Condition category
Mental and Behavioural Disorders
Date applied
26/02/2019
Date assigned
15/05/2019
Last edited
15/05/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Background and study aims
Clinical depression is a common disorder usually treated in primary care with psychological therapies and antidepressant medication. However a significant proportion of people (about 2-3 in 10) do not improve with current first-line therapies and are regarded as having treatment resistant depression (TRD).
TRD is a major problem for both patients and society because of the high level of suffering and associated disability. Current medicines for TRD are not particularly effective for many people and often have adverse effects which patients find distressing.
There is some evidence that pramipexole, a medicine already commonly used in Parkinson's Disease, may be an effective treatment for TRD. PAX-D will compare the effects of pramipexole with placebo when added to current antidepressant medication for people with TRD. The trial will look at effectiveness in the short- term (after 12 week’s treatment) and in the longer-term (48 weeks). The trial will also assess the adverse effects of pramipexole and explore patients’ experiences of taking it.
Pramipexole is unlike current antidepressant drugs in that it acts like a brain chemical called dopamine, which is known to influence people’s motivation to pursue goals and affect how rewarding they find them. Lack of motivation is a key symptom of depression so any antidepressant effects of pramipexole may be linked to increased motivation. PAX-D participants will be asked to carry out a computer task designed to measure how pramipexole affects the dopamine system in the brain and how far this can explain its antidepressant effects.
If pramipexole is effective it could become a very useful treatment option for patients with TRD and this information will be disseminated through scientific publications, meetings with patient groups and NHS innovation programmes.

Who can participate?
People aged over 18 years old with a diagnosis of Treatment Resistant Depression.

What does the study involve?
Participants will attend a screening visit to confirm that they are eligible to join the trial. They will then be randomly assigned to receive either pramipexole or to a placebo and will attend a further four study visits over 48 weeks. At study visits, participants will be asked to complete questionnaires and will complete a cognitive task at a computer. Between study visits, participants will be contacted by a trained research assistant and asked to regularly complete questionnaires by phone and by using an online system called True Colours.

What are the possible benefits and risks of participating?
The aim of the trial is to find out if pramipexole is a useful treatment for treatment resistant depression. If participants are randomised to receive pramipexole, this may help treat their depression but this cannot be guaranteed. Participants using True Colours will be able to monitor their responses to the questionnaires over time and this may provide greater insight into their depression. Pramipexole has a range of common and uncommon side effects. Not everyone will experience side effects to pramipexole but participants will be advised how to recognise them and when to seek medical help. The effects of pramipexole on pregnancy and breast-feeding are not known. Pregnant women will not be able to take part in the trial, and women of childbearing potential will be asked to use effective contraception during the 48-week treatment period.

Where is the study run from?
Warneford Hospital, Oxford, UK

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

Who is funding the study?
NIHR Efficacy and Mechanism Evaluation Programme, UK

Who is the main contact?
1. Mr James Griffiths (public contact), pax-d@psych.ox.ac.uk
2. Prof. John Geddes (scientific contact), john.geddes@psych.ox.ac.uk
3. Dr Michael Browning (scientific contact), michael.browning@psych.ox.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Mr James Griffiths

ORCID ID

http://orcid.org/0000-0002-3386-8100

Contact details

Department of Psychiatry
Warneford Hospital
University of Oxford
Oxford
OX3 7JX
United Kingdom
01865618160
pax-d@psych.ox.ac.uk

Type

Scientific

Additional contact

Prof John Geddes

ORCID ID

Contact details

NIHR Oxford Health Biomedical Research Centre
Warneford Hospital
Oxford
OX3 7JX
United Kingdom
01865618202
john.geddes@psych.ox.ac.uk

Type

Scientific

Additional contact

Dr Michael Browning

ORCID ID

Contact details

Department of Psychiatry
University of Oxford
Oxford
OX3 7JX
United Kingdom
01865618316
michael.browning@psych.ox.ac.uk

Additional identifiers

EudraCT number

2019-001023-13

ClinicalTrials.gov number

Protocol/serial number

Ox_Psych_PAXD

Study information

Scientific title

Randomised placebo-controlled trial evaluating the efficacy and mechanism of pramipexole as add-on treatment for people with treatment resistant depression

Acronym

PAX-D

Study hypothesis

That pramipexole will produce greater improvement than placebo in depressive symptoms after twelve weeks of treatment.

Ethics approval

Not provided at time of registration

Study design

Randomised double-blind placebo-controlled trial

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 contact details to request a participant information sheet.

Condition

Treatment resistant depression

Intervention

In addition to their standard antidepressant medication, participants will be randomised 1:1 to receive either Pramipexole dihydrochloride monohydrate or a matched placebo. Randomisation will be via minimisation facilitated by an online randomisation system hosted by the Primary Care CTU at the University of Oxford.

Pramipexole dihydrochloride monohydrate or matched placebo will be initiated at 0.25mg/day and, in the absence of concerns about tolerability, the dose will be increased by 0.25mg/day every three days towards a target dose of 2.5mg/day. Participants unable to tolerate a scheduled dose increase will be advised to remain on the highest tolerable dose.

