Background
Aims
Objectives and measures
Screening | Pre-randomisation | Screening and Randomisation | 0 | Treatment weeks (Post-randomisation) | Tapering (5, 6, 7) | |||||||||||||||||||||||||||||
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1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 to 11 | 12 | 13 to 15 | 16 | 17 to 19 | 20 | 21 to 23 | 24 | 25 to 27 | 28 | 29 to 31 | 32 | 33 to 35 | 36 | 37 to 39 | 40 | 41 to 43 | 44 | 45 to 47 | 48 | 49 to 51 | 52* | |||||
Informed consent (1,2) | ✓ | ✓ | ||||||||||||||||||||||||||||||||
Demographics | ✓ | ✓ | ||||||||||||||||||||||||||||||||
Eligibility assessment | ✓ | ✓ | ||||||||||||||||||||||||||||||||
Randomisation | ✓ | |||||||||||||||||||||||||||||||||
RA safety monitoring call (3, 8) | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |||||||||||
CSO contact (4) | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |||||||||||||||||||||||||||
QIDS-SR, GAD-7 and ASRM | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||
SHAPS | ✓ | ✓ | ✓ | |||||||||||||||||||||||||||||||
WSAS | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ||||||||||||||||||||||||||||
TSQM | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |||||||||||||||||||||||
QUIP-RS | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |||||||||||||||||||||
MADRS, QIDS-C and YMRS | ✓ | ✓ | ||||||||||||||||||||||||||||||||
IMP Dispensings | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |||||||||||||||||||||||||||
Qualitative Interviews | ✓ | ✓ | ||||||||||||||||||||||||||||||||
Participant Vouchers | ✓ | ✓ | ✓ | |||||||||||||||||||||||||||||||
Unblinding (9) | ✓ |
Primary objective
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To evaluate the clinical effectiveness of pramipexole versus placebo alongside standard mood stabilising medication, over 12 weeks, in the management of participants with treatment resistant bipolar depression, assessed using the QIDS-SR [33].
Secondary efficacy objectives
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To examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks, and pleasure symptoms over 12 weeks. In addition to the weekly assessment of depressive and anxiety symptoms with the QIDS-SR and GAD-7 [33, 35] respectively, the ability to experience pleasure is assessed using the Snaith-Hamilton Pleasure Scale (SHAPS) [38] at randomisation and at weeks 6 and 12 post-randomisation.
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To examine the impact of pramipexole on psychosocial function over 48 weeks, using the self-reported Work and Social Adjustment Scale (WSAS) [39].
Secondary safety and acceptability objectives
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To examine risk of switching to mania and occurrence of psychosis or impulse control disorders, which are known possible side-effects of pramipexole [24], over 48 weeks. Manic symptoms are assessed weekly using an on-line version of the ASRM scale [34]. Rates of impulsivity during the study are monitored using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease – Rating Scale (QUIP-RS) [40], administered by telephone by the study RAs. Psychosis is not formally rated but is specifically screened for during regular RA phone calls.
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To examine side effects and overall acceptability of pramipexole treatment over 48 weeks using the Treatment Satisfaction Questionnaire for Medication (TSQM) [41] administered by phone by the study RAs.
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To examine tolerability of pramipexole by reviewing the rates, severity, seriousness, causality and expectedness Adverse Events (AEs) and Adverse Reactions (ARs).
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To examine adherence to medication over 48 weeks. Medication is provided to participants by post from the Cumbria, Northumberland, Tyne and Wear (CNTW) pharmacy on seven occasions over the course of the study. Adherence is assessed through a pill count of un-used medication returned by participants at the end of each prescription period.
Health economic objectives
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To examine the quality of life, wellbeing, health and social care and broader societal costs of participants randomised to either pramipexole or placebo. To establish the incremental cost-effectiveness of pramipexole in comparison to placebo over 48 weeks. Assessments are conducted via participant completion of on-line versions of the EuroQoL 5 Dimension 5 Level (EQ-5D-5L) [42] measure of health-related quality of life, and the ICEpop CAPability measure for Adults (ICECAP-A) [43] and the Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH) [44] capturing broader wellbeing, and the Health Economics Questionnaire (HEQ) [45] for information on health and social services utilisation and broader societal costs.
Qualitative interviews
Sample size, power and effect size
Methods
Study design
Drug | Maximum daily dose |
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Aripiprazole | 15 mg |
Aripiprazole depot | 400 mg every 4 weeks |
Chlorpromazine | 200 mg |
Flupentixol depot | 200 mg every 4 weeks |
Haloperidol | 2 mg |
Haloperidol depot | 100 mg every 4 weeks |
Lurasidone | 111 mg |
Olanzapine | 10 mg |
Olanzapine depot | 150 mg every 2 weeks |
Paliperidone | 3 mg |
Paliperidone depot | 75 mg every month |
Quetiapine | 300 mg |
Risperidone | 1 mg |
Risperidone depot | 25 mg every 2 weeks |
Zuclopenthixol depot | 500 mg every 4 weeks |
Participants
Recruitment
Inclusion criteria for entry to the pre-randomisation phase
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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.
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A decision made by the patient’s clinical team that a change in medication is indicated.
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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).
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Aged 18 or over at the point of consent.
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Willing and able to provide written informed consent prior to any trial procedures taking place.
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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.
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The patient, if female and of child-bearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)].
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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:
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combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
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progestogen only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
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intrauterine device
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intrauterine hormone-releasing system
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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)
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bilateral tubal occlusion
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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)
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Exclusion criteria for the pre-randomisation phase
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DSM-5 defined severe substance use disorder.
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Current psychotic symptoms as assessed using the MINI.
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History of retinal disease.
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Current cardiovascular symptoms or significant concerns around cardiovascular disease.
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History of significant renal disease (for example within the last 6 months estimated Glomerular Filtration Rate (eGFR) is less than 50 ml/min/1.73 m2 or there is a concern that eGFR is deteriorating and may be expected to fall below 50 during the course of the study).
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Any known sensitivity to trial drug including its excipients.
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Current pregnancy or planned pregnancy during the trial period, or breastfeeding.
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Starting specific psychotherapy from four weeks before randomisation through to Week 12 post-randomisation.
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Currently taking part in another clinical trial that would interfere with the outcomes of PAX-BD.
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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).
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Significant clinical concern regarding impulse control behaviours.
Inclusion for randomisation
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Been in pre-randomisation for a minimum of 23 calendar days.
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Severity of depression still meeting the criteria of QIDS-SR > 10.
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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
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On mood stabilising medication (lithium, valproate, carbamazepine, lamotrigine)
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If on an antipsychotic this must be one listed, and at a dose of no more than the maximum stated in Table 2.
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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.
Exclusion criteria for randomisation
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Psychotic symptoms over the preceding 4 weeks.
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Any deterioration in physical or mental health since pre-randomisation that means there is a clinical concern to proceed with the study.
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Any study team’s concern regarding the patient’s ability to remain engaged in the study collecting self-ratings of their symptoms.