Efficacy and Safety of MK-7622 as Adjunct Therapy in Participants With Alzheimer's Disease (MK-7622-012)

Study Overview
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Brief Summary
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The purpose of this multicenter trial is to assess the efficacy and safety of MK-7622 compared with placebo as adjunctive therapy to acetylcholinesterase inhibitors (AChEIs) for the symptomatic treatment of participants with mild to moderate Alzheimer's Disease (AD). The trial consists of two stages: Stage 1 and Stage 2. In Stage 1, participants will be randomized to receive either placebo or MK-7622 45 mg once daily. In Stage 2, participants will be randomized to receive either placebo or MK-7622 (dose: 5, 15 or 45 mg once daily). Participants will be enrolled in only one stage; the duration of each stage is approximately 26 weeks. Interim analyses will be performed in both Stage 1 and Stage 2 to determine whether the trial should continue. The primary study hypotheses are the following: Stage 1 - MK-7622 45 mg once daily is superior to placebo with respect to improving cognition in participants with mild to moderate AD as assessed by mean change from baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) at Week 12; Stage 2 - At least one of the top two doses of MK-7622 (15 mg once daily, 45 mg once daily) is superior to placebo with respect to improving cognition in participants with mild to moderate AD as assessed by mean change from baseline in ADAS-Cog11 at Week 12.

Detailed Description
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If the double-blind treatment dose is not tolerated during the first 2 weeks, the participant will be discontinued. After the first 2 weeks, if the dose is not tolerated, the regimen may be modified according to a defined algorithm. Specifically, the participant will begin administration of a reduced dose for up to 2 weeks, followed by a re-challenge at the original dose only if tolerability issues diminish or resolve at the reduced dose.

Official Title
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A Seamless Phase IIa/IIb, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial to Evaluate the Efficacy and Safety of MK-7622 as an Adjunctive Therapy for Symptomatic Treatment in Subjects With Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: MK-7622
* Drug: Placebo
* Drug: AChEI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD AD is of mild to moderate severity Clear history of cognitive and functional decline over at least one year that is either a) documented in medical records or b) documented by history from an informant who knows the participant well On a stable and effective daily dose of AChEI (either donepezil, rivastigmine, or galantamine), for at least two months before Screening, and willing to remain on the same dose for the duration of the trial. Effective doses are considered to be: donepezil, 10 mg total daily dose administered orally; rivastigmine, 9.5 or 13.3 mg/24 hours administered by transdermal patch or 6-12 mg total daily dose administered orally; galantamine, 16-24 mg total daily dose administered orally Able to read at a 6th grade level or equivalent, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation Have a reliable and competent trial partner who must have a close relationship with the subject Exclusion Criteria: History of clinically significant stroke Evidence of a neurological disorder other than the disease being studied (i.e., probable AD) History of seizures or epilepsy within the last 5 years before Screening Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission Is at imminent risk of self-harm or of harm to others History of alcoholism or drug dependency/abuse within the last 5 years before Screening Does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at Screening History of hepatitis or liver disease that has been active within the six months prior to Screening Visit Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that participation in the trial would pose a significant medical risk to the participant. Controlled co-morbid conditions are not exclusionary if stable within three months of the Screening Visit History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes History of malignancy occurring within the five years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma which has been treated with potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy Clinically significant vitamin B12 deficiency, or increased thyroid stimulating hormone (TSH) in the six months before Screening Major surgery within 3 months of Screening

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-7622 High Dose - 45 mg (Stage 1)<br>Single 45 mg MK-7622 capsule once daily, taken orally. Dose escalated as follows: 15 mg MK-7622 once daily for 1 week; 30 mg MK-7622 once daily for 1 week; and 45 mg MK-7622 once daily for the remainder of treatment. | Drug: MK-7622<br>* MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|
| Placebo Comparator: Placebo (Stage 1)<br>Matching placebo to MK-7622 capsule once daily, taken orally. | Drug: Placebo<br>* Matching placebo to MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|
| Experimental: MK-7622 Low Dose - 5 mg (Stage 2)<br>Single 5 mg MK-7622 capsule once daily, taken orally. | Drug: MK-7622<br>* MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|
| Experimental: MK-7622 Mid Dose - 15 mg (Stage 2)<br>Single 15 mg MK-7622 capsule once daily, taken orally. | Drug: MK-7622<br>* MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|
| Experimental: MK-7622 High Dose - 45 mg (Stage 2)<br>Single 45 mg MK-7622 capsule once daily, taken orally. Dose escalated as follows: 15 mg MK-7622 once daily for 1 week; 30 mg MK-7622 once daily for 1 week; and 45 mg MK-7622 once daily for the remainder of treatment. | Drug: MK-7622<br>* MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|
| Placebo Comparator: Placebo (Stage 2)<br>Matching placebo to MK-7622 capsule once daily, taken orally. | Drug: Placebo<br>* Matching placebo to MK-7622 capsule<br>Drug: AChEI<br>* One of the following AChEIs, as prescribed by the participant's primary care physician: Donepezil: 10 mg total daily dose, administered orally Rivastigmine: 9.5 or 13.3 mg/24 hours, administered by transdermal patch; or 6-12 mg total daily dose administered orally Galantamine: 16-24 mg total daily dose, administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 11-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at Week 12 (Stage 1, MK-7622 45 mg Versus Placebo) | Mean change from baseline at week 12 was assessed for ADAS-Cog11 score. ADAS-Cog11 measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog11 score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog11 score. | Baseline and week 12 | 
| Change From Baseline in ADAS-Cog11 Score at Week 12 (Stage 2, MK-7622 45 mg and 15 mg Versus Placebo) | Mean change from baseline at week 12 was assessed for ADAS-Cog11 score. ADAS-Cog11 measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog11 score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog11 score. | Baseline and week 12 | 
| Number of Participants Experiencing an Adverse Event (AE) | The number of participants experiencing an adverse event (AE) was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE. | Up to 26 weeks | 
| Number of Participants Who Discontinued Study Drug Due to an AE | The number of participants discontinuing study drug due to an AE was assessed. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in CCS-3D at Week 12 (Stage 2, MK-7622 45 mg and 15 mg Versus Placebo) | CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline. | Baseline and Week 12 | 
| Change From Baseline in Composite Cognition Score-3 Domain (CCS-3D) at Week 12 (Stage 1, MK-7622 45 mg Versus Placebo) | CCS-3D is composed of individual cognitive tests, grouped into 3 domains: 1) episodic memory; 2) executive function; and 3) attention/processing speed. For each cognitive test, a z-score (Z) is calculated at each time point [Z = (observed value - study population mean at baseline) / study population standard deviation at baseline]. These individual Zs are first combined into domain-specific Zs, and then into a composite Z, (i.e. CCS-3D). Theoretically, 99.9% of CCS-3D will be ± 3; more positive CCS-3D indicate greater cognitive impairment relative to the total study population at baseline. Further, negative changes in CCS-3D over time indicate improved cognition relative to the total study population at baseline. | Baseline and week 12 | 
| Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) at Week 24 (Combining Stage 1 and 2, MK-7622 45 mg Versus Placebo) | Mean change from baseline at week 24 was assessed for ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with potential total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. | Baseline and week 24 |