E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Schizophrenia characterised by persistent negative symptoms |
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MedDRA Classification |
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 |
Main hypothesis: Augmentation of stable antipsychotic medication with an SSRI antidepressant, citalopram, is clinically and cost effective for ameliorating persistent negative symptoms in schizophrenia and is not associated with an additional side effect burden. |
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E.2.2 | Secondary objectives of the trial |
Objectives of the study: 1. To test the benefits of citalopram, an SSRI antidepressant, for people with schizophrenia and negative symptoms in terms of quality of life and negative symptoms as well as the relative risks and costs of augmenting antipsychotic medication. 2. To extend the current evidence, which indicates that SSRI augmentation in the treatment of schizophrenia acts directly on negative symptoms, has only limited efficacy in treating depressive symptoms, and does not have a detrimental effect on positive symptoms or extrapyramidal side effects. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet the following criteria to be eligible for enrolment: 1. An OPCRIT (Operational Criteria Checklist for Psychosis: 57) diagnosis of schizophrenia, schizophreniform, schizoaffective disorder or psychosis NOS as defined by DSM-IV. 2. A negative subscale score of 20 or more on the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). At least three of the seven items on the negative symptom subscale should be rated 3 or more. Negative symptoms that reflect, sometimes very subtly, manifestations of depressive symptoms, antipsychotic side effects such as bradykinesia, or positive symptoms, are referred to as secondary negative symptoms, and the assessors will attempt to distinguish these from primary negative symptoms. However, persistent negative symptoms will be used as an inclusion criterion rather than primary negative symptoms, as the former are the clinically-relevant target, and the latter represent a hypothesis about aetiology that cannot be definitely determined on cross-sectional assessment. 3. Age 18-65 years, inclusive 4. Clinically stable for the last 3 months with a consistent antipsychotic regimen. 5. Competent and willing to provide written, informed consent. |
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E.4 | Principal exclusion criteria |
Any of the following criteria will exclude a patient from the study: 1. Any medical contraindications to an SSRI antidepressant. 2. Taking any drug that risks interaction with citalopram (see citalopram SmPC and Appendix 3), e.g. pimozide, MAOIs, metoprolol, St John’s Wort (Hypericum perforatum), lithium, tryptophan, anticonvulsants, insulin, other medicines for diabetes, anticoagulants, regular aspirin or non-steroidal anti-inflammatory drugs such as ibuprofen, serotonergic drugs, such as tramadol and sumatriptan including those that may prolong the QT interval e.g. cimetidine, CYP3A4 and 2C19 inhibitors except antipsychotics other than pimozide (See appendix 4 for a full list of drugs other than antipsychotics that are known to prolong the QTc). 3. known QT interval prolongation or congenital long QT syndrome; congestive heart failure, bradyarrhythmias 4. Serum potassium and/or magnesium levels below the lower limits of normal. 5. Currently receiving any antidepressant drug or clinician wants to treat with an antidepressant. 6. Currently fulfil criteria for major depressive disorder; alcohol/substance hazardous use or dependence in past 3 months 7. Pregnancy or planning to become pregnant. 8. Treated with ECT in the last 8 weeks. 9. Cognitive or language difficulties that would preclude subjects providing informed consent or compromise participation in study procedures. 10. Lack of capacity, as judged by the patient’s psychiatrist. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Our primary outcome will be quality-of-life measured at 3 months, assessed using an observer-rated scale, the Heinrich’s Quality of Life Scale (Heinrichs et al 1984). Quality of life over 12 months will be a second primary outcome, alhough as the 3 month point for quality of life is the first primary outcome, there will be some overlap in these analyses. The negative symptoms subscale of the PANSS scale will be a third primary outcome since, from a clinical perspective, reduction in negative symptoms is an important outcome. |
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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) | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
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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The trial will finish at end of the last/final assessment of the last participant in 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 | 4 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 29 |