clinical concern to proceed with the study. 4. On an antipsychotic at the point of randomisation. 5. Current or planned pregnancy during the trial period, or breast feeding. 6. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation. 7. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt). 8. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome (where restless legs syndrome has been formally diagnosed by a sleep clinic). 9. Significant clinical concern regarding impulse control behaviours 10. Any study team’s concern regarding the patient’s ability to remain engaged in the study collecting self-ratings of their symptoms. _____ Previous exclusion criteria: Stage 1/ pre-randomisation: 1. DSM-5 defined severe substance use disorder 2. Current psychotic symptoms as assessed using the MINI 3. History of retinal disease 4. Current cardiovascular symptoms or significant concerns around cardiovascular disease 5. History of renal disease 6. Any known sensitivity to trial drug including its excipients 7. Current pregnancy or planned pregnancy during the trial period, or breastfeeding 8. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation 9. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt) 10. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome 11. Clinical concern of previous impulse control behaviours including harmful alcohol or drug use, binge eating, gambling or sexual behaviours, or regarding significant suicidal risks Stage 2/ at randomisation: 1. Psychotic symptoms over the preceding 4 weeks 2. Any known sensitivity to trial drug including its excipients 3. Any deterioration in physical or mental health since pre-randomisation that means there is a clinical concern to proceed with the study 4. On an antipsychotic at the point of randomisation 5. Current or planned pregnancy during the trial period, or breastfeeding 6. Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation 7. Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD (site team to check with the CI and Trial Management Group if in doubt) 8. Confirmed diagnosis with potential confounding factors such as Parkinson’s disease, restless leg syndrome 9. Clinical concern of previous impulse control behaviours including harmful alcohol or drug use, binge eating, gambling or sexual behaviours or regarding significant suicidal risks 10. Any study team’s concern regarding the patient’s ability to remain engaged in the study collecting self-ratings of their symptoms 2019-09-30T00:00:00.000Z 2022-06-14T00:00:00.000Z Treatment-resistant bipolar depression Mental and Behavioural Disorders Bipolar affective disorder Current interventions as of 29/07/2022: The pre-randomisation phase will allow patients to have their antipsychotics adjusted and mood stabiliser initiated if necessary. Once this is done, 290 participants will be randomly allocated in a 1:1 ratio to receive either pramipexole or placebo, in addition to an ongoing mood stabiliser. Randomisations will be carried out by a delegated and trained member of the research team at each site using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). The trial team, participants and their treating mental health team will not know whether the participant receives pramipexole or placebo; the trial is ‘double-blind’. For all participants, initiation of trial treatment will follow a 4-week titration schedule starting at 0.25 mg/day in a single (oral) dose usually at night for 3 days. Thereafter the dose will be increased by 0.25 mg/day every 3 days. The target dose will be 2.5 mg/day but titration will be based on tolerability and response. The dose attained at the end of Week 4 is then continued throughout weeks 5-12. Then from weeks 13- 48 pramipexole will be flexibly dosed between 0.25 and 2.5mg/day, determined by response and tolerability. During the flexible dosing stage of the study, decisions around medication dose alterations will be based on weekly mood scores (QIDS-SR and ASRM) and scores from the side effect items of the TSQM administered 4-weekly. Patient’s mood and response and tolerability will be categorised every 4 weeks. Participants will be provided with medication via 7 separate dispensing at specified timepoints during the study – as part of the last dispensing participants will be provided with enough medication to last them up until week 52 to ensure they have enough to taper down slowly (if this is required) as pramipexole should not be stopped suddenly The effectiveness of pramipexole after 12 weeks will be assessed, and participants will continue to be monitored by trial researchers for 48 weeks, even if they discontinue the initial treatment, giving real-life information on the use of this treatment. The effect on depressive symptoms and quality of life will be assessed, along with side-effects and whether any other treatments are needed. Assessments will be self-reported using an online system completed by participants, who will be supported by email prompts. These methods have worked well in previous studies and participants approve of their use. The system allows more frequent (weekly) self-ratings of bipolar depression symptoms and thus gives a more complete picture of long-term symptom control. Where necessary paper versions will be provided. Participants will be telephoned monthly to assess concomitant medication use and side-effects. _____ Previous interventions: In the pre-randomisation stage, if participants are on an antipsychotic it will be gradually withdrawn, as it may block the effect of pramipexole. Additionally, if participants are not on a ‘mood stabiliser’, one will be started. Once this is done, 290 participants will be randomly allocated in a 1:1 ratio to receive either pramipexole or placebo, in addition to an ongoing mood stabiliser. Randomisations will be carried out by a delegated and trained member of the research team at each site using the Sealed Envelope system (a central, secure, 24-hour web-based randomisation system with concealed allocation). The trial team, participants and their treating mental health team will not know whether the participant receives pramipexole or placebo; the trial is ‘double-blind’. For all participants, initiation of trial treatment will follow a 4-week titration schedule starting at 0.25 mg/day in a single (oral) dose usually at night for 3 days. Thereafter the dose will be increased by 0.25 mg/day every 3 days. The target dose will be 2.5 mg/day but titration will be based on tolerability and response. The dose attained at the end of Week 4 is then continued throughout weeks 5-12. Then from weeks 13- 48 pramipexole will be flexibly dosed between 0.25 and 2.5mg/day, determined by response and tolerability. During the flexible dosing stage of the study, decisions around medication dose alterations will be based on weekly mood scores (QIDS-SR and ASRM) and scores from the side effect items of the TSQM administered 4-weekly. Patient’s mood and response and tolerability will be categorised every 4 weeks. Participants will be provided with medication via 7 separate dispensing at specified timepoints during the study – as part of the last dispensing participants will be provided with enough medication to last them up until week 52 to ensure they have enough to taper down slowly (if this is required) as pramipexole should not be stopped suddenly The effectiveness of pramipexole after 12 weeks will be assessed, and participants will continue to be monitored by trial researchers for 48 weeks, even if they discontinue the initial treatment, giving real-life information on the use of this treatment. The effect on depressive symptoms and quality of life will be assessed, along with side-effects and whether any other treatments are needed. Assessments will be self-reported using an online system completed by participants, who will be supported by email prompts. These methods have worked well in previous studies and participants approve of their use. The system allows more frequent (weekly) self-ratings of bipolar depression symptoms and thus gives a more complete picture of long-term symptom control. Where necessary paper versions will be provided. Participants will be telephoned monthly to assess concomitant medication use and side-effects. Drug Not Applicable Pramipexole The data sharing plans for the current study are unknown and will be made available at a later date Data sharing statement to be made available at a later date 2025 Results article in https://pubmed.ncbi.nlm.nih.gov/39829389/ (added 29/04/2025) 2025 Results article in https://pubmed.ncbi.nlm.nih.gov/40455248/ (added 05/06/2025) 2021 Protocol article in https://pubmed.ncbi.nlm.nih.gov/34225686/ (added 07/07/2021) Results

