Alzheimer's Disease
Conditions
Keywords
SUVN-502, 5-HT6, Phase 2, Cognition, Donepezil, Memantine, Alzheimer's Disease, Triple Combination, Proof of Concept (POC)
Brief summary
This is a phase 2a, proof-of-concept, 26-week, double-blind, multicenter, randomized, parallel group, placebo-controlled study to compare the efficacy and safety of treatment with SUVN-502 to placebo treatment in subjects with moderate Alzheimer's disease receiving stable doses of donepezil HCl and memantine HCl.
Detailed description
This is a phase 2a, proof-of-concept, 26-week, double-blind, multicenter, randomized, parallel group, placebo-controlled study to compare the efficacy and safety of treatment with SUVN-502 to placebo treatment in subjects with moderate Alzheimer's disease receiving donepezil HCl (10 mg qd) and either memantine HCl (10 mg twice daily \[bid\]) or Namenda XR® (Extended Release, 28 mg qd) or the combination therapy, Namzaric™ The primary objective of the study is to evaluate the efficacy of a serotonin receptor subtype 6 (5-HT6) antagonist, SUVN-502, compared to placebo, as adjunct treatment in subjects with moderate Alzheimer's disease (Mini-Mental State Examination \[MMSE\] score of 12 to 20) currently treated with the acetylcholinesterase inhibitor, donepezil hydrochloride (HCl), and the N-methyl-D-aspartic acid (NMDA) antagonist, memantine HCl. Efficacy will be assessed by the 11-item Alzheimer's Disease Assessment Scale for Cognitive Behavior (ADAScog-11) after 26 weeks of treatment.
Interventions
DRUGSUVN-502
Once-daily, tablets, orally
DRUGPlacebo
Once-daily, tablets, orally
DRUGDonepezil
Donepezil HCl (10 mg, once a day)
DRUGMemantine
Memantine HCl (10 mg, twice a day or 28 mg extended-release, once a day).
Sponsors
Suven Life Sciences Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of probable Alzheimer's disease based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria at least 1 year prior to the screening visit. * Has a score between 12 and 20 inclusive on the MMSE at the screening and baseline visits. * Has a MRI or CT scan performed within 12 months prior to screening with findings consistent with the diagnosis of dementia due to Alzheimer's disease without any other clinically significant comorbid pathologies. * Must be receiving treatment with stable doses of donepezil HCl and memantine HCl for at least 3 months prior to the screening visit * Availability of an eligible and reliable caregiver * Must be living in the community or an assisted living facility. * Must be ambulatory or ambulatory aided (use of cane or walker). * Is not pregnant or planning to become pregnant during the study. * Subject (or subject's legally acceptable representative) and caregiver must sign an Informed Consent to participate in the study.
Exclusion criteria
* Has a diagnosis of dementia due to other than Alzheimer's Disease * Is taking cholinesterase inhibitors other than donepezil HCl or taking doses of donepezil HCl other than 10 mg * Is taking doses of memantine HCl other than 10 mg bid or Namenda XR® 28 mg qd. * Has uncontrolled cardiac disease or hypertension. * Has clinically significant renal or hepatic impairment. * Has cancer or a malignant tumor, untreated thyroid disorder or has a history of seizure disorder * Is treated or likely to require treatment during the study, with any medications prohibited by the study protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week-26 in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Baseline to Week 26 | Mean change from baseline at week 26 is assessed for ADAS-Cog11 score. The ADAS-Cog11 is a structured scale that evaluates memory, orientation, attention, reasoning, language, and constructional praxis. ADAS-Cog11 measures cognition by assessing 11 metrics impaired in AD: word recall; commands; constructional praxis; naming objects and fingers; ideational praxis; orientation; word recognition; remembering test instructions; spoken language ability; word-finding difficulty; and comprehension of spoken language. The scale ranges from 0 to 70, with higher scores indicate greater impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week-26 in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) | Baseline to Week 26 | Clinical Dementia Rating-Sum of Boxes (CDR-SB) - Sum of Boxes CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity. |
| Change From Baseline to Week-26 in Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Baseline to Week 26 | The Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score is a 23-item inventory. The ADCS-ADL measures both basic and instrumental activities of daily living The total ADCS-ADL score ranges from 0 to 78, with lower scores indicating greater disease severity. |
| Change From Baseline to Week-26 in Neuropsychiatric Inventory (NPI) | Baseline to Week 26 | Neuropsychiatric Inventory (NPI) 12 item - Total Score NPI assesses psychopathology in participants with dementia and other neurologic disorders. Total score ranges from 12 to 144; higher scores indicate greater disease severity. |
| Change From Baseline to Week-26 in Change in Mini Mental State Examination (MMSE) | Baseline to Week 26 | Change in Mini-Mental State Examination (MMSE) - Total Score Minimum Score - 0, Maximum Score - 30. Higher score means better outcome. |
Countries
United States
Participant flow
Recruitment details
Study centers located in the United States of America (USA) participated in the study
Participants by arm
| Arm | Count |
|---|---|
| SUVN-502 Low Dose (50 mg) SUVN-502 Low dose (50 mg) adjunct to base treatment with Donepezil and Memantine | 184 |
| SUVN-502 High Dose (100 mg) SUVN-502 High dose (100 mg) adjunct to base treatment with Donepezil and Memantine | 176 |
| Placebo Placebo adjunct to base treatment with Donepezil and Memantine | 183 |
| Total | 543 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 15 | 19 | 10 |
| Overall Study | Lack of Efficacy | 5 | 0 | 2 |
| Overall Study | Lost to Follow-up | 4 | 4 | 2 |
| Overall Study | Protocol Violation | 4 | 9 | 6 |
| Overall Study | Randomized in error and never treated | 4 | 8 | 5 |
| Overall Study | Withdrawal by Subject | 11 | 9 | 7 |
Baseline characteristics
| Characteristic | SUVN-502 Low Dose (50 mg) | SUVN-502 High Dose (100 mg) | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 73.4 years STANDARD_DEVIATION 8.08 | 74.4 years STANDARD_DEVIATION 6.97 | 72.9 years STANDARD_DEVIATION 7.23 | 73.6 years STANDARD_DEVIATION 7.46 |
| Age, Customized Age group greater than or equal to 65 years | 159 Participants | 155 Participants | 157 Participants | 471 Participants |
| APO-E4 Carrier Status Carrier one allele | 77 Participants | 79 Participants | 84 Participants | 240 Participants |
| APO-E4 Carrier Status Carrier two allele | 24 Participants | 31 Participants | 35 Participants | 90 Participants |
| Mini-Mental State Examination | 16.9 units on a scale STANDARD_DEVIATION 2.21 | 17.0 units on a scale STANDARD_DEVIATION 2.47 | 16.5 units on a scale STANDARD_DEVIATION 2.48 | 16.8 units on a scale STANDARD_DEVIATION 2.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 10 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 171 Participants | 162 Participants | 168 Participants | 501 Participants |
| Sex: Female, Male Female | 95 Participants | 96 Participants | 106 Participants | 297 Participants |
| Sex: Female, Male Male | 89 Participants | 80 Participants | 77 Participants | 246 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 187 | 2 / 181 | 1 / 188 |
| other Total, other adverse events | 50 / 187 | 44 / 181 | 40 / 188 |
| serious Total, serious adverse events | 10 / 187 | 14 / 181 | 12 / 188 |
Outcome results
Primary
Change From Baseline to Week-26 in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11)
Mean change from baseline at week 26 is assessed for ADAS-Cog11 score. The ADAS-Cog11 is a structured scale that evaluates memory, orientation, attention, reasoning, language, and constructional praxis. ADAS-Cog11 measures cognition by assessing 11 metrics impaired in AD: word recall; commands; constructional praxis; naming objects and fingers; ideational praxis; orientation; word recognition; remembering test instructions; spoken language ability; word-finding difficulty; and comprehension of spoken language. The scale ranges from 0 to 70, with higher scores indicate greater impairment.
Time frame: Baseline to Week 26
Population: modified intent to treat (mITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUVN-502 Low Dose (50 mg) | Change From Baseline to Week-26 in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | 2.0 score on a scale | Standard Error 0.5 |
| SUVN-502 High Dose (100 mg) | Change From Baseline to Week-26 in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | 2.5 score on a scale | Standard Error 0.5 |
| Placebo | Change From Baseline to Week-26 in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | 2.6 score on a scale | Standard Error 0.5 |
p-value: 0.41Mixed Models Analysis
p-value: 0.9Mixed Models Analysis
Secondary
Change From Baseline to Week-26 in Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL)
The Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score is a 23-item inventory. The ADCS-ADL measures both basic and instrumental activities of daily living The total ADCS-ADL score ranges from 0 to 78, with lower scores indicating greater disease severity.
Time frame: Baseline to Week 26
Population: modified intent to treat (mITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUVN-502 Low Dose (50 mg) | Change From Baseline to Week-26 in Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | -4.6 score on a scale | Standard Error 0.6 |
| SUVN-502 High Dose (100 mg) | Change From Baseline to Week-26 in Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | -3.4 score on a scale | Standard Error 0.6 |
| Placebo | Change From Baseline to Week-26 in Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | -4.4 score on a scale | Standard Error 0.6 |
p-value: 0.83Mixed Models Analysis
p-value: 0.24Mixed Models Analysis
Secondary
Change From Baseline to Week-26 in Change in Mini Mental State Examination (MMSE)
Change in Mini-Mental State Examination (MMSE) - Total Score Minimum Score - 0, Maximum Score - 30. Higher score means better outcome.
Time frame: Baseline to Week 26
Population: modified intent to treat (mITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUVN-502 Low Dose (50 mg) | Change From Baseline to Week-26 in Change in Mini Mental State Examination (MMSE) | -1.1 score on a scale | Standard Error 0.3 |
| SUVN-502 High Dose (100 mg) | Change From Baseline to Week-26 in Change in Mini Mental State Examination (MMSE) | -1.1 score on a scale | Standard Error 0.3 |
| Placebo | Change From Baseline to Week-26 in Change in Mini Mental State Examination (MMSE) | -1.0 score on a scale | Standard Error 0.3 |
p-value: 0.79Mixed Models Analysis
p-value: 0.92Mixed Models Analysis
Secondary
Change From Baseline to Week-26 in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)
Clinical Dementia Rating-Sum of Boxes (CDR-SB) - Sum of Boxes CDR-SB is a semi-structured interview of participants and their caregivers. Participant's cognitive status is rated across 6 domains of functioning, including memory, orientation, judgment/problem solving, community affairs, home/hobbies, and personal care. Severity score assigned for each of 6 domains; total score (SB) ranges from 0 to 18. Higher scores indicate greater disease severity.
Time frame: Baseline to Week 26
Population: modified intent to treat (mITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUVN-502 Low Dose (50 mg) | Change From Baseline to Week-26 in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) | 1.3 score on a scale | Standard Error 0.2 |
| SUVN-502 High Dose (100 mg) | Change From Baseline to Week-26 in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) | 1.0 score on a scale | Standard Error 0.2 |
| Placebo | Change From Baseline to Week-26 in Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) | 1.2 score on a scale | Standard Error 0.2 |
p-value: 0.46Mixed Models Analysis
p-value: 0.48Mixed Models Analysis
Secondary
Change From Baseline to Week-26 in Neuropsychiatric Inventory (NPI)
Neuropsychiatric Inventory (NPI) 12 item - Total Score NPI assesses psychopathology in participants with dementia and other neurologic disorders. Total score ranges from 12 to 144; higher scores indicate greater disease severity.
Time frame: Baseline to Week 26
Population: modified intent to treat (mITT) population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| SUVN-502 Low Dose (50 mg) | Change From Baseline to Week-26 in Neuropsychiatric Inventory (NPI) | 0.5 score on a scale | Standard Error 0.8 |
| SUVN-502 High Dose (100 mg) | Change From Baseline to Week-26 in Neuropsychiatric Inventory (NPI) | 0.4 score on a scale | Standard Error 0.9 |
| Placebo | Change From Baseline to Week-26 in Neuropsychiatric Inventory (NPI) | 2.1 score on a scale | Standard Error 0.8 |
p-value: 0.17Mixed Models Analysis
p-value: 0.14Mixed Models Analysis