Alzheimer's Disease
Conditions
Keywords
Alzheimer's disease, RVT-101, donepezil, intepirdine, dementia
Brief summary
This study seeks to confirm a demonstrated treatment effect of intepirdine (RVT-101) as an adjunctive therapy to donepezil for the treatment of subjects with Alzheimer's disease.
Detailed description
This Phase 3 study seeks to confirm a demonstrated treatment effect of intepirdine (RVT-101) on both cognition and activities of daily living when added to stable donepezil treatment in subjects with mild-to-moderate Alzheimer's disease after 24 weeks of double-blind treatment. This study will also provide further information on the safety and tolerability of the 35-mg dose of intepirdine (RVT-101) when used in combination with donepezil compared to donepezil alone. This study is being conducted under the agreement of a Special Protocol Assessment by FDA. Subjects completing this study will be eligible to enroll in a 12 month open-label study of RVT-101 (RVT-101-3002) in which concomitant medications for the treatment of Alzheimer's disease including memantine will be allowed.
Interventions
DRUGRVT-101
once daily, oral, 35 mg tablets
DRUGPlacebo
once daily, oral, pill manufactured to match RVT-101 35 mg tablet
Sponsors
Axovant Sciences Ltd.
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
* Male or female subject with AD * Ongoing donepezil therapy for AD * An MMSE score 12 to 24 inclusive at Screening; MMSE score 10-26 inclusive at Baseline * Hachinski Ischaemia score less than or equal to 4 at Screening. * If female, subject must be: a. of non-childbearing potential or surgically sterile; or, b. willing to use an adequate methods of birth control. Male subjects who are sexually active will also be required to use an adequate form of birth control. * Subject has the ability to comply with procedures for cognitive and other testing in the opinion of the investigator. * Subject has a reliable caregiver who is willing to report on subject's status throughout the study.
Exclusion criteria
Other Causes for Dementia * Diagnosis of vascular dementia * Atypical clinical features or clinical course of dementia that would lead the investigator to conclude symptoms are more likely due to an alternate dementia diagnosis including, but not limited to, frontotemporal dementia, Lewy body dementia, or others. Confounding Medical Conditions * History of significant psychiatric illness such as schizophrenia or bipolar affective disorder or any other significant psychiatric illness that in the opinion of the investigator would interfere with participation in the study; * Any clinically relevant concomitant disease, which, in the opinion of the investigator, makes the subject unsuitable for inclusion in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale - Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24 | Baseline, 24 weeks | The 11-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. The ADAS-Cog-11 total score range is from 0 to 70, with a higher score indicating more severe cognitive impairment. |
| Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24 | Baseline, 24 weeks | The ADCS-ADL scale measures functional impairment in terms of activities of daily living. The score ranges from 0 to 78. The lower the score, the greater the impairment; higher scores indicate better (more desirable) function |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24 | Baseline and Week 24 | The NPI is a behavior rating scale composed of a 12-item structured interview of the caregiver that is scored from 0 to 144 (the higher the score, the greater the psychiatric disturbance). It assesses 12 behavioral disturbances occurring in dementia patients: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor activity, night-time behavior disturbances, and eating disturbances. Both the frequency and the severity of each behavior are determined. |
| Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24 | 24 weeks | The CIBIC+ assessment measures the global functioning of the subject. The CIBIC+ is scored as a seven-point categorical rating, ranging from a score of 1 (indicating very much improved), to a score of 4 (indicating no change), or to a score of 7 (indicating very much worse.) Lower CIBIC+ scores indicate better (more desirable) function |
| Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma | Week 6, Week 12, Week 18, Week 24 | Measurement collected at timepoints Week 6, Week 12, Week 18, and Week 24 |
| ADAS-Cog-13 Score Change From Baseline to Week 24 | Baseline, 24 weeks | 13-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 additional items: delayed word recall and total digit cancellation. Scores for the ADAS-Cog-13 range from 0 to 85 with higher scores indicating greater dysfunction. |
| The Dependence Scale (DS) Score Change From Baseline to Week 24 | Baseline, 24 weeks | The DS measures the amount of assistance patients with dementia require in performing daily activities. The scale consists of 13 items, representing a range of severity from mild to severe levels of dependency. The score range is from 0 to 15 with higher scores indicating greater dependency. |
Countries
Argentina, Australia, Bulgaria, Canada, Chile, Croatia, Czechia, France, Germany, Italy, Poland, Serbia, Singapore, Slovakia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
2173 participants signed consent and were screened for participation. Of these, 1470 entered a 3-week single-blind placebo run-in period with treatment with placebo qd + stable dose of donepezil 5 or 10 mg qd. There was an overlap between the participants from the run-in period and the participants that were randomized during the treatment period.
