Clinical trial NCT01852110: Efficacy and Safety of MK-7622 as Adjunct Therapy in Participants With Alzheimer's Disease (MK-7622-012)
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer's Disease
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2013-05-13
Enrollment: 240
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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)
timeFrame: Baseline and week 12
measure: Change From Baseline in ADAS-Cog11 Score at Week 12 (Stage 2, MK-7622 45 mg and 15 mg Versus Placebo)
timeFrame: Baseline and week 12
measure: Number of Participants Experiencing an Adverse Event (AE)
timeFrame: Up to 26 weeks
measure: Number of Participants Who Discontinued Study Drug Due to an AE
timeFrame: Up to 24 weeks
Secondary outcomes:
measure: 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)
timeFrame: Baseline and week 24
measure: Change From Baseline in Composite Cognition Score-3 Domain (CCS-3D) at Week 12 (Stage 1, MK-7622 45 mg Versus Placebo)
timeFrame: Baseline and week 12
measure: Change From Baseline in CCS-3D at Week 12 (Stage 2, MK-7622 45 mg and 15 mg Versus Placebo)
timeFrame: Baseline and Week 12
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Voss T, Li J, Cummings J, Farlow M, Assaid C, Froman S, Leibensperger H, Snow-Adami L, McMahon KB, Egan M, Michelson D. Randomized, controlled, proof-of-concept trial of MK-7622 in Alzheimer's disease. Alzheimers Dement (N Y). 2018 Apr 26;4:173-181. doi: 10.1016/j.trci.2018.03.004. eCollection 2018.