Alzheimer Disease
Conditions
Brief summary
This is a randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of 2 dose levels of COR388 in subjects with a clinical diagnosis of mild to moderate Alzheimer's disease (AD) dementia.
Detailed description
This was a randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of 2 dose levels of COR388 oral capsules in subjects with probable Alzheimer's disease (AD) dementia according to the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria. The subject did not have other conditions or brain imaging abnormalities that could explain the symptoms of dementia. All subjects were encouraged to have lumbar punctures (LPs) (during screening, week 24 and week 48) in the absence of medical conditions that could increase the risk of the procedure in the opinion of the Investigator. Cerebrospinal fluid (CSF), saliva, and blood were analyzed for measurements of biomarkers of AD and neuroinflammation, and for the presence of bacterial deoxyribonucleic acid (DNA) of Porphyromonas gingivalis (P. gingivalis). A subset of sites monitored subjects for clinical evidence of periodontitis at baseline, 24 and 48 weeks. The study consisted of 3 phases: a screening phase of up to 6 weeks, a treatment phase of up to 48 weeks, and a safety follow-up phase of 6 weeks.
Interventions
DRUGCOR388 capsule
BID (twice daily)
DRUGPlacebo capsule
BID
Sponsors
Cortexyme Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subject has probable AD dementia according to the NIA-AA criteria. * Subject has an Mini-Mental State Examination (MMSE) score 12 and 24 inclusive at both screening and Visit 2 and a ≤3-point difference between these visits. * Subject has brain MRI scan consistent with the diagnosis of AD performed during the screening period. Computed Tomography scan can be used only if the subject has an absolute contraindication for MRI. * Subject has a Modified Hachinski score ≤4 at screening. * Subjects with background symptomatic therapy with acetylcholine esterase inhibitors, and/or memantine, are allowed as long as the dose has been stable for 90 days prior to screening and no changes are planned during the study. * Subject has a primary caregiver willing to accept responsibility for supervising the treatment (e.g., administering study drug) and assessing the condition of the subject throughout the study in accordance with all protocol requirements. * Subject has body mass index \<38 kg/m2 at Screening Key
Exclusion criteria
* Subject has imaging consistent with a dementia diagnosis other than AD. * Subject has had an increase or restoration of cognition based on medical history. * Subject with history or current evidence of major psychiatric illness such as schizophrenia, bipolar disorder, or major depressive disorder that may interfere with the patient's ability to perform the study and all assessments. Note: Mild depression or depressive mood arising in the context of AD are not criteria for exclusion. The use of anti-depressants or the use of anti epileptic medication for non seizure-related treatment is allowed if the dose has remained stable for at least 60 days prior to enrollment. * Subject has any of the following laboratory findings at screening: 1. Alanine aminotransferase \>3 x upper limit of normal (ULN), aspartate aminotransferase \>3 x ULN, or history of clinically significant liver disease in the Investigator's judgment. 2. Hemoglobin ≤10 g/dl. 3. Creatinine clearance (CL) of \<45 ml/min. 4. Poorly controlled diabetes as defined by hemoglobin A1C (HbA1C) \>8. 5. Positive blood screen for Human Immunodeficiency Virus (HIV 1 and 2), Hepatitis B surface antigen (HBsAg), or Hepatitis C virus antibodies (HCV-Ab) at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Baseline to Week 48 | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) - Total Score The cognitive subscale of the ADAS (ADAS Cog11) was used as a primary efficacy measure and consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. he scale ranges from 0 to 70, with higher scores indicating greater disease severity. |
| Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Baseline to Week 48 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mini-Mental State Examination (MMSE) | Baseline to Week 48 | Change in Mini-Mental State Examination (MMSE) - Total Score Minimum Score - 0 Maximum Score - 30 Higher score means better outcome |
| Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline to Week 48 | 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. |
| Neuropsychiatric Inventory (NPI) | Baseline to Week 48 | Neuropsychiatric Inventory (NPI) - 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Resonance Imaging | Baseline to Week 48 | Change in magnetic resonance imaging - bilateral whole brain volume Larger volume may represent effect of the drug on its target |
| Periodontal (or Gum) Pocket Depth | Baseline to Week 48 | Periodontal (or gum) pocket depth - pocket depth for only sites with depth \>= 4mm. The primary endpoint was mean change in pocket depth from baseline to the end of the double-blind treatment period for tooth sites with depth ≥ 4mm at any time during the study. Therefore, values presented may be less than 4mm. Larger measure means worse outcome |
| Anti-P. Gingivalis IgG in Serum | Baseline to Week 48 | Anti-P. gingivalis immunoglobulin G (IgG) in serum Antibody levels were measured by ELISA and outcome measure are ELISA UNITS (EU) Lower levels represent a pharmacodynamic effect of the drug on its target |
Countries
France, Netherlands, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 89 centers worldwide screened subjects and included 57 centers in the United States, 9 centers in the United Kingdom, 8 centers in Spain, 7 centers in Poland, 5 centers in France, and 3 centers in the Netherlands.
Pre-assignment details
Randomized subjects were stratified by baseline Mini-Mental State Examination (MMSE) score (MMSE ≥12 and ≤18, and MMSE ≥19 and ≤24) and Apolipoprotein E genotype (ApoE4 positive either homozygous or heterozygous vs. all others) to assure balanced distribution of mild and moderate Alzheimer's disease and a balanced distribution of ApoE4 subjects, across treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| COR388 80 mg BID (Twice Daily) COR388 capsule: BID | 214 |
| COR388 40 mg BID (Twice Daily) COR388 capsule: BID | 212 |
| Placebo BID (Twice Daily) Placebo capsule: BID | 217 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 35 | 38 | 8 |
| Overall Study | Death | 4 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 | 3 |
| Overall Study | Other: Various reasons provided | 5 | 5 | 6 |
| Overall Study | Protocol Violation | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 38 | 40 | 35 |
Baseline characteristics
| Characteristic | COR388 80 mg BID (Twice Daily) | COR388 40 mg BID (Twice Daily) | Placebo BID (Twice Daily) | Total |
|---|---|---|---|---|
| Age, Continuous | 69.3 years STANDARD_DEVIATION 6.9 | 68.6 years STANDARD_DEVIATION 6.9 | 69.5 years STANDARD_DEVIATION 6.9 | 69.1 years STANDARD_DEVIATION 6.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 35 Participants | 18 Participants | 25 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 174 Participants | 188 Participants | 187 Participants | 549 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 5 Participants | 16 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 12 Participants | 17 Participants | 42 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 5 Participants | 6 Participants | 17 Participants |
| Race (NIH/OMB) White | 194 Participants | 188 Participants | 192 Participants | 574 Participants |
| Region of Enrollment France | 10 participants | 8 participants | 10 participants | 28 participants |
| Region of Enrollment Netherlands | 10 participants | 13 participants | 8 participants | 31 participants |
| Region of Enrollment Poland | 11 participants | 22 participants | 21 participants | 54 participants |
| Region of Enrollment Spain | 7 participants | 14 participants | 13 participants | 34 participants |
| Region of Enrollment United Kingdom | 24 participants | 12 participants | 13 participants | 49 participants |
| Region of Enrollment United States | 152 participants | 143 participants | 152 participants | 447 participants |
| Sex: Female, Male Female | 117 Participants | 123 Participants | 125 Participants | 365 Participants |
| Sex: Female, Male Male | 97 Participants | 89 Participants | 92 Participants | 278 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 214 | 1 / 212 | 0 / 217 |
| other Total, other adverse events | 139 / 214 | 150 / 212 | 88 / 217 |
| serious Total, serious adverse events | 25 / 214 | 20 / 212 | 19 / 217 |
Outcome results
Primary
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11)
Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) - Total Score The cognitive subscale of the ADAS (ADAS Cog11) was used as a primary efficacy measure and consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. he scale ranges from 0 to 70, with higher scores indicating greater disease severity.
Time frame: Baseline to Week 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Baseline | 23.7 score on a scale | Standard Deviation 8.8 |
| COR388 80 mg BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Average of Weeks 40/48 | 26.6 score on a scale | Standard Deviation 12 |
| COR388 40 mg BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Baseline | 23.4 score on a scale | Standard Deviation 8.6 |
| COR388 40 mg BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Average of Weeks 40/48 | 27.9 score on a scale | Standard Deviation 11.8 |
| Placebo BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Baseline | 23.6 score on a scale | Standard Deviation 9.3 |
| Placebo BID (Twice Daily) | Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) | Average of Weeks 40/48 | 28.4 score on a scale | Standard Deviation 12.2 |
p-value: <0.0455mixed-effects model for repeated measure
Primary
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 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Baseline | 59.9 score on a scale | Standard Deviation 11.2 |
| COR388 80 mg BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Average of Weeks 40/48 | 55.4 score on a scale | Standard Deviation 13.9 |
| COR388 40 mg BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Baseline | 60.1 score on a scale | Standard Deviation 11.3 |
| COR388 40 mg BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Average of Weeks 40/48 | 54.4 score on a scale | Standard Deviation 13.7 |
| Placebo BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Baseline | 60.4 score on a scale | Standard Deviation 11.3 |
| Placebo BID (Twice Daily) | Alzheimer's Disease Cooperative Study Group-Activities of Daily Living (ADCS-ADL) | Average of Weeks 40/48 | 55.5 score on a scale | Standard Deviation 14.1 |
p-value: <455Mixed Models Analysis
Secondary
Clinical Dementia Rating-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 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline | 5.7 score on a scale | Standard Deviation 2.6 |
| COR388 80 mg BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Average of Weeks 40/48 | 7.2 score on a scale | Standard Deviation 3.6 |
| COR388 40 mg BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Average of Weeks 40/48 | 7.2 score on a scale | Standard Deviation 3.4 |
| COR388 40 mg BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline | 6.0 score on a scale | Standard Deviation 2.7 |
| Placebo BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Baseline | 5.9 score on a scale | Standard Deviation 2.8 |
| Placebo BID (Twice Daily) | Clinical Dementia Rating-Sum of Boxes (CDR-SB) | Average of Weeks 40/48 | 7.4 score on a scale | Standard Deviation 3.5 |
Secondary
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 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Baseline | 18.3 score on a scale | Standard Deviation 3.3 |
| COR388 80 mg BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Average of Week 40/48 | 16.9 score on a scale | Standard Deviation 5.7 |
| COR388 40 mg BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Baseline | 18.4 score on a scale | Standard Deviation 3.2 |
| COR388 40 mg BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Average of Week 40/48 | 16.4 score on a scale | Standard Deviation 5.7 |
| Placebo BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Baseline | 18.2 score on a scale | Standard Deviation 3.3 |
| Placebo BID (Twice Daily) | Mini-Mental State Examination (MMSE) | Average of Week 40/48 | 16.2 score on a scale | Standard Deviation 5.9 |
Secondary
Neuropsychiatric Inventory (NPI)
Neuropsychiatric Inventory (NPI) - 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 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Baseline | 6.7 score on a scale | Standard Deviation 8.7 |
| COR388 80 mg BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Average of Weeks 40/48 | 10.7 score on a scale | Standard Deviation 13.7 |
| COR388 40 mg BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Baseline | 8.2 score on a scale | Standard Deviation 11.2 |
| COR388 40 mg BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Average of Weeks 40/48 | 9.2 score on a scale | Standard Deviation 12.1 |
| Placebo BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Baseline | 8.1 score on a scale | Standard Deviation 10.6 |
| Placebo BID (Twice Daily) | Neuropsychiatric Inventory (NPI) | Average of Weeks 40/48 | 10.4 score on a scale | Standard Deviation 13.9 |
Other Pre-specified
Anti-P. Gingivalis IgG in Serum
Anti-P. gingivalis immunoglobulin G (IgG) in serum Antibody levels were measured by ELISA and outcome measure are ELISA UNITS (EU) Lower levels represent a pharmacodynamic effect of the drug on its target
Time frame: Baseline to Week 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Baseline | 191.6 EU | Standard Deviation 216.8 |
| COR388 80 mg BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Week 48 | 77.8 EU | Standard Deviation 123.2 |
| COR388 40 mg BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Baseline | 202.4 EU | Standard Deviation 214 |
| COR388 40 mg BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Week 48 | 110.8 EU | Standard Deviation 184.3 |
| Placebo BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Baseline | 193.1 EU | Standard Deviation 199.5 |
| Placebo BID (Twice Daily) | Anti-P. Gingivalis IgG in Serum | Week 48 | 134.4 EU | Standard Deviation 201 |
Other Pre-specified
Magnetic Resonance Imaging
Change in magnetic resonance imaging - bilateral whole brain volume Larger volume may represent effect of the drug on its target
Time frame: Baseline to Week 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Magnetic Resonance Imaging | Baseline | 1005154 volume (CM^3) | Standard Deviation 106682 |
| COR388 80 mg BID (Twice Daily) | Magnetic Resonance Imaging | Week 48 | 982782 volume (CM^3) | Standard Deviation 111888 |
| COR388 40 mg BID (Twice Daily) | Magnetic Resonance Imaging | Baseline | 1008135 volume (CM^3) | Standard Deviation 105765 |
| COR388 40 mg BID (Twice Daily) | Magnetic Resonance Imaging | Week 48 | 987998 volume (CM^3) | Standard Deviation 102961 |
| Placebo BID (Twice Daily) | Magnetic Resonance Imaging | Baseline | 1001711 volume (CM^3) | Standard Deviation 111145 |
| Placebo BID (Twice Daily) | Magnetic Resonance Imaging | Week 48 | 986119 volume (CM^3) | Standard Deviation 111779 |
Other Pre-specified
Periodontal (or Gum) Pocket Depth
Periodontal (or gum) pocket depth - pocket depth for only sites with depth \>= 4mm. The primary endpoint was mean change in pocket depth from baseline to the end of the double-blind treatment period for tooth sites with depth ≥ 4mm at any time during the study. Therefore, values presented may be less than 4mm. Larger measure means worse outcome
Time frame: Baseline to Week 48
Population: Intent-to-Treat Population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| COR388 80 mg BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Baseline | 4.04 mm | Standard Deviation 0.75 |
| COR388 80 mg BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Week 48 | 3.67 mm | Standard Deviation 0.92 |
| COR388 40 mg BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Baseline | 4.03 mm | Standard Deviation 0.59 |
| COR388 40 mg BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Week 48 | 3.78 mm | Standard Deviation 0.71 |
| Placebo BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Baseline | 3.74 mm | Standard Deviation 0.66 |
| Placebo BID (Twice Daily) | Periodontal (or Gum) Pocket Depth | Week 48 | 3.57 mm | Standard Deviation 0.61 |