E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039626 |
E.1.2 | Term | Schizophrenia |
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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 investigate the safety and tolerability of multiple ascending oral doses of AZD3480 when administered to schizophrenic patients on stable antipsychotic monotherapy with either quetiapine, risperidone or olanzapine.
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E.2.2 | Secondary objectives of the trial |
1. To investigate the pharmacokinetic (PK) interaction between AZD3480 and three commonly used antipsychotic drugs. 2. To investigate the dose-concentration-effect relationship by exploring the AZD3480 effect on cognition in schizophrenic patients on stable antipsychotic monotherapy. 3. To explore the effect of AZD3480 on severity of schizophrenic illness. 4. To explore the effect of AZD3480 on antipsychotic drug-related extra pyramidal symptoms (EPS).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For inclusion in the study patients must fulfil all of the following criteria: 1. Patients able to communicate with the study personnel, able to understand and are willing to comply with study procedures, restrictions and requirements. 2. Provision of signed Informed Consent, including genetic sampling for CYP2D6. 3. Genotyped to be rapid metabolisers or slow metabolisers with regard to CYP2D6. Rapid metabolisers, in this study, is defined as individuals with at least one fully functional CYP2D6 allele (CYP2D6*1, CYP2D6*2, CYP2D6*35) on one of the two chromosomes and slow metabolisers as the rest of the genotypes. (Patients receiving potent CYP2D6 inhibitors such as paroxetine and fluoxetine will functionally be characterised as belonging to the slow metaboliser group). 4. Male and female schizophrenic patients, aged 20 to 65 years (inclusive), clinically stable and in the residual (non-acute) phase of their illness for at least 3 months. 5. Receiving treatment with oral quetiapine, risperidone or olanzapine for at least 2 months, at the current dose schedule for at least the last month. 6. At screening, showing not more than “moderate” severity of hallucinations and delusions (PANSS item P3: Hallucinatory Behaviour ≤ 4 , and PANSS item G9: Unusual Thought Content item score ≤ 4), positive formal thought disorder (PANSS item P2: Conceptual Disorganization item score ≤ 4), or negative symptoms (PANSS negative syndrome total score ≤ 22, scale range 1-7). Minimal level of EPS (SAS total score ≤ 6) and depressive symptoms (CDS for Schizophrenia total score ≤ 10). 7. Clinically normal physical findings, including BP, heart rate, baseline ECG and laboratory assessments as judged by the investigator. 8. Documented clinical diagnosis meeting DSM-IV criteria for any of the following: Schizophrenia DSM-IV catatonic 295.20 disorganised 295.10 paranoid 295.30 undifferentiated 295.90 residual 295.60
9. BMI (body weight/height2) 19 to 30 kg/m2.
For inclusion in the additional genetic component of the study, patients must fulfil the following criterion: 1. Provision of informed consent for additional genetic research. If a patient declines to participate in the additional genetic component of the study, there will be no penalty or loss of benefit to the patient and the patient will not be excluded from other aspects of the study described in the Clinical Pharmacology Study Protocol, as long as they have given consent.
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E.4 | Principal exclusion criteria |
Any of the following is regarded as a criterion for exclusion from the study: 1. Clinically significant illness, apart from schizophrenia, within the two weeks prior to the first dose of the investigational product, including a suspected/manifested infection according to World Health Organisation (WHO) risk categories 2, 3 or 4, as judged by the investigator. 2. Diagnosis of any DSM-IV Axis I disorder other than those included in inclusion criteria (3) above (eg, alcohol dependence or psychoactive substance dependence not in full remission, concurrent organic mental disorder, schizophreniform and schizoaffective disorder) or mental retardation, of a degree that may interfere with the patient’s ability to co-operate. 3. History of clinically significant cardio-or cerebrovascular, pulmonary, renal, hepatic, neurological, mental (apart from schizophrenia), heamatologic or gastrointestinal disorder or any other major disorder that may interfere with the objectives of the study, as judged by the investigator. 4. ECG result considered showing clinically significant abnormality as determined by an experienced cardiologist. 5. QT interval corrected for heart-rate, where the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle (QTc) Bazett >450 ms taken from the ECG at baseline as determined by an experienced cardiologist. 6. A patient with diabetes mellitus (DM) fulfilling one of the following criteria (Note: If a diabetic patient meets one of these criteria the patient will be excluded even if the treating physician believes that the patient is stable and can participate in the study): -unstable DM defined as enrolment glycated haemoglobin A1c (HbA1c) >8.5% - admitted to hospital for treatment of DM or DM related illness in the past 12 weeks - not under care of physician responsible for patient’s DM care - physician responsible for patient’s DM care has not indicated that the patient’s DM is controlled - physician responsible for patient’s DM care has not approved patient’s participation in the study - has not been on the same dose of oral hypoglycemic drug(s) and/or diet for the last 4 weeks prior to enrolment. For thiazolidinediones (glitazones) this period should not be less than 8 weeks - taking insulin where the daily dose on one occasion has been more than 10% above or below the patient’s mean dose in the 4 weeks preceding enrolment. 7. Known or suspected drug or alcohol abuse or positive drugs of abuse test as judged by the investigator. 8. Patient who has received any investigational drug and/or has participated in a clinical study during the last 3 months before first administration of investigational drug. 9. Donation of blood within 3 months prior to enrolment. 10. Donation of plasma within 14 days prior to enrolment. 11. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity (except for seasonal hay fever) as judged by the investigator. 12. Excessive use of caffeine containing drinks (equivalent to more than 5 cups of coffee per day). 13. Pregnancy or lactation. Female patients must not be at risk of pregnancy and must use a reliable method of birth control, ie, double barrier method, oral contraceptive, implant, long-term injectable contraceptive, intrauterine device, or tubal ligation. 14. Patients injected with depot antipsychotic drugs during the last 3 months, including depot, risperidone and olanzapine. 15. Previous bone marrow transplant. 16. Whole blood transfusion within 120 days prior to enrolment. 17. Intake of alcohol within 48 hours prior to visit 2. 18. Patients on anticholinergic medication for treatment of EPS for a treatment period of less than two weeks before randomisation. 19. Use of any prescribed or non-prescribed (OTC) medication and/or herbal medication (eg, St Johns Wort) that could possibly interfere with the objectives of this study (eg, drugs inducing or inhibiting the potential of drug metabolic enzymes or transporter proteins or drugs with sedative components that might confound cognition tests) during the 3 weeks prior to the first administration of the investigational product (or 5 half-lives of the compound, whichever is the longer) until the follow-up visit are not allowed. However, paracetamol (acetaminophen) may be administered (up to a maximum dose of 3 g/day) for headache and other benign pain, and OTC adrenergic nasal spray medication will be allowed for the relief of nasal congestion.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints:
Safety & tolerability: laboratory assessments, vital signs, physical examination, concomitant medication and adverse events (AEs)
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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 | 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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End of trial is defined in the protocol as last database lock (the timepoint after which no patient will be exposed to study related activities). There will be separate database locks for each group of concomitant antipsycotics when completed. |
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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 | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 6 |