Condition category
Mental and Behavioural Disorders
Date applied
19/08/2019
Date assigned
28/08/2019
Last edited
28/08/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

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 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If participants are on an antipsychotic it is gradually withdrawn, as it may block the effect of pramipexole.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 NTW (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?
1. Northumberland, Tyne and Wear NHS Foundation Trust
2. Nottinghamshire Healthcare NHS Foundation Trust
3. Surrey and Borders Partnership NHS Foundation Trust
4. Avon And Wiltshire Mental Health Partnership NHS Trust
5. Derbyshire Healthcare NHS Foundation Trust
6. Oxford Health NHS Foundation Trust
7. Cheshire and Wirral Partnership NHS Foundation Trust
8. Devon Partnership NHS Trust
9. Midlands Partnership NHS Foundation Trust
10. Leicestershire Partnership NHS Trust
11. Dudley And Walsall Mental Health Partnership NHS Trust
12. Lincolnshire Partnership NHS Foundation Trust
13. Berkshire Healthcare NHS Foundation Trust
14. Rotherham Doncaster and South Humber NHS Foundation Trust
15. Bradford District Care NHS Foundation Trust
16. South West Yorkshire Partnership NHS Foundation Trust
17. Norfolk And Suffolk NHS Foundation Trust
18. Camden and Islington NHS Foundation Trust
19. Sheffield Health & Social Care NHS Foundation Trust
20. South London and Maudsley NHS Foundation Trust
21. Essex Partnership University NHS Foundation Trust
22. South West London and St George's Mental Health NHS Trust
23. NHS Tayside
24. NHS Lothian
25. NHS Greater Glasgow and Clyde
26. Northern Heath & Social Care Trust
27. South London and Maudsley NHS Foundation Trust

When is the study starting and how long is it expected to run for?
September 2019 to October 2021

Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) (UK)

Who is the main contact?
Dr Nicola Goudie
nicola.goudie@newcastle.ac.uk

Trial website

http://mood-disorders.co.uk/PAX-BD/

Contact information

Type

Scientific

Primary contact

Dr Nicola Goudie

ORCID ID

Contact details

Trial Manager
Newcastle Clinical Trials Unit
Newcastle University
1-4 Claremont Terrace
Newcastle upon Tyne
NE2 4AE
United Kingdom
+44 (0) 191 2087187
nicola.goudie@newcastle.ac.uk

Additional identifiers

EudraCT number

2018-002869-18

ClinicalTrials.gov number

Nil known

Protocol/serial number

39561

Study information

Scientific title

A randomised, double-blind, placebo-controlled trial of pramipexole in addition to mood stabilisers for patients with treatment-resistant bipolar depression

Acronym

PAX-BD

Study hypothesis

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.

Ethics approval

Approval pending, 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

Study design

Randomised; Both; Design type: Treatment, Drug, Health Economic

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Treatment-resistant bipolar depression

Intervention

In a 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.

Intervention type

Drug

Phase

Not Applicable

Drug names

Pramipexole

Primary outcome measure

Depression symptoms measured using QIDS-SR questionnaire (Quick Inventory of Depressive Symptomatology) at 12 weeks

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

Overall trial start date

25/04/2018

Overall trial end date

31/10/2021

Reason abandoned (if study stopped)

Eligibility

Participant 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.

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 290; UK Sample Size: 290

Participant 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

Recruitment start date

30/09/2019

Recruitment end date

29/09/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Northumberland, Tyne and Wear NHS Foundation Trust
St. Nicholas Hospital Jubilee Road Gosforth
Newcastle Upon Tyne
NE3 3XT
United Kingdom

Trial participating centre

Nottinghamshire Healthcare NHS Foundation Trust
The Resource, Trust HQ Duncan Macmillan House Porchester Road
Nottingham
NG3 6AA
United Kingdom

Trial participating centre

Surrey and Borders Partnership NHS Foundation Trust
18 Mole Business Park Randalls Road
Leatherhead
KT22 7AD
United Kingdom

Trial participating centre

Avon And Wiltshire Mental Health Partnership NHS Trust
Jenner House Avon Way Langley Park
Chippenham
SN15 1GG
United Kingdom

Trial participating centre

Derbyshire Healthcare NHS Foundation Trust
Trust Headquarters Kingsway Hospital Kingsway
Derby
DE22 3LZ
United Kingdom

Trial participating centre

Oxford Health NHS Foundation Trust
Warneford Hospital Warneford Lane Headington
Oxford
OX3 7JX
United Kingdom

Trial participating centre

Cheshire and Wirral Partnership NHS Foundation Trust
Trust Board Offices Upton Lea Resource Centre The Countess Of Chester Health Park
Chester
CH2 1BQ
United Kingdom

Trial participating centre

Devon Partnership NHS Trust
Wonford House Hospital Dryden Road
Exeter
EX2 5AF
United Kingdom

Trial participating centre

Midlands Partnership NHS Foundation Trust
Trust Headquarters St. Georges Hospital Corporation Street
Stafford
ST16 3SR
United Kingdom

Trial participating centre

Leicestershire Partnership NHS Trust
Riverside House Bridge Park Plaza Bridge Park Road Thurmaston
Leicester
LE4 8PQ
United Kingdom

Trial participating centre

Dudley And Walsall Mental Health Partnership NHS Trust
Trafalgar House 47-49 King Street
Dudley
DY2 8PS
United Kingdom

Trial participating centre

Lincolnshire Partnership NHS Foundation Trust
Unit's 8 & 9 The Point Lions Way
Sleaford
NG34 8GG
United Kingdom

Trial participating centre

Berkshire Healthcare NHS Foundation Trust
Fitzwilliam House Skimped Hill Lane
Bracknell
RG12 1BQ
United Kingdom

Trial participating centre

Rotherham Doncaster and South Humber NHS Foundation Trust
St. Catherine's House St. Catherine's Hospital Tickhill Road
Doncaster
DN4 8QN
United Kingdom

Trial participating centre

Bradford District Care NHS Foundation Trust
New Mill Victoria Road Saltaire
Shipley
BD18 3LA
United Kingdom

Trial participating centre

South West Yorkshire Partnership NHS Foundation Trust
Trust Headquarters Fieldhead Ouchthorpe Lane
Wakefield
WF1 3SP
United Kingdom

Trial participating centre

Norfolk And Suffolk NHS Foundation Trust
Hellesdon Hospital Drayton High Road
Norwich
NR6 5BE
United Kingdom

Trial participating centre

Camden and Islington NHS Foundation Trust
St. Pancras Hospital 4 St. Pancras Way
London
NW1 0PE
United Kingdom

Trial participating centre

Sheffield Health & Social Care NHS Foundation Trust
Fulwood House Old Fulwood Road
Sheffield
S10 3TH
United Kingdom

Trial participating centre

South London and Maudsley NHS Foundation Trust
Maudsley Hospital Denmark Hill
London
SE5 8AZ
United Kingdom

Trial participating centre

Essex Partnership University NHS Foundation Trust
The Lodge Runwell Chase Runwell
Wickford
SS11 7XX
United Kingdom

Trial participating centre

South West London and St George's Mental Health NHS Trust
Springfield Hospital 61 Glenburnie Road
London
SW17 7DJ
United Kingdom

Trial participating centre

NHS Tayside
Ninewells Hospital and Medical School James Arrott Drive
Dundee
DD1 9SY
United Kingdom

Trial participating centre

NHS Lothian
Waverley Gate 2-4 Waterloo Place
Edinburgh
EH1 3EG
United Kingdom

Trial participating centre

NHS Greater Glasgow and Clyde
J B Russell House Gartnavel Royal Hospital 1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Trial participating centre

Northern Heath & Social Care Trust
Trust Headquarters Bretten Hall Bush Road
Antrim
BT41 2RL
United Kingdom

Trial participating centre

South London and Maudsley NHS Foundation Trust
Maudsley Hospital Denmark Hill
London
SE5 8AZ
United Kingdom

Sponsor information

Organisation

Northumberland, Tyne and Wear NHS Foundation Trust

Sponsor details

c/o Ms Lyndsey Dixon
St Nicholas Hospital
Jubilee Road
Gosforth
Newcastle Upon Tyne
NE3 3XT
United Kingdom
+44 (0)191 246 7222
abc@email.com

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/154/01

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

1. The protocol is not yet published – the SAP is not yet available
2. Peer reviewed scientific journals
3. Conference presentation
4. Publication on website
5. Other publication
6. Submission to regulatory authorities

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date

Intention to publish date

31/10/2022

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

19/08/2019: Trial's existence confirmed by the NIHR.