| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| A mental disorder that causes periods of depression and periods of abnormally elevated mood. |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012386 |
| E.1.2 | Term | Depression mental |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the clinical effectiveness of pramipexole versus placebo alongside standard mood stabilising medication, over 12 weeks, in the management of patients with treatment resistant bipolar depression.
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| E.2.2 | Secondary objectives of the trial |
1. To examine the impact of pramipexole treatment on mood and anxiety symptoms over 48 weeks, and pleasure symptoms over 12 weeks.
2. To examine the impact of pramipexole on psychosocial function over 48 weeks.
3. To examine cardiovascular side effects of pramipexole.
4. To examine risk of switching to mania and occurrence of psychosis or impulse control disorders, which are known possible side-effects of pramipexole.
5. To examine rates of impulsivity during treatment with pramipexole, using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease.
6. To examine side effects and overall acceptability of pramipexole treatment.
7. To examine adherence to medication to which patients are randomised.
8. To examine the quality of life, wellbeing, health and social care and broader societal costs of patients randomised to either pramipexole or placebo. To establish the incremental cost-effectiveness of pramipexole in comparison to placebo over 48 weeks.
9. To increase c |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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) (52).
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:
- 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 (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:
- 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.
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.
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| E.4 | Principal 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 breast feeding.
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 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.
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. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome measure for the trial is the Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR), recorded at 12 weeks and covarying for baseline score. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR)
- Generalised Anxiety Disorder Assessment 7 (GAD-7)
- Snaith–Hamilton Pleasure Scale (SHAPS)
- Work and Social Adjustment Scale (WSAS)
- Pulse and blood pressure measures
- Altman Self Rating Scale of Mania (ASRM)
- Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease – Rating Scale (QUIP-RS)
- Treatment Satisfaction Questionnaire for Medication (TSQM)
- Dose taken as reported during RA phone calls and from central trial medication accountability and reconciliation records.
- EuroQoL 5 Dimension 5 Level (EQ-5D-5L)
- ICEpop CAPability measure for Adults (ICECAP-A)
- Oxford CAPabilities questionnaire-Mental Health (OxCAP-MH)
- The Health Economics Questionnaire (HEQ)
- Young Mania Self-Rating Scale (YMRS)
- Montgomery Asberg Depression Rating Scale (MADRS) at baseline and week 12.
- Quick Inventory of Depressive Symptomatology – Clinician Rated (QIDS-C)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- QIDS-SR: weekly from baseline to week 48
- GAD-7: weekly from baseline to week 48
- SHAPS: baseline and weeks 6 and 12
- WSAS: baseline and weeks 6, 12, 24, 36 and 48
- Pulse and blood pressure: baseline, weeks 2, 6, 12, 24, 36 and 48
- ASRM: weekly from baseline to week 48
- QUIP-RS: baseline and weeks 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48
- TSQM: weeks 6, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48
- EQ-5D-5L: at start of pre-randomisation, baseline and weeks 6, 12, 24, 36 and 48
- ICECAP-A: at start of pre-randomisation, baseline and weeks 6, 12, 24, 36 and 48
- OxCAP-MH: at start of pre-randomisation, baseline and weeks 6, 12, 24, 36 and 48
- HEQ: at start of pre-randomisation, baseline and weeks 6, 12, 24, 36 and 48
- YMRS: baseline and week 12
- QIDS-C: baseline and we |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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