Participants will be asked to complete the QIDS-SR16 at baseline and at 12 weeks post-randomisation and the scores will be compared between those treated with pramipexole and those treated with placebo. To further understand the mechanism and effects of pramipexole, participants will also complete additional questionnaires and a cognitive task at intervals throughout the 48-week treatment period.

Intervention type

Drug

Phase

Phase IV

Drug names

Pramipexole

Primary outcome measure

Improvement (change from baseline) of depressive symptoms measured on the Quick Inventory of Depressive Symptomatology, self-report version (QIDS-SR16) measured at baseline and 12 weeks post-randomisation

Secondary outcome measures

1. Safety (emergence of new symptoms) and Tolerability during the 48 week randomised phase assessed by:
1.1 Termination of trial treatment due to intolerance
1.2 Adverse reactions
1.3 TSQM
1.4 ALTMAN (manic symptoms)
1.5 QUIP-RS (impulse control)
1.6 Suicidal ideation (QIDS-SR16)
2. Change in reward sensitivity parameter from model fitted to learning/decision making task between baseline, week 2 and 12 weeks
3. Change in QIDS-SR16 and SHAPS scores between baseline and week 12 and change in reward sensitivity between baseline and week 2
4. Change scores in the learning/decision making task at 2 weeks and the change in the QID-SR16 at 12 weeks
5. Baseline scores on the learning/decision making task and the change in QIDS-SR16 at 12 weeks
6. Baseline scores on the SHAPS and change in the QID-SR16 at 12 weeks
7. QIDS-SR16 scores collected weekly across 48 weeks of the trial
8. QIDS-SR16 response, defined as a reduction of ≥50% in baseline score by week 12. QIDS-SR16 remission defined as a score of ≤5 at week 12
9. Change scores for the SHAPS, GAD-7 and QIDS-C between baseline and week 12
10. Change scores for the WSAS-screener between baseline and week 48
11. Change in: EQ-5D-5L, ICECAP-A, and OxCAP-MH over 48 weeks
12. HEQ information and costs over 50 weeks (2 weeks prior to randomisation and 48 weeks during the randomised phase)
13. Qualitative interviews with selected participants and investigators

Overall trial start date

01/04/2019

Overall trial end date

31/03/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Once informed consent has been given, participants will enter a run-in phase prior to randomisation.
Inclusion criteria for entry to run-in phase:
1. Willing and able to give informed consent to participate in the trial
2. Age 18 years or over
3. Diagnosis of DSM-V major depression
4. Quick Inventory of Depressive Symptomatology self-report version (QIDS-SR16) score >10 (moderate, severe or very severe depression)
5. Currently taking and tolerating antidepressant medication
6. Lack of response to at least 2 antidepressants at therapeutic doses (based on Maudsley Prescribing Guidelines and/or British National Formulary) in the current episode
7. Indication for change in treatment
8. Willing to continue an antidepressant treatment
9. Negative urine pregnancy test result (in females of child-bearing potential only)

Inclusion criteria for entry to randomised phase:
1. Verbal consent to randomisation
2. QIDS-SR16 score >10
3. On a stable dose of an antidepressant for at least 4 weeks

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

204

Participant exclusion criteria

Exclusion criteria for entry to run-in phase:
1. Diagnosis of current or previous psychosis, bipolar disorder or Parkinson’s Disease
2. Current antipsychotic medication
3. Clinically significant current or previous impulse control difficulties
4. Serious suicide or homicide risk
5. Current treatment with any medication known to interfere with pramipexole metabolism including cimetidine, memantine and methyldopa
6. Contraindications to pramipexole including history of or current treatment for eye disease, significant, symptomatic cardiovascular or renal disease or significant, symptomatic orthostatic hypotension
7. Previous course of pramipexole (>2 weeks duration)
8. Untreated or unstable medical condition which, in the judgement of the investigator, could interfere with the safety of receiving pramipexole or ability to complete the trial
9. Female and pregnant, lactating or planning pregnancy
10. Female of child-bearing potential not willing to use effective contraception

Exclusion criteria for entry to randomised phase:
1. eGFR (from screening blood test) < 50 mL/min/1.73m2
2. Psychotherapy started in past 4 weeks or planned to start within next 12 weeks

Recruitment start date

01/07/2019

Recruitment end date

31/12/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Warneford Hospital
Warneford Lane
Oxford
OX3 7JX
United Kingdom

Sponsor information

Organisation

University of Oxford

Sponsor details

University of Oxford
Joint Research Office
1st floor Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7LQ
United Kingdom
01865289885
karl.shepherd@admin.ox.ac.uk

Sponsor type

University/education

Website

https://researchsupport.admin.ox.ac.uk/ctrg

Funders

Funder type

Government

Funder name

Efficacy and Mechanism Evaluation Programme

Alternative name(s)

NIHR Efficacy and Mechanism Evaluation Programme, EME

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

The findings will be published in high impact, peer-reviewed journals with open access and with full acknowledgement of the support provided by NIHR/NETSCC/EME. A full and complete account of the research will also be published in the relevant NIHR programme journal. The primary report will be attributed to the PAX-D Investigators and collaborators. The names of all investigators who enter a participant into the randomised phase and of members of the trial management team will be listed at the end of the primary publication.

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

Intention to publish date

31/03/2023

Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

15/05/2019: Trial’s existence confirmed by NIHR.