A Study of RO4602522 in Participants With Moderate Severity Alzheimer Disease on Background Alzheimer Disease Therapy

Study Overview
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Brief Summary
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This Phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled study will evaluate the efficacy and safety of RO4602522 in participants with moderate severity Alzheimer's disease. Participants who are taking background therapy of acetylcholinesterase inhibitors (AChEI) alone or in combination with memantine for at least 4 months before screening will be randomized to receive either one of two doses of RO4602522 or placebo for 12 months.

Official Title
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A Phase II, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Efficacy and Safety of RO4602522 Added to Background Alzheimer's Disease Therapy in Patients With Moderate Severity Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: RO4602522
* Drug: Placebo
* Drug: Donepezil
* Drug: Memantine
* Drug: Rivastigmine
* Drug: Galantamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Probable Alzheimer disease, based on the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) and Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV-TR) criteria Mini-Mental State Exam (MMSE) score at screening between 13 and 20, inclusive Body mass index (BMI) between 18 and 36 kilograms per square meter (kg/m^2) (inclusive) at screening Modified Hachinski Ischemia Score of less than or equal to (</=) 4 Participants with Cornell Scale for Depression in Dementia (CSDD) scores </= 13 at screening Receiving treatment with donepezil, rivastigmine, galantamine or any AChEIs in combination with memantine for at least 4 months before screening, with their dose and formulation stabilized at least 3 months before screening. All formulation and dosages are allowed except donezepil 23 mg (alone or in combination) Females of childbearing potential must have a negative pregnancy test and must agree to use effective contraception Generally healthy and ambulatory or ambulatory-aided (i.e., walker or cane) Have a reliable caregiver or some other identified responsible person who has frequent contact with the participant Exclusion Criteria: Any neurological or psychiatric condition that may occur currently or during the course of the study that can impair cognition or functioning that is not associated with Alzheimer's disease Background of mental retardation Uncontrolled behavioral symptoms incompatible with compliance or evaluability Alcohol and/or substance abuse or dependence (DSM-IV-TR) in the past 2 years, except nicotine use which is allowed. However, smokers treated with nicotine replacement therapy or bupropion are excluded Unstable or poorly controlled hypertension as assessed by the investigator regardless of whether or not the participant is taking antihypertensive medications 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 the assessment of the clinical or mental status of the participant Inadequate hepatic, renal or thyroid function Positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection Poorly controlled diabetes (glycosylated hemoglobin [HbA1c] greater than or equal to [>/=] 9 percent at screening) Requiring nursing home care. Participants living in assisted living facilities are allowed if a reliable caregiver is available (see inclusion criteria) Current treatment for Alzheimer's disease other than those listed in inclusion criteria Participation at any time in an active Alzheimer's disease vaccine study Participation in a passive Alzheimer's disease immunization study less than 1 year before screening except for a) participants where documented medical history indicate that they were randomized to the placebo group in these studies, b) participants treated with bapineuzumab where a 6-month exclusion period applies Recent (</= 12 weeks) or concomitant use of other Monoamine oxidase inhibitors (selective or not) including selegiline or rasagiline Antidepressant treatments are not allowed except for citalopram up to 20 mg daily, escitalopram up to 10 mg daily, paroxetine up to 30 mg daily, sertraline up to 100 mg daily and trazodone up to 100 mg daily. If treated with one of these antidepressants, the treatment should be present for at least 6 weeks at screening. All other antidepressants including other SSRIs, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), St. John's wort and bupropion are excluded Anti-psychotic use within 4 weeks before screening is not permitted except risperidone up to 1.5 mg/day, quetiapine up to 100 milligrams per day (mg/day), olanzapine up to 5 mg/day, and aripiprazole up to 10 mg daily Anxiolytics/ hypnotics use is not permitted except for benzodiazepines of short or intermediate half-life for anxiety/sleeping disorders. Zolpidem (up to 5 mg/day), zopiclone (up to 7.5 mg/day), eszopiclone (up to 2 mg/day), trazodone (up to 50 mg/day, at bedtime) or zaleplon (up to 5 mg/day) is permitted for insomnia Anti-Parkinson's agents within 2 weeks before screening are not permitted Recent (less than 4 weeks prior to screening) or concomitant use of anticonvulsants Anticholinergics/ antihistaminics within 2 weeks before screening are not permitted, except i) if used episodically more than 3 days before the screening cognitive measurement, ii) non-sedating antihistaminic medications (without anticholinergic effects such as cetirizine) or peripheral anticholinergics without central anticholinergic effects (such as, trospium for the treatment of hyperactive bladder), which are permitted Recent (less than 1 week prior to screening) or concomitant use of opioid drugs (tramadol, methadone, propoxyphene, or meperidine), cyclobenzaprine and dextromethorphan Concomitant use of sympathomimetic drugs, including sympathomimetics in local anesthetics and ephedra supplements

