E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to moderate Alzheimer’s Disease |
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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 | 10001896 |
E.1.2 | Term | Alzheimer's disease |
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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 primary objective is to evaluate efficacy of 24 weeks treatment of 3 - 4 fixed doses of RO5313534 (1, 5, 15 mg/day with an option of 30 mg/day) added to donepezil (5 or 10 mg/day) on cognitive endpoint (measured with the ADAS-Cog) as compared to placebo added to donepezil. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the tolerability and safety 2. To evaluate efficacy on behavioral, global and functional endpoints 3. To evaluate on cognitive endpoints measured with the cognitive battery CANTAB (The Cambridge Neuropsychological Test Automated Battery) 4. To evaluate maintenance of efficacy (primary and secondary variables) 4 weeks after discontinuation of treatment 5. To investigate by a population PK analysis approach the pharmacokinetics of RO5313534 in the target population, including the influence of covariates such as age, gender, body-weight and renal function. 6. To explore the relationship between PK exposure and response using population PK-PD methods. 7. To evaluate whether the genetic markers of APOEε4, Nicotinic alpha7 and duplicated alpha 7 are predictive of response to RO5313534 treatment.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Probable AD, based on the NINCDS/ADRDA and DSM-IV criteria. 2. Males, females of non-childbearing potential (more than two years after the cessation of menses or surgically sterile by means of hysterectomy, bilateral oopherectomy or tubal ligation). Additional blood tests will be done if required by the local regulations/guidelines/EC/IRB for further confirmation of non-childbearing potential. 3. Age range: 50-85 years of age at the time of screening visit. 4. Non smokers and not using nicotine-containing products for at least 3 months prior to baseline. 5. Have a MMSE score at screening between 13 and 22 inclusive. 6. Have a Modified Hachinski Ischemia Scale score of ≤ 4 (see Appendix 5) 7. Are under stable donepezil treatment given at a fixed dose either 5 or 10 mg daily for at least 4 months prior to baseline. 8. Adequate vision & hearing (physical ability to perform all the study assessments). 9. Not requiring nursing home care. 10. Have a caregiver or some other identified responsible person (e.g., family member, social worker, caseworker or nurse) who is considered reliable by the Investigator to provide support to the patient to ensure compliance with study treatment, accompany patient to study visits and help with protocol procedures, and who is also able and willing to provide input for completing the caregiver scales and sign the caregiver consent form. 11. Are cooperative, willing and able to complete all aspects of the study, and capable of doing so either alone or with the help of a responsible caregiver. 12. Signed a written consent for participation in the study (co-signed by the patient’s next of kin or caregiver, if required by the local regulations/guidelines/EC/IRB). |
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E.4 | Principal exclusion criteria |
1. Dementia due to condition other than AD 2. Other significant neurological disorder, including seizures, stroke (patients found with clinically silent lacunar stroke at MRI or CT may be allowed if the lesion is unique, ≤1 cm in max. diameter and not located in any of the following regions: hippocampus of either hemisphere, head of the left caudate, dorsomedial region of the left thalamus) a history of head traumatism (resulting in hospitalization), Parkinson’s disease (as a primary diagnosis) 3. Background of mental retardation 4. Untreated/non stabilized Major Depressive Disorder (DSM-IV) 5. Bipolar disorder, schizophrenia or any serious psychiatric condition (Axis I Disorder, DSM-IV-TR) 6. At risk of suicide in opinion of the investigator 7. Uncontrolled behavioral symptoms incompatible with compliance or evaluability: e.g. severe agitation, lack of impulse control, violence, severe dysphoria 8. Alcohol and/or substance abuse or dependence (DSM –IV) in the past 2 yrs 9. Unstable or poorly controlled hypertension 10. Unstable or clinically significant cardiovascular disease that could be expected to progress, recur or change during study period to such an extent that it could bias assessment of the clinical or mental status of the patient. 11. Patients with a screening QTcF >450 msec (males) or >470 msec (females), based on the average interval on triplicate ECGs obtained after 5 minutes rest in a supine position using a digital ECG machine algorithm. 12. Screening AST, ALT or total bilirubin ≥2 times the upper limit of normal (ULN) which is still ≥2 times ULN when retested. 13. Screening creatinine clearance <30 mL/min as calculated by the central lab using the Cockcroft-Gault formula, which remains <30 mL/min when retested. 14. History of HIV infection, history of Hep B infection within the past year, or history of Hep C infection. 15. Hep B surface Antigen and/or Hep C core antibodies positivity at screening 16. Screening thyroid function tests (TSH, free T3, free T4) that are clinically significantly abnormal (taking into account prior results and treatments) . 17. Screening folic acid or B12 levels that are clinically significantly abnormal (taking into account prior results and treatments). 18. Poorly controlled diabetes (Hb1Ac≥ 9% at screening) 19. BMI >36 at screening. 20. History of cancer with survival expected to be less than 3 yrs or within the next 3 yrs may require systemic treatment. Except for localized, non recurrent treated skin cancer and stabilized prostate adenocarcinoma, i.e.: patients stable w/o treatment or under hormone therapy for at least 6 mo., these patients must be individually approved by the Study science leader. 21. Any other medical condition not previously mentioned that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical or mental status of the patient to a significant degree or put the patient at special risk 22. Clinically significant abnormal blood or urine safety tests which do not improve when retested. 23. Positive result for either drug of abuse, alcohol breath test or continine test at screening. 24. Recent (within 60 days of screening) intake of investigational drug or prior intake of (RO5313534) 25. Does not make an effortful attempt to perform the cognition batteries (at screening) 26. Treatment for Alzheimer’s disease other than donepezil, i.e. •Rivastigmine, galantamine or memantine within 6 mo. before baseline are not permitted •Nutritional supplements used at doses higher than Recommended Daily Intake as assessed by the investigator, Ginkgo, huperizine, lecithin within 2 wks before baseline are not permitted •Estrogen hormone replacement, NSAIDs within 2 wks before baseline are not permitted (both are permitted if used to treat conditions other than AD) 27. Psychotropic medication: •Antidepressants use (SNRIs, MAOIS and tricyclics) within 2 wks before screening are not permitted, except antidepressant medication with minimal or no anticholinergic effects, •Anti-psychotic use within 4 wks before screening are not permitted except haloperidol at a max dose of 1 mg/day, or risperidone 1 mg/day or quetiapine at the max dose of 100mg/day •Anxiolytics/Hypnotics use within 2 wks before screening are not permitted except for •Benzodiazepines of short half life (such as lorazepam or alprazolam) for anxiety/sleeping disorders, if the patient is on stable dosage and regimen on them for at least 1 mo. prior to baseline. •Zolpidem, zopiclone for insomnia, if the patient is on stable dosage and regimen on them for at least 1 mo. prior to baseline •Anticonvulsant except those prescribed for neuropathic pain, anti-parkinson, opioid within 2 wks before screening are not permitted •Anticholinergics/antihistaminics within 8 wks before screening are not permitted, except non sedating antihistaminic medications (i.e. w/o anticholinergic effects such as cetirizine) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the ADAS-Cog score change from baseline at week 24 |
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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 | Yes |
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 | 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) | 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 | 30 |
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. |
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |