Alzheimer Disease
Conditions
Brief summary
The purpose of this study is to evaluate the dose-related safety and efficacy of multiple oral dosages of ELND005 as treatment for Alzheimer's disease (AD).
Detailed description
ELND005 (formerly known as AZD-103), scyllo-inositol, is being investigated as an orally administered treatment for AD. ELND005 may prevent or inhibit the build up of amyloid protein in the brains of AD patients. This is a randomized, double-blind, placebo-controlled, dose-ranging, safety and efficacy study of oral ELND005 in male and female participants aged 50-85 years with mild to moderate AD. Approximately 340 patients will be enrolled into the study at approximately 65 study sites. Patients will be randomized to receive either ELND005 or placebo. Each patient's participation will last approximately 18 months.
Interventions
DRUGPlacebo Control
ELND005 matched placebo capsules for oral administration, bid for 78 weeks
DRUGELND005
ELND005 capsules for oral administration at a dose of 2000 mg bid for 78 weeks
Sponsors
OPKO Health, Inc.
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
* Diagnosis of probable AD * Age 50 to 85 years, inclusive * Mini-Mental Status Exam (MMSE) score of 16-26, inclusive * Brain magnetic resonance imaging (MRI) scan consistent with the diagnosis of AD * Fluency in English, French, or Spanish * Stable doses of medications (cholinesterase inhibitors and memantine allowed) * Caregiver is able to attend all study visits
Exclusion criteria
* Significant neurological disease other than AD * Major psychiatric disorder * Significant medical illness * History of stroke or seizure * History of a heart attack within the last 2 years * Prior treatment with certain experimental medicines * Presence of pacemakers or foreign metal objects in the eyes, skin, or body that would prevent patient from having MRI scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS) | Baseline and 78 weeks | The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment. |
| Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS) | Baseline and 78 weeks | The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment. |
| Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS) | Baseline and 78 weeks | The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment. |
| Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS) | Baseline and 78 weeks | The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS) | Baseline and 78 weeks | The CDR-SB consists of 6 items; 3 measuring cognitive ability and 3 measuring functional ability. The score for each of the six items range from 0 to 3; hence the total score is between 0 and 18. Higher scores suggest greater cognitive impairment. |
| Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS) | Baseline and 78 weeks | The NPI is used to obtain information on the presence of severity of neuropsychological symptoms, and was specifically designed for use in Alzheimer's disease subjects. The scale consists of 12 items with each item having outcomes from 0 to 12; hence the total score ranges from 0 to 144. Higher scores suggest greater psychiatric impairment. |
| Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS) | Baseline and 78 weeks | The ADAS-Cog primarily measures cognitive ability. The version used in this study was comprised of 12 items with scores ranging from 0 to 75. Higher scores suggest greater cognitive impairment. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo BID oral administration for 78 weeks | 83 |
| ELND005 250 mg BID oral administration for 78 weeks | 88 |
| ELND005 1000 mg BID oral administration for 78 weeks | 89 |
| ELND005 2000 mg BID oral administration for 78 weeks | 91 |
| Total | 351 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 8 | 10 | 8 |
| Overall Study | Death | 0 | 1 | 4 | 3 |
| Overall Study | Lack of Efficacy | 2 | 2 | 2 | 4 |
| Overall Study | Loss of Caregiver | 0 | 2 | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 1 |
| Overall Study | Miscellaeneous | 3 | 3 | 1 | 4 |
| Overall Study | Physician Decision | 0 | 2 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 1 |
| Overall Study | Sponsor Decision | 2 | 2 | 41 | 42 |
| Overall Study | Withdrawal by Subject | 13 | 15 | 13 | 7 |
Baseline characteristics
| Characteristic | Placebo BID | ELND005 250 mg BID | ELND005 1000 mg BID | ELND005 2000 mg BID | Total |
|---|---|---|---|---|---|
| Age, Continuous | 73.4 years STANDARD_DEVIATION 7.83 | 73.4 years STANDARD_DEVIATION 7.26 | 73.4 years STANDARD_DEVIATION 7.56 | 72.2 years STANDARD_DEVIATION 8.2 | 73.1 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment Canada | 15 patients | 13 patients | 18 patients | 16 patients | 62 patients |
| Region of Enrollment United States | 68 patients | 75 patients | 71 patients | 75 patients | 289 patients |
| Sex: Female, Male Female | 47 Participants | 51 Participants | 48 Participants | 51 Participants | 197 Participants |
| Sex: Female, Male Male | 36 Participants | 37 Participants | 41 Participants | 40 Participants | 154 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 83 | 46 / 88 | 45 / 89 | 57 / 91 |
| serious Total, serious adverse events | 11 / 83 | 19 / 88 | 20 / 89 | 21 / 91 |
Outcome results
Primary
Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS)
The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment.
Time frame: Baseline and 78 weeks
Population: Per Protocol Set (PPS): all randomized patients who received at least one dose of ELND005 250 mg or placebo, completed all scheduled visits up to Week 78, were at least 80% compliant with study drug, and met all inclusion/exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS) | -9.635 Scores on a Scale | Standard Error 1.779 |
| ELND005 250 mg BID | Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Per Protocol Set; PPS) | -8.987 Scores on a Scale | Standard Error 1.76 |
p-value: 0.7795% CI: [-3.73, 5.03]Mixed Models Analysis
Primary
Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS)
The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment.
Time frame: Baseline and 78 weeks
Population: Per Protocol Set (PPS): all randomized patients who received at least one dose of ELND005 250 mg or placebo, completed all scheduled visits up to Week 78, were at least 80% compliant with study drug, and met all inclusion/exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS) | -0.369 Scores on a Scale | Standard Error 0.093 |
| ELND005 250 mg BID | Additional Analysis of Primary Outcome Measure: Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Per Protocol Set; PPS) | -0.222 Scores on a Scale | Standard Error 0.095 |
p-value: 0.1795% CI: [-0.06, 0.36]Mixed Models Analysis
Primary
Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS)
The ADCS-ADL is a 23-item scale that measures a subject's functional abilities as assessed by the subject's caregiver. This scale ranges from 0 to 78, with lower scores suggesting greater functional impairment.
Time frame: Baseline and 78 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS) | -9.467 Scores on a Scale | Standard Error 1.641 |
| ELND005 250 mg BID | Change From Baseline to Week 78 in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score (Full Analysis Set; FAS) | -10.861 Scores on a Scale | Standard Error 1.604 |
p-value: 0.4995% CI: [-5.41, 2.62]Mixed Models Analysis
Primary
Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS)
The NTB assessment is comprised of 9 instruments that measure cognition and executive function. Three of these tests measure immediate memory, next three measure delayed memory, and remaining three assess executive function. The total score is a weighted mean of the nine tests, referred to as the Z-score. Typically, scores range from -3 and 3, with lower scores suggesting greater cognitive impairment.
Time frame: Baseline and 78 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS) | -0.383 Scores on a Scale | Standard Error 0.075 |
| ELND005 250 mg BID | Change From Baseline to Week 78 in Neuropsychological Test Battery (NTB) Z-score (Full Analysis Set; FAS) | -0.350 Scores on a Scale | Standard Error 0.074 |
p-value: 0.7195% CI: [-0.14, 0.21]Mixed Models Analysis
Secondary
Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS)
The ADAS-Cog primarily measures cognitive ability. The version used in this study was comprised of 12 items with scores ranging from 0 to 75. Higher scores suggest greater cognitive impairment.
Time frame: Baseline and 78 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -8.239 Scores on a Scale | Standard Error 1.531 |
| ELND005 250 mg BID | Change in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -10.796 Scores on a Scale | Standard Error 1.54 |
p-value: 0.1895% CI: [-6.33, 1.22]Mixed Models Analysis
Secondary
Change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS)
The CDR-SB consists of 6 items; 3 measuring cognitive ability and 3 measuring functional ability. The score for each of the six items range from 0 to 3; hence the total score is between 0 and 18. Higher scores suggest greater cognitive impairment.
Time frame: Baseline and 78 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -2.742 Scores on a Scale | Standard Error 0.363 |
| ELND005 250 mg BID | Change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -2.452 Scores on a Scale | Standard Error 0.357 |
p-value: 0.5495% CI: [-0.63, 1.21]Mixed Models Analysis
Secondary
Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS)
The NPI is used to obtain information on the presence of severity of neuropsychological symptoms, and was specifically designed for use in Alzheimer's disease subjects. The scale consists of 12 items with each item having outcomes from 0 to 12; hence the total score ranges from 0 to 144. Higher scores suggest greater psychiatric impairment.
Time frame: Baseline and 78 weeks
Population: Full Analysis Set (FAS): all randomized patients who received at least one dose of study drug and completed the baseline visit and at least one post-baseline visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo BID | Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -6.132 Scores on a Scale | Standard Error 1.851 |
| ELND005 250 mg BID | Change in Neuropsychiatric Inventory (NPI) Score From Baseline to Week 78 (Full Analysis Set; FAS) | -5.116 Scores on a Scale | Standard Error 1.814 |
p-value: 0.6595% CI: [-3.43, 5.46]Mixed Models Analysis