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 | 9.1 |
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 evaluate the effect of RO4917838 compared to placebo on negative symptoms based on the mean change from baseline in Positive and Negative Syndrome Scale (PANSS) negative factor score after 8 weeks of treatment |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effects of 8 weeks of treatment with RO4917838 relative to placebo on: • Overall symptoms based on the mean change from baseline in total PANSS score • Mean change from baseline for the PANSS subscales and remaining PANSS factors • Negative symptom clinical response based on proportion of patients having a 20% or greater improvement in PANSS negative factor score • Clinical Global scores: CGI-Improvement, CGI-I Improvement in Negative Symptoms, CGI-Severity and CGI-Severity in Negative Symptoms • Cognition status changes based on the Cognitive Battery • Functional response based on the mean change in Personal and Social Performance Scale (PSP) total score • Quality of life based on change in the Schizophrenia Quality of Life Scale (SQLS) • Safety assessments as described in the statistical section • Pharmacokinetics as described in the pharmacokinetics section • Biomarker assessments as described in the biomarker section (BSR)
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
NN20372-RG, version 1 dated Oct 29, 2007: the objective is to obtain a single blood sample from consenting patients enrolled in associated study NN20372 for pharmacogenetic and genetic research analysis.
BSR (included in protocol NN20372) OCT 29, 2007: Blood samples will be taken for the assessment of RNA and proteins. These biomarker samples will be collected to promote, facilitate and improve individualized health care by better understanding/predicting: RO4917838 efficacy, dose responses, safety, RO4917838 mode of action, progression of schizophrenia and associated diseases. closure.
expanded PK sampling (included in protocol NN20372) Oct 29, 2007: Samples will be analyzed for the parent compound, RO4917838, and for metabolites (if possible).
metabolic enzymes and GLYT 1 genotyping (included in protocol NN20372) Oct 29, 2007: a blood sample (3 ml) will be taken for DNA extraction and assessment of CYP3A4*1B, CYP3A5*3, CYP2C9*2, CYP2C9*3, UGT1A1*28, UGT1A9_T-275A, UGT1A9_C-2152T, UGT1A9*3, MDR1 (C1236T_exon 12, G2677T_exon 21, 3435A_exon 26) genotypes. The DNA will be used to determine if alleles affect the pharmacokinetics of RO4917838 and its metabolites. SLC6A9 (the gene which encodes GLYT1) genotype will also be determined. |
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E.3 | Principal inclusion criteria |
1. Capable of providing informed consent and informed consent form signed by the patient before any study assessments are done 2. Age 18-55 3. Males or females. If female must meet one or more of the following: a) surgically sterile b) postmenopausal with spontaneous amenorrhea for the past two years with an FSH level greater than 40 mIU/mL c) agree for the 12 weeks of the study to refrain from heterosexual intercourse or d) agree for the 12 weeks of the study to use one of the following forms of contraception 1) systemic hormonal treatment 2) an IUD which was implanted at least 2 months prior to screening or 3) "double-barrier" contraception (condom, diaphragm and spermicide are each considered a barrier) 4. Has a caregiver or some other identified responsible person (eg, family member, social worker, caseworker or nurse) considered reliable by the investigator in providing support to the patient to help ensure compliance with study treatment, study visits and protocol procedures who preferably is also able to provide input helpful for completing study rating scales. 5. Based on the screening SCID-CT a DSM-IV TR diagnosis of schizophrenia 6. Outpatient with no hospitalization for worsening of schizophrenia within 3 months (hospitalization for social management within this time is acceptable) 7. Medically and psychiatrically stable over the prior 1 month 8. Except for risperidone long-acting, no depot or long-acting antipsychotics or clozapine within 3 months 9. If on risperidone long-acting, no dose change within 3 months 10. For oral antipsychotics, no dose change within 1 month 11. On no more than 2 antipsychotics where risperidone and risperidone long-acting are considered to be two different antipsychotics 12. Antipsychotic regimen: a) Patients must be on a "primary" antipsychotic. Patients may also be on a second antipsychotic. However, if a patient is on a second antipsychotic, by using approximate dose equivalents (explained below), the following will apply: i) The amount of the second antipsychotic must be less than the equivalent dose of the primary antipsychotic ii) The sum of the primary and secondary antipsychotics must be less than or equal to 6 mg of risperidone equivalents b)The five allowed primary antipsychotics are olanzapine, quetiapine, paliperidone, oral risperidone and risperidone long-acting by injection. As a primary agent the allowed ranges are: i) Risperidone 2-6 mg/day or ii) Olanzapine 7.5-20 mg/day or iii) Quetiapine 150-750 mg/day or iv) Paliperidone 3-12 mg/day or v) Risperidone long-acting injection 25-50 mg every 2 weeks c) For patients on a second antipsychotic, [Appendix 3] explains, for each primary antipsychotic regimen, what the allowed second antipsychotics are and the maximum dose of the second antipsychotic. The table considers 4 mg risperidone to be equipotent to 15 mg of olanzapine, 600 mg of quetiapine, 9 mg of paliperidone and 37.5 mg of risperidone long-acting (given every 2 weeks) and that this ratio remains the same for all allowed doses (i.e. 2 mg of risperidone is equipotent to 7.5 mg of olanzapine etc.). (The table is based on J Clin Psych 67:8, August 2006 p1197, Table 1). 13. Total score of 40 or greater on the sum of the 14 negative and disorganized thought/cognition PANSS items in below (items scored 1-7 for a maximum possible score of 98) 14. Total score of 22 or less on the sum of the 8 positive symptoms PANSS factor items
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E.4 | Principal exclusion criteria |
Treatment history 1. Previously received RO4917838 2. Previously entered screening for this study but did not meet inclusion/exclusion criteria based on a screening assessment (see [Table 2]) 3. Participation in a clinical trial within 3 months or more than 2 clinical trials within 12 months 4. ECT within 6 months 5. Lithium, anticonvulsants, or any other agent used as a mood stabilizer within 4 months 6. On more than one antidepressant or if on one antidepressant, a change in dose within 3 months 7. Change in benzodiazepine or sleep medication regimen within 1 month (regimen may be PRN or continuous treatment) 8. Except for medications mentioned above, receiving any other psychotropic or medication used as a psychotropic within 1 month (defined in Concomitant Medications and Treatment section [9]). 9. Change in anti-EPS medication within 2 weeks (see Concomitant Medications and Treatment section [9]) 10.Taking any medication which is an inhibitor or inducer of CYP3A4 (see [Appendix 4] for a list of common medications to exclude) Diagnosis and psychiatric history 11. Based on the screening SCID-CT: a) other current DSM-IV TR Axis I diagnosis requiring exclusion b) alcohol or substance abuse or dependence within 3 months (excluding nicotine) 12. PANSS item G6, depression moderate or worse 13. Urine drug screen detects heroin, amphetamines (including MDMA/ecstasy), cocaine, hallucinogens or PCP 14. In the investigator’s judgment, a significant risk of suicide or violent behavior Past and current medical history 15. History of neuroleptic malignant syndrome 16. A prior or current general medical condition that may be impairing cognition or other psychiatric functioning (e.g. head trauma, dementia, seizure disorder, stroke, neurodegenerative, inflammatory, infectious, neoplastic, toxic, metabolic, endocrine etc.) 17. A movement disorder due to antipsychotic treatment not currently controlled with anti-EPS treatment or another movement disorder which may affect the ratings on the EPS scales (e.g. Parkinson's disease) 18. Pregnant or breastfeeding females 19. Hemoglobin less than 130 g/L (13 g/dL) in males or 120 g/L (12 g/dL) in females 20. History of hemoglobinopathy such as thalassemia major or sickle-cell anemia 21. History of G6PDH (glucose-6-phosphate dehydrogenase) deficiency 22. History of HIV infection, or history of HepB infection within the past year, or history of HepC infection which has not been adequately treated 23. QTc interval greater than 450 msec or other clinically significant abnormality on screening ECG based on centralized reading 24. Clinically significant abnormality on screening blood or urine safety tests which does not improve on retesting (for ALT and AST clinically significant is above twice the upper limit of normal) 25. Gastrointestinal, hepatic or renal disease which may significantly alter the absorption, metabolism or elimination of RO4917838 26. Significant or unstable physical condition which in the investigator’s judgment may require a change in medication or hospitalization within the next 3 months 27. Does not make an effortful attempt to complete the cognition battery at screening as explained in section [11.3.3.5].
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is change from baseline at week 8 in PANSS total score. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
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 |
the followings are investigated in substudies: Biomarkers, genetics, metabolic enzyme, GLYT1 genotyp |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
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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The end of the study will be considered to be the date of the last visit (including the last follow-up visit) of the last patient in the study : section 3.2 - page 19 of the protocol |
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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 | 1 |
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 | 1 |
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 |