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo as add-on to a background therapy of AChEI (donepezil, rivastigmine, or galantamine) alone or in combination with memantine. | Drug: Placebo<br>* Participants will receive placebo for RO4602522 orally once daily for 12 months.<br>Drug: Donepezil<br>* Stable dose as background medication<br>Drug: Memantine<br>* Stable dose as background medication in combination with AChEIs<br>Drug: Rivastigmine<br>* Stable dose as background medication<br>Drug: Galantamine<br>* Stable dose as background medication<br>|
| Experimental: RO4602522 1 milligram (mg)<br>Participants will receive RO4602522 1 mg as add-on to a background therapy of AChEI (donepezil, rivastigmine, or galantamine) alone or in combination with memantine. | Drug: RO4602522<br>* Participants will receive RO4602522 orally once daily for 12 months.<br>Drug: Donepezil<br>* Stable dose as background medication<br>Drug: Memantine<br>* Stable dose as background medication in combination with AChEIs<br>Drug: Rivastigmine<br>* Stable dose as background medication<br>Drug: Galantamine<br>* Stable dose as background medication<br>|
| Experimental: RO4602522 5 mg<br>Participants will receive RO4602522 5 mg as add-on to a background therapy of AChEI (donepezil, rivastigmine, or galantamine) alone or in combination with memantine. | Drug: RO4602522<br>* Participants will receive RO4602522 orally once daily for 12 months.<br>Drug: Donepezil<br>* Stable dose as background medication<br>Drug: Memantine<br>* Stable dose as background medication in combination with AChEIs<br>Drug: Rivastigmine<br>* Stable dose as background medication<br>Drug: Galantamine<br>* Stable dose as background medication<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Behavior Subscale (ADAS-Cog-11) Score at Month 12 |  | Baseline, Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Response, Defined as an Increase From Baseline of Less Than or Equal to (<=) 4 Points in ADAS-Cog-11 |  | Baseline, Month 12 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Scale Score at Month 12 |  | Baseline, Month 12 | 
| Change From Baseline in Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) Score at Month 12 |  | Baseline, Month 12 | 
| Percentage of Participants With Worsening in BEHAVE-AD-FW Score |  | Baseline to Month 12 | 
| Change From Baseline in Apathy Evaluation Scale (AES) Score at 12 months |  | Baseline, Month 12 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Scale Score at 12 months |  | Baseline, Month 12 | 
| Percentage of Participants With Worsening in ADCS-CGIC Score |  | Baseline to Month 12 | 
| Change From Baseline in Global Deterioration Scale (GDS) Score at 12 months |  | Baseline, Month 12 | 
| Change From Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) Score at 12 months |  | Baseline, Month 12 | 
| Percentage of Participants with Adverse Events |  | Baseline up to 13 months | 
| Percentage of Participants with Change in Lens Opacity Grading |  | Baseline; Months 6, and 12 | 
| Percentage of Participants with Abnormal Visual Acuity Test Results |  | Baseline, Months 6, and 12 | 
| Change From Baseline in Michigan Neuropathy Screening Instrument Score |  | Baseline, Weeks 8, 18, 30, 44, 52, and at the last follow-up visit (12 weeks after last dose, up to 64 weeks) | 
| Percentage of Participants Receiving Concomitant Medications |  | Baseline to 13 Months | 
| Apparent Total Clearance of the Drug From Plasma After Administration of RO4602522 |  | Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364 | 
| Apparent Volume of Distribution at Steady State after Administration of RO4602522 |  | Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364 | 
| Area Under the Plasma Concentration-Time Curve of RO4602522 |  | Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364 | 
| Maximum Plasma Concentration of RO4602522 |  | Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364 |