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An Efficacy and Safety Trial of Verubecestat (MK-8931) in Mild to Moderate Alzheimer's Disease (P07738) (EPOCH)

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ClinicalTrials.gov Identifier: NCT01739348
Recruitment Status : Terminated
First Posted : December 3, 2012
Results First Posted : May 16, 2018
Last Update Posted : May 16, 2018
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition: Alzheimer's Disease
Interventions: Drug: Verubecestat (Part I and Part II)
Drug: Placebo (Part I)
Drug: Verubecestat (Part II)

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Part I began by enrolling approximately 50 participants per arm (200 total). Enrollment continued until the first 200 participants reached 13 weeks treatment; total enrollment at that time: ~400. For these ~400 participants (Safety Cohort), an interim analysis (IA) was conducted to assess safety. Following IA, enrollment continued (Main Cohort).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
2211 participants were randomized in Part I, with 2210 receiving treatment. As planned per protocol, no participants were randomized to the Verubecestat 60 mg arm (Arm C) in the Main Cohort. Participants completing Part I were eligible to continue to Part II. The trial was terminated early and did not complete as planned.

Reporting Groups
  Description
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.

Participant Flow for 2 periods

Period 1:   Part I (Base Study)
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]   Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]   Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]   Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
STARTED   703   700   103   705 
Treated   702   700   103   705 
COMPLETED   501   497   77   516 
NOT COMPLETED   202   203   26   189 
Adverse Event                41                52                8                33 
Death                10                7                2                8 
Lack of Efficacy                3                8                0                7 
Lost to Follow-up                4                2                4                4 
Non-Compliance with Study Drug                3                2                0                0 
Physician Decision                10                7                1                4 
Protocol Violation                2                0                1                2 
Screen Failure                2                0                0                0 
Site Discontinued Study Participation                1                3                0                0 
Study Terminated by Sponsor                72                73                0                86 
Participant Moved                4                3                1                7 
Trial Partner/Caregiver Withdrew Consent                27                25                2                18 
Withdrawal by Subject                23                21                7                20 

Period 2:   Part II (Extension Study)
    Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]   Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]   Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]   Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
STARTED   379 [1]   366 [1]   61 [1]   396 [1] 
Treated   379   365   61   394 
COMPLETED   0   0   0   0 
NOT COMPLETED   379   366   61   396 
Adverse Event                10                11                7                26 
Death                3                3                2                6 
Lack of Efficacy                1                5                0                1 
Lost to Follow-up                3                4                0                1 
Non-Compliance with Study Drug                0                0                0                1 
Physician Decision                7                11                6                12 
Study Terminated by Sponsor                329                315                34                323 
Participant Moved                3                3                0                3 
Trial Partner/Caregiver Withdrew Consent                18                12                8                16 
Withdrawal by Subject                5                2                4                7 
[1] Number started refers only to participants completing Part I, volunteering to continue to Part II.



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All randomized participants in Study Part I (Base Study)

Reporting Groups
  Description
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II] [Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II] [Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II] [Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II] [Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
Total Total of all reporting groups

Baseline Measures
   Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]   Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]   Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]   Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]   Total 
Overall Participants Analyzed 
[Units: Participants]
 703   700   103   705   2211 
Age 
[Units: Years]
Mean (Standard Deviation)
         
Participants Analyzed   703   700   103   705   2211 
   71.2  (7.4)   71.8  (7.6)   72.3  (7.4)   72.4  (7.6)   71.8  (7.5) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
         
Participants Analyzed   703   700   103   705   2211 
Female      383  54.5%      403  57.6%      56  54.4%      376  53.3%      1218  55.1% 
Male      320  45.5%      297  42.4%      47  45.6%      329  46.7%      993  44.9% 
Race (NIH/OMB) 
[Units: Participants]
Count of Participants
         