Added from spreadsheet

Study website Migrated from study website field

cc2ea4b3-20a9-475f-b661-32dac49bfa4c 96b9006f-ded9-42d5-a49a-34fa5e155a18 549baab0-3c39-4704-877b-023dd0fadb01 ca8e9915-a225-4d70-8c01-34a65d79da93 3a8ffc89-d51b-4540-95c6-47b05d6c0ebc No Plain English results ISRCTN72151939_ResultsPlainEnglish_V01_11Jan2024.pdf 5b0b753c-414d-41e4-b981-34238aa18c1d true application/pdf 199768 f35e04f81d7db06c48b3786d66ab1dc2 Zoë Walmsley Public

Trial Manager Newcastle Clinical Trials Unit Newcastle University 1-4 Claremont Terrace

Newcastle upon Tyne United Kingdom NE2 4AE - PAX.BD@newcastle.ac.uk Public Nicola Goudie https://orcid.org/0000-0003-1211-936X Public

Trial Manager Newcastle Clinical Trials Unit Newcastle University 1-4 Claremont Terrace

Newcastle upon Tyne United Kingdom NE2 4AE - PAX.BD@newcastle.ac.uk Public Andrew Swain Public

Trial Manager Newcastle Clinical Trials Unit 1-4 Claremont Terrace Newcastle University

Newcastle upon Tyne United Kingdom NE2 4AE - PAX.BD@newcastle.ac.uk Public Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust Hospital/treatment centre https://ror.org/01ajv0n48 Non-commercial NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/154/01 79119671 true The effectiveness of cognitive remediation therapy as a component of treatment for anorexia nervosa: a randomised controlled trial Cognitive remediation therapy will increase the effectiveness of cognitive behavioural therapy Background and study aims Anorexia nervosa is a serious mental health condition where a person keeps their body weight as low as possible. Individuals with anorexia nervosa have been found to have difficulties with cognitive flexibility. Cognitive flexibility is the ability to shift attention. Shifting attention allows individuals to change their thinking and/or behaviour to adapt to changes in the environment. Cognitive Remediation Therapy was designed to improve cognitive flexibility, memory and planning skills through the use of mental exercises, reflection on thinking styles and exploring new ways of thinking in everyday life. Mental exercises include tasks that involve switching attention and estimating. The aims of this study are to investigate the effectiveness and acceptability of Cognitive Remediation Therapy as a component of treatment for anorexia nervosa, and to examine whether Cognitive Remediation Therapy enhances the effectiveness of Cognitive Behavioural Therapy. Who can participate? Women aged between 18 and 65 with anorexia nervosa What does the study involve? Participants are randomly allocated to either Group 1 or Group 2. Participants in Group 1 receive 6 individual sessions of Cognitive Remediation Therapy followed by 6 individual sessions of Cognitive Behavioural Therapy. They also undergo assessments at the start of the study, after the 6 individual sessions of Cognitive Remediation Therapy, and after the 6 sessions of Cognitive Behavioural Therapy. Group 2 receive 6 individual sessions of Cognitive Behavioural Therapy. They also undergo assessments at the start of the study and after the 6 sessions of Cognitive Behavioural Therapy. What are the possible benefits and risks of participating? Participants may feel positive about being involved in research investigating the effectiveness of a new treatment that could benefit future patients. It is hoped that the information gathered will be of value in improving treatment for anorexia nervosa. The time required to participate in the tests may be inconvenient for some participants, but previous studies have found that participants enjoy the tests. Concentration and attention are required throughout the tests and participants’ performance could be adversely affected by fatigue. To reduce the effect of fatigue, participants are offered a break between the tests. Another identified risk is the potential distress of participants. During the tests participants are asked about their eating behaviour and their thoughts/concerns about body shape and weight. The questionnaires are widely used in research and clinical practice with eating disorder patients. There is no evidence to suggest that these tests cause distress, but it is possible that focusing on psychological difficulties may result in some participants experiencing a degree of distress. In the unlikely event that this happens, participants will be encouraged to discuss any upsetting issues with clinical staff within NHS Tayside Eating Disorders Service who are involved in their routine outpatient care. The researcher will liaise with clinical staff and rely on their judgement as to whether specific patients are too emotionally or physically frail to participate. Participation in the study will be confidential, but if there is a risk to the participant or others the researcher will inform a named clinical member of staff within NHS Tayside Eating Disorders Service. This would be discussed with the participant prior to disclosing the information. Only the researcher and her supervisor will have access to identifiable data. Data stored on a computer will be anonymised and password protected. Where is the study run from? NHS Tayside (UK) When is study starting and how long is it expected to run for? April 2012 to July 2013 Who is funding the study? NHS Tayside and University of Edinburgh (UK) Who is the main contact? Moira Cook Eating Disorders Examination Questionnaire (EDE-Q) (Fairburn & Cooper, 1993) 1. Wisconsin Card Sorting Test (Heaton, 1981) 2. National Adult Reading Test (NART) (Nelson, 1982) 3. Hayling Sentence Completion Test (Burgess & Shallice, 1997) 4. Brixton Spatial Anticipation Test (Burgess & Shallice, 1997) 5. Delis-Kaplan Executive Function System (Delis, Kaplan & Kramer, 2001) 6. Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983) 7. Social Problem Solving Inventory Revised (SPSI-R) (D'Zurilla, Nezu & Maydeu-Olivares, 1999) 8. Obsessive Compulsive Inventory (Foa, Kozak, Salkovskis, Coles & Amir, 1998) 9. Perfectionism, Perseveration and Persistence Questionnaire (Serpell, Waller, Fearon & Meyer, 2009) Old ethics approval format Not provided at time of registration 10.1186/ISRCTN79119671 Single-site randomised controlled trial Interventional Randomised controlled trial Treatment 2012-07-31T00:00:00.000Z United Kingdom Scotland Ninewells Hospital

