E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The goal of this work is to identify genes associated with good response of bipolar patients to two commonly used mood stabilizing agents, lithium and valproate. 1. All patients will be started on lithium, then enter the maintenance phase where they will be followed for 2 years or until relapse. Those that fail lithium will be crossed over to valproic acid (VPA). Those that fail on VPA will be again crossed-over to a standardized treatment as usual (TAU) arm. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004908 |
E.1.2 | Term | Bipolar affective disorder |
E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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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 |
1. The study will have an algorithmic design. All patients will be started on lithium. Those that fail lithium will be crossed over to valproic acid (VPA). Those that fail that VPA will be again crossed-over to a standardized treatment as usual (TAU) arm.
2. The study will be designed to identify genes for relapse prevention. All patients will be stabilized on lithium monotherapy and then enter the maintenance phase where they will be followed for 2 years or until relapse. On relapse, they are discontinued or crossed over as appropriate.
3. All subjects will be genotyped at 1M single nucleotide polymorphism (SNP) DNA markers for a genomewide association study. The primary outcome measure will be time to relapse. Response and genotype data will be analyzed using survival analysis in order to identify genes whose alleles are associated with longer time to relapse.
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E.2.2 | Secondary objectives of the trial |
Secondary outcomes include studies of sub-phenotypes, co-morbidity and neuropsychological data. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria:
1) Any phase of bipolar I disorder including, depressive, manic, hypomanic, mixed, or baseline/euthymic/not symptomatic,
2) Lithium naïve patients and inadequately past lithium treated patients will be required to have had at least one affective episode in the last 12 months meeting DSM-IV criteria.Current lithium treated patients (CLTPs) will be stable on lithium monotherapy and will be exempted from this criterion if they have had no mood episodes meeting DSM-IV criteria in the last 6 months,
3) Both outpatients and inpatients will be permitted to enroll into this study,
4) Able to give informed consent, in the judgment of the investigator;
5) Age greater than or equal to 18 years;
6) Women of child bearing potential agree to inform their doctor at the earliest possible time of their plans to conceive, and to use adequate contraception (e.g. oral contraceptives, intrauterine device, barrier methods, or total abstinence from intercourse), and to understand the risks of lithium to the fetus and infant. Depo Provera is acceptable if it is started 3 months prior to enrollment;
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E.4 | Principal exclusion criteria |
Exclusion Criteria:
1) Unwilling or unable to comply with study requirements;
2) Renal impairment (serum creatinine >1.5 mg/dL);
3) Thyroid stimulating hormone (TSH) over >20% above the upper normal limit (participants maintained on thyroid medication must be euthyroid for at least 3 months before Visit 1;
4) Other contraindication to lithium,
5) Currently in crisis such that inpatient hospitalization or other crisis management should take priority;
6) Subjects with alcohol/drug dependence who meet criteria for physical dependence requiring acute detoxification
7) Pregnant or breastfeeding;
8) Women of child-bearing potential who aren’t able to agree to the requirements specified above;
9) Those who have participated in a clinical trial of an investigational drug within the past 1 month;
10) Inability to agree to comply with the visit schedule or study procedures;
11) History of lithium toxicity, not due to mismanagement or overdose that required treatment.
12) Current unstable medical condition.
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E.5 End points |
E.5.1 | Primary end point(s) |
Relapse is the primary outcome measure for the study, so its definition and assessment is key. Subjects whose rating scales suggest a relapse will be reviewed using the Mood Episode Checklist that summarizes DSM IV criteria for mania and depression. Relapse will be defined by the following criteria: 1) meets criteria for mania; 2) meets criteria for major depression; 3) meets criteria for a mixed episode. |
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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 | Yes |
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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
crossover if fails on lithium |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |