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 |
Bipolar disorder is a common psychiatric disorder, formerly known as manio-depressive disorder.It has a life-long course characterized by high risk of recurrence of manic and depressive episodes. |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004935 |
E.1.2 | Term | Bipolar affective disorder, unspecified |
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 |
The objective of the present study is to conduct an RCT investigating whether add-on low-dose Aspirin versus placebo add-on to standard treatment improves mood stabilization and other critical patient outcomes in subjects with BD, and whether its principal effects are antimanic, antidepressant or prophylactic against relapse.
Primary hypothesis: Add on low dose aspirin versus placebo to standard treatment improves mood stabilization in BD |
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E.2.2 | Secondary objectives of the trial |
Secondary hypothesis: II. Associations between inflammatory markers and BD and treatment allocation a. Baseline inflammatory marker levels (hsCRP, cytokines ( IL-6, IL-10, IL-18, TNFr-alpha, etc., and hsCRP) and other inflammation-related biomarkers (oxidative stress, hair cortisol and gut microbiome composition) predict or moderate clinical improvement following treatment with low dose aspirin vs. placebo at t=3 months and t=6 months b. Changes in inflammatory markers represent indirect mediators of response, i.e. 1) allocated treatment affect inflammatory markers levels at t=3 months and t=6 months, and 2) inflammatory markers changes at t=3 months and t=6 months are associated with clinical outcome measures.
III. Allocated treatment (low-dose aspirin versus placebo) improves cognition at t=3 months and t=6 months compared to t=0.
IV. Baseline (before randomization) inflammatory marker levels are increased or altered in BD patients compared to HC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Bipolar disorder (type 1 or 2), with diagnoses confirmed by SCAN interview. - Age 18-65 years - Speaks and writes Danish at a level equal to mother tongue - Habile (i.e. able to give informed consent) |
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E.4 | Principal exclusion criteria |
- Chronic kidney disease with GFR 0-10 ml/min - Severe cardiac insufficiency (NYHA IIIb-IV) - History of gastric ulcers, gastro-intestinal bleeding or other pathological bleeding tendency (thrombocytopenia, hemophilia, vitamin K deficiency) - Asthma or other allergic symptoms developed after intake of salicylates, paracetamol or other NSAID or any of the excipients - Patients already on aspirin or other NSAID, anticoagulants or SSRIs. - For fertile females: o Reluctance to use effective contraception (IUD or hormonal contraception) during enrollment, including a safety period of one week following last medication day/trial completion o Pregnancy; pregnancy ruled out by HCG test before enrollment o Breastfeeding - Planned major surgery during trial period . If a subject has scheduled major surgery (i.e. with bleeding risk), enrollment will be postponed until this is completed
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E.5 End points |
E.5.1 | Primary end point(s) |
Mood stabilization will be measured by a mood instability score reflecting the daily variability in self-monitored mood as described in section |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Trial participation will include three visits (with an optional fourth visit for a subgroup of patients): An assessment at inclusion/baseline (T=0), one after three months (T=3), one after six months (T=6), and, for a subset of patients enrolled within the first trial year, we will also include an assessment at twelve months (T=12). Scheduling of the visits will be done as follows: T=0: Represents enrollment/baseline. The first trial week (week 1) begins immediately after enrollment. T=3: Can be scheduled in trial week 11-13, i.e. a two-week interval placed midway. T=6: Can be sheduled in trial week 23-25 T=12: Can be scheduled in trial week 47-49
The primary end point will be evaluated at T=3, T=6 and T=12
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E.5.2 | Secondary end point(s) |
Secondary/additional endpoints:
2. Associations between inflammatory markers and BD and treatment allocation: Level of inflammatory activity will be assessed by measuring inflammatory blood marker levels and other inflammation-related biomarkers (urinary oxidative stress, hair cortisol and gut microbiome composition): - Blood based biomarkers: High sensitive CRP (hsCRP), IL-6, IL-10, IL-18, TNF-alpha and BDNF. - Other inflammation-related biomarkers: o Urinary oxidative stress biomarker levels (oxidized nucleosides 8-oxodG and 9-oxoGuo) o Gut microbiome composition o Hair cortisol concentration
3. Allocated treatment (low-dose aspirin versus placebo) improves cognition at t=3 months and t=6 months compared to t=0 Cognition will be assessed by neuropsychological testing according to our newly developed Internet-based Cognition Assessment Tool (ICAT), which is self-administered by trial subjects in their home setting at start, midway and end of the RCT. The ICAT contains a set of five short tasks, representing different cognitive domains. Each subtest/task results in a score summing up to a total score.
4. Baseline (before randomization) inflammatory marker levels are increased or altered in BD subjects compared to healthy controls As described above
5. Additional endpoints a. Self-rated or observer-rated - Other daily self-reported smartphone-based data including daily activity level and sleep, as recently reported - Clinically rated observer-based scores at start, midway and end of the 6-month trial on the following three scales: Hamilton Depression Scale-6 items (HAM-D6) (being more sensitive in RCTs than the HAM-D17, the Young Mania Rating Scale (YMRS) and the Functional Assessment Short Test (FAST) (a 24-item interviewer-administered interview concerning autonomy, occupational functioning, cognitive functioning, financial issues, interpersonal relationships and leisure time) - Self-assessed scores on the following questionnaires: Quality of life according to WHO Quality of Life-BREF (WHOQoL), general well-being according to the WHO (Five) well-being index and perceived stress according to Cohen’s Perceived stress scale (PSS). b. Automatically smartphone-generated data on: - Physical activity measured by an accelerometer every 5 min - Social activity expressed as numbers of outgoing and incoming calls and text messages/24h - Voice features like variance, pitch etc., defined numerically, as described by Faurholt-Jepsen et al. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary end points will be evaluated at T=3, T=6 and T=12 with baseline values at T=0 as reference |
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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 | No |
E.6.5 | Efficacy | No |
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) | 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 | 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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | No |
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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Definition of the end of trial is the last visit of the last subject |
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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 |