Dundee United Kingdom DD1 9SY Patient 1. Female, aged 18-65 2. English as first language 3. Meet International Classification of Diseases, Tenth Revision (ICD-10) criteria for a diagnosis of anorexia nervosa or atypical anorexia nervosa 4. Receiving outpatient treatment within NHS Tayside Eating Disorders Service Adult 18 Years 65 Years Female 40 1. Deemed by clinical staff to be too emotionally or physically frail to participate 2. Current psychosis 3. History of Learning Disability/Developmental Disorder 4. History of head injury involving loss of consciousness 5. History/current neurological disorder 6. Uncorrected significant visual or motor impairment 7. Current/previous substance misuse 8. Administrated neuropsychological measures in the past - knowledge of neuropsychological measures 2012-04-01T00:00:00.000Z 2012-07-31T00:00:00.000Z Anorexia nervosa Mental and Behavioural Disorders Anorexia nervosa Group 1 will receive 6 sessions of Cognitive Remediation Therapy (CRT) followed by 6 sessions of Cognitive Behavioural Therapy (CBT). Group 2 will receive 6 sessions of CBT. Both CRT and CBT interventions will consist of individual 1 hour sessions on a weekly or maximum fortnightly basis. CRT consists of cognitive tasks aimed at increasing the flexibility of thinking skills, improving holistic thinking skills, reflection of thinking skills and information processing. Each session will be made up of a number of tasks consisting of the following: 1. Stroop tasks 2. Estimation task 3. Card stack task 4. Switching time zones task 5. Switch-attention task 6. Maps task 7. Prioritising task 8. Up and Down task 9. How To task 10. Search and Count task 11. Main ideas task CBT consists of making the connections between thinking, emotion, behaviour and physiology explicit to individuals through the use of behavioural experiments and guided discovery. The sessions will cover the following topics: 1. Providing education about, and explaining the multiple functions of, anorexic symptomatology 2. Presenting the cognitive rationale for treatment 3. Explaining the rationale and providing advice for restoring normal nutrition and weight 4. Prescribing normalised eating patterns 5. Implementing self-monitoring and meal planning 6. Strategies for interrupting bingeing, purgative and over-exercising behaviours as appropriate 7. Increasing motivation for change 8. Identifying dysfunctional thinking patterns 9. Developing cognitive restructuring skills 10. Modifying concepts of the self 11. Challenging cultural values regarding weight and shape 12. Summarising progress and areas of continued vulnerability 13. Reviewing warning signs of relapse 14. Reviewing fundamentals of continued progress Other Not Applicable Not provided at time of registration 2815dd8f-9385-4efd-98b0-35db25199e5b 83e4c59f-5973-416d-8f18-72d4eaa7df66 efbb9524-0f31-4350-b95f-f2d5883e5f84 834bdbb3-caeb-4d5f-910a-bd52caf4cd9d No Moira Cook Scientific

Department of Clinical Neuropsychology South Block Ninewells Hospital

Dundee United Kingdom DD1 9SY Protected NHS Tayside Health Board (UK) Hospital/treatment centre https://ror.org/000ywep40 Non-commercial NHS Tayside (UK) University of Edinburgh (UK) http://dx.doi.org/10.13039/501100000848