Participants Analyzed   703   700   103   705   2211 
American Indian or Alaska Native      1   0.1%      3   0.4%      0   0.0%      3   0.4%      7   0.3% 
Asian      118  16.8%      125  17.9%      11  10.7%      115  16.3%      369  16.7% 
Native Hawaiian or Other Pacific Islander      0   0.0%      0   0.0%      0   0.0%      0   0.0%      0   0.0% 
Black or African American      8   1.1%      13   1.9%      2   1.9%      7   1.0%      30   1.4% 
White      566  80.5%      547  78.1%      88  85.4%      578  82.0%      1779  80.5% 
More than one race      4   0.6%      4   0.6%      2   1.9%      0   0.0%      10   0.5% 
Unknown or Not Reported      6   0.9%      8   1.1%      0   0.0%      2   0.3%      16   0.7% 
Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score [1] [2] 
[Units: Score on a Scale]
Mean (Standard Deviation)
         
Participants Analyzed   681   672   97   694   2144 
   21.4  (7.5)   21.3  (7.6)   20.6  (6.2)   21.7  (7.6)   21.42  (7.49) 
[1] ADAS-Cog 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-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment.
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window ADAS-Cog observation subsequent to ≥1 dose of study drug (Full Analysis Set [FAS] population).
Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score [1] [2] 
[Units: Score on a Scale]
Mean (Standard Deviation)
         
Participants Analyzed   677   668   98   686   2129 
   63.0  (9.5)   62.9  (9.8)   63.5  (10.3)   62.1  (10.4)   62.74  (9.93) 
[1] 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 total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance.
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for ADCS-ADL subsequent to ≥1 dose of study drug (FAS population).
Clinical Dementia Rating Sum of Boxes (CDR-SB) Score [1] [2] 
[Units: Score on a Scale]
Mean (Standard Deviation)
         
Participants Analyzed   660   643   91   673   2067 
   5.4  (2.1)   5.3  (2.1)   5.5  (2.3)   5.6  (2.3)   5.43  (2.17) 
[1] The CDR-SB score is a clinical rating of global cognitive function, comprised of 6 domains including: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant’s caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores sum to the total CDR-SB score, with total scores ranging from 0-18. Higher scores indicate more severe cognitive impairment.
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CDR-SB subsequent to ≥1 dose of study drug (FAS population).
Total Hippocampal Volume [1] [2] 
[Units: Microliters]
Mean (Standard Deviation)
         
Participants Analyzed   332   307   55   346   1040 
   5894.1  (1231.5)   5823.4  (1189.9)   5653.5  (1148.4)   5800.7  (1069.2)   5829.4  (1162.6) 
[1] Total Hippocampal Volume (THV) was measured by volumetric magnetic resonance imaging (vMRI).
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for THV subsequent to ≥1 dose of study drug (FAS population).
Cerebrospinal Fluid (CSF) Total Tau Concentration [1] [2] 
[Units: Picograms (pg)/mL]
Mean (Standard Deviation)
         
Participants Analyzed   38   57   12   41   148 
   206.7  (90.4)   231.5  (113.9)   268.6  (136.2)   246.2  (192.9)   232.2  (137.3) 
[1] Total Tau concentration in the cerebrospinal fluid (CSF) was monitored as a measure of brain tau pathology.
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window observation for CSF Total Tau subsequent to ≥1 dose of study drug (FAS population). Per protocol, CSF Total Tau concentration was analyzed as part of a substudy in Part I, with testing occurring at select trial sites.
[18F]Flutemetamol Positron Emission Tomography (PET) Standard Uptake Value Ratio (SUVR) [1] [2] 
[Units: SUVR]
Mean (Standard Deviation)
         
Participants Analyzed   20   10   0   14   44 
   0.89  (0.10)   0.87  (0.11)      0.88  (0.11)   0.88  (0.10) 
[1] [18F]Flutemetamol PET SUVR measures brain cortical amyloid load. The PET tracer [18F]Flutemetamol was given intravenously (IV). After 90 minutes, participants receive 4 PET scans. Using the PET scan images, regional SUVRs are calculated for brain regions of interest (ROIs), defined as the ratio of pixel intensities at a specific ROI compared to a reference region (RR; subcortical white matter). Regional SUVRs are averaged to compute a composite SUVR. Higher composite SUVR values indicate increased amyloid load.
[2] All randomized participants with a baseline and ≥1 within-analysis-window SUVR observation subsequent to ≥1 dose of study drug (FAS population). SUVR testing occurred at select sites as a Part I substudy. Per protocol, SUVR was not analyzed for the 200 participants enrolled before IA (all arms) and all participants receiving 60mg Verubecestat.
Neuropsychiatric Inventory (NPI) Score [1] [2] 
[Units: Score on a Scale]
Mean (Standard Deviation)
         
Participants Analyzed   682   679   100   691   2152 
   8.7  (10.5)   8.2  (9.8)   6.9  (9.5)   9.2  (11.6)   8.64  (10.6) 
[1] NPI is a clinical assessment of psychiatric status, covering 12 domains. Based on an interview of the participant’s caregiver, each domain is assessed for symptom frequency [range: 1 (occasional) to 4 (very frequent)] and severity [range: 1 (mild) to 3 (severe)]. Domain scores [range: 0 to 12] are calculated as the product of the frequency and severity scores (i.e. frequency x severity); if no symptoms are present, domain score is 0. The 12 domain scores sum to a total NPI score [range: 0 (no symptoms in any domain) to 144]. Higher scores reflect more severe psychiatric impairment.
[2] All randomized participants (Part I) with a baseline and ≥1 within-analysis-window NPI observation subsequent to ≥1 dose of study drug (FAS population).
Mini-Mental State Examination (MMSE) Score [1] [2] 
[Units: Score on a Scale]
Mean (Standard Deviation)
         
Participants Analyzed   660   648   98   679   2085 
   20.4  (3.3)   20.2  (3.3)   20.6  (3.3)   20.3  (3.2)   20.3  (3.3) 
[1] The MMSE is a cognitive assessment of 5 domains including: orientation; attention; memory; language; and constructional praxis. These domains are assessed with 11 total questions related to the participant. Participants are scored based on the number of correct responses; depending on the question, potential scores range from 0 (no correct response) to either 1 (4 questions), 2 (1 question), 3 (3 questions), or 5 (3 questions). Scores from each question are summed to the total MMSE score, with total scores ranging from 0-30. Higher scores indicate better cognitive performance.
[2] All randomized participants (Part I) with a baseline and ≥1within-analysis-window MMSE observation subsequent to ≥1 dose of study drug (FAS population).


  Outcome Measures

1.  Primary:   [Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score   [ Time Frame: Baseline and week 78 ]

2.  Primary:   [Part I (Base Study)] Change From Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score   [ Time Frame: Baseline and week 78 ]

3.  Primary:   [Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score   [ Time Frame: Baseline and week 104 ]

4.  Primary:   [Part II (Extension Study)] Change From Baseline in Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score   [ Time Frame: Baseline and week 104 ]

5.  Primary:   [Part I (Base Study)] Number of Participants Who Experienced an Adverse Event   [ Time Frame: Up to week 80 (up to 2 weeks following cessation of study treatment in Part I) ]

6.  Primary:   [Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event   [ Time Frame: From week 78 (end of treatment in Part I) up to week 262 of Part II ]

7.  Primary:   [Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event   [ Time Frame: Up to week 78 ]

8.  Primary:   [Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event   [ Time Frame: From week 78 (end of treatment in Part I) up to week 260 of Part II ]

9.  Secondary:   [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score   [ Time Frame: Baseline and week 78 ]

10.  Secondary:   [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)   [ Time Frame: Baseline and week 78 ]

11.  Secondary:   [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau   [ Time Frame: Baseline and week 78 ]

12.  Secondary:   [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)   [ Time Frame: Baseline and week 78 ]

13.  Secondary:   [Part I (Base Study)] Percentage of Participants Achieving Responder Status   [ Time Frame: Week 78 ]

14.  Secondary:   [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score   [ Time Frame: Baseline and week 78 ]

15.  Secondary:   [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score   [ Time Frame: Baseline and week 78 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
phone: 1-800-672-6372
e-mail: ClinicalTrialsDisclosure@merck.com


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01739348     History of Changes
Other Study ID Numbers: P07738
MK-8931-017 ( Other Identifier: Merck Protocol Number )
2011-003151-20 ( EudraCT Number )
132229 ( Registry Identifier: JAPIC-CTI )
First Submitted: November 29, 2012
First Posted: December 3, 2012
Results First Submitted: April 11, 2018
Results First Posted: May 16, 2018
Last Update Posted: May 16, 2018