Participants by arm
| Arm | Count |
|---|---|
| RVT-101 RVT-101 adjunct to 5 mg or 10 mg donepezil
RVT-101: once daily, oral, 35 mg tablets for up to 27 weeks | 643 |
| Placebo Placebo adjunct to 5 mg or 10 mg donepezil
Placebo: once daily, oral, pill manufactured to match RVT-101 35 mg tablet for up to 27 weeks | 633 |
| Total | 1,276 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 22 |
| Overall Study | Another Reason | 10 | 5 |
| Overall Study | Caregiver Withdrew Consent | 7 | 7 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | Physician Decision | 3 | 2 |
| Overall Study | Protocol Violation | 14 | 11 |
| Overall Study | Sponsor Termination | 1 | 2 |
| Overall Study | Withdrawal by Subject | 7 | 21 |
Baseline characteristics
| Characteristic | RVT-101 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 72.7 years | 72.5 years | 72.6 years |
| Age, Customized < 65 years | 98 Participants | 97 Participants | 195 Participants |
| Age, Customized >/=65 years | 545 Participants | 536 Participants | 1081 Participants |
| Age, Customized < 74 years | 309 Participants | 312 Participants | 621 Participants |
| Age, Customized >/= 74 years | 334 Participants | 321 Participants | 655 Participants |
| BMI | 26.4 kg/m^2 | 26.5 kg/m^2 | 26.4 kg/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 120 Participants | 108 Participants | 228 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 518 Participants | 519 Participants | 1037 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 11 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 27 Participants | 20 Participants | 47 Participants |
| Race/Ethnicity, Customized Race Black or African American | 12 Participants | 10 Participants | 22 Participants |
| Race/Ethnicity, Customized Race Missing | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Applicable | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Others | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 595 Participants | 592 Participants | 1187 Participants |
| Sex: Female, Male Female | 386 Participants | 394 Participants | 780 Participants |
| Sex: Female, Male Male | 257 Participants | 239 Participants | 496 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 656 | 2 / 651 | 1 / 2,173 | 1 / 1,470 | 0 / 656 | 1 / 651 |
| other Total, other adverse events | 191 / 656 | 166 / 651 | 0 / 2,173 | 0 / 1,470 | 0 / 656 | 0 / 651 |
| serious Total, serious adverse events | 40 / 656 | 44 / 651 | 12 / 2,173 | 14 / 1,470 | 3 / 656 | 3 / 651 |
Outcome results
Primary
Alzheimer's Disease Assessment Scale - Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24
The 11-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. The ADAS-Cog-11 total score range is from 0 to 70, with a higher score indicating more severe cognitive impairment.
Time frame: Baseline, 24 weeks
Population: ITT Population with data at both timepoints.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | Alzheimer's Disease Assessment Scale - Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24 | 0.39 units on a scale | Standard Error 0.211 |
| Placebo | Alzheimer's Disease Assessment Scale - Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24 | 0.75 units on a scale | Standard Error 0.213 |
p-value: 0.224995% CI: [-0.95, 0.22]Mixed Models Analysis
Primary
Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24
The ADCS-ADL scale measures functional impairment in terms of activities of daily living. The score ranges from 0 to 78. The lower the score, the greater the impairment; higher scores indicate better (more desirable) function
Time frame: Baseline, 24 weeks
Population: ITT Population with data at both endpoints
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24 | -1.06 units on a scale | Standard Error 0.289 |
| Placebo | Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24 | -0.97 units on a scale | Standard Error 0.293 |
p-value: 0.82695% CI: [-0.9, 0.72]Mixed Models Analysis
Secondary
ADAS-Cog-13 Score Change From Baseline to Week 24
13-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 additional items: delayed word recall and total digit cancellation. Scores for the ADAS-Cog-13 range from 0 to 85 with higher scores indicating greater dysfunction.
Time frame: Baseline, 24 weeks
Population: ITT at both timepoints
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | ADAS-Cog-13 Score Change From Baseline to Week 24 | 0.26 units on a scale | Standard Error 0.233 |
| Placebo | ADAS-Cog-13 Score Change From Baseline to Week 24 | 0.64 units on a scale | Standard Error 0.236 |
p-value: 0.247295% CI: [-1.03, 0.27]Mixed Models Analysis
Secondary
Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24
The CIBIC+ assessment measures the global functioning of the subject. The CIBIC+ is scored as a seven-point categorical rating, ranging from a score of 1 (indicating very much improved), to a score of 4 (indicating no change), or to a score of 7 (indicating very much worse.) Lower CIBIC+ scores indicate better (more desirable) function
Time frame: 24 weeks
Population: ITT population at the Week 24 timepoint
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24 | 4.18 units on a scale | Standard Error 0.037 |
| Placebo | Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24 | 4.30 units on a scale | Standard Error 0.037 |
p-value: 0.023495% CI: [-0.22, -0.02]Mixed Models Analysis
Secondary
Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma
Measurement collected at timepoints Week 6, Week 12, Week 18, and Week 24
Time frame: Week 6, Week 12, Week 18, Week 24
Population: PK population at specified timepoints: Week 6, Week 12, Week 18, and Week 24
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| RVT-101 | Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma | Summary Statistics at Week 6 | 201.11 ng/mL |
| RVT-101 | Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma | Summary Statistics at Week 12 | 170.95 ng/mL |
| RVT-101 | Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma | Summary Statistics at Week 18 | 198.69 ng/mL |
| RVT-101 | Measurement of Concentrations of RVT-101 (Intepirdine) in Plasma | Summary Statistics at Week 24 | 193.36 ng/mL |
Secondary
Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24
The NPI is a behavior rating scale composed of a 12-item structured interview of the caregiver that is scored from 0 to 144 (the higher the score, the greater the psychiatric disturbance). It assesses 12 behavioral disturbances occurring in dementia patients: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor activity, night-time behavior disturbances, and eating disturbances. Both the frequency and the severity of each behavior are determined.
Time frame: Baseline and Week 24
Population: ITT Population at both timepoints
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24 | -0.08 units on a scale | Standard Error 0.339 |
| Placebo | Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24 | 0.06 units on a scale | Standard Error 0.344 |
p-value: 0.76595% CI: [-1.09, 0.8]Mixed Models Analysis
Secondary
The Dependence Scale (DS) Score Change From Baseline to Week 24
The DS measures the amount of assistance patients with dementia require in performing daily activities. The scale consists of 13 items, representing a range of severity from mild to severe levels of dependency. The score range is from 0 to 15 with higher scores indicating greater dependency.
Time frame: Baseline, 24 weeks
Population: ITT population at both timepoints
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| RVT-101 | The Dependence Scale (DS) Score Change From Baseline to Week 24 | 0.30 units on a scale | Standard Error 0.07 |
| Placebo | The Dependence Scale (DS) Score Change From Baseline to Week 24 | 0.17 units on a scale | Standard Error 0.071 |
p-value: 0.209695% CI: [-0.07, 0.32]Mixed Models Analysis