A Randomized, Double-blind, Placebo-controlled, Two-cohort, Parallel Group Study to Evaluate the Efficacy of CAD106 and CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease.
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 480
- 试验地点
- 59
- 主要终点
- Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))
研究概览
简要总结
The purpose of this study was to test whether two investigational drugs called CAD106 and CNP520, administered separately, could slow down the onset and progression of clinical symptoms associated with Alzheimer's disease (AD) in participants at the risk to develop clinical symptoms based on their age and genotype.
详细描述
The study (also known as the Generation Study 1, GS1) was conducted as part of the Alzheimer's Prevention Initiative (API) program.
This trial was a randomized, double-blind, placebo-controlled, parallel group, adaptive design with variable treatment duration planned in cognitively unimpaired APOE4 homozygotes (HMs) aged 60 to 75 years. Participants were enrolled into Cohort I (CAD106) or Cohort II (CNP520).
The planned treatment period of 5 to 8 years was not achieved due to early study termination.
The study was terminated due to unexpected changes in cognitive function, brain volume loss, and body weight loss. Cohort II (CNP520) treatment was stopped and evaluated through an off-treatment follow-up period. After the decision to terminate Cohort II of the study (CNP520), treatment with CAD106 (Cohort I) was also terminated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 60 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Consented to receive disclosure of their risk estimates to develop clinical symptoms of AD based on their APOE genotype.
- •Male or female, age 60 to 75 years inclusive. Females were to be post-menopausal.
- •Mini-Mental State Examination (MMSE) total score ≥ 24 and cognitively unimpaired as evaluated by memory tests
- •Homozygous APOE4 genotype.
- •Participant willing to have a study partner.
排除标准
- •Any disability that prevented the participant from completing all study requirements.
- •Current medical or neurological condition that could have impacted cognition or performance on cognitive assessments.
- •Advanced, severe progressive or unstable disease that may have interfered with the safety, tolerability and study assessments, or put the participant at special risk.
- •History of malignancy of any organ system, treated or untreated, within 60 months prior to screening.
- •History of hypersensitivity to any of the investigational drugs or their excipients / adjuvant or to drugs of similar chemical classes.
- •Indication or on current treatment with ChEIs and/or another AD treatment (e.g. memantine).
- •Contraindication or intolerance to MRI or PET investigations (with fluorinated radio ligands).
- •Brain MRI results showing findings unrelated to AD that, in the opinion of the Investigator could have been a leading cause to future cognitive decline, pose a risk to the participant, or prevent a satisfactory MRI assessment for safety monitoring.
- •Suicidal Ideation in the past six months or Suicidal Behavior in the past two years, prior to screening.
- •A positive drug screen at Screening, if, in the Investigator's opinion, this was due to drug abuse.
- •Significantly abnormal laboratory results at Screening, or infection not as a result of a temporary condition.
- •Current clinically significant ECG findings. For Cohort - I only: Participants with previous organ transplantation or stem cell transplantation, or indication for treatment with anti-coagulants.
- •For Cohort - II only: Participants with depigmenting or hypopigmenting conditions (e.g. albinism vitiligo) or active / history of chronic urticarial in the past year.
研究组 & 干预措施
Cohort II (CNP520 Placebo)
Matching Placebo to CNP520 capsules taken orally once daily
干预措施: Placebo to CNP520 (Other)
Cohort I (CAD106)
CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
干预措施: CAD106 Immunotherapy (Biological)
Cohort I (CAD106)
CAD106 (450 µg) + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
干预措施: Alum (Other)
Cohort I (CAD106 Placebo)
Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
干预措施: Placebo to CAD106 (Other)
Cohort I (CAD106 Placebo)
Placebo to CAD106 + Alum (450 µg) intra-muscular injection at Weeks 1, 7, 13 and every 13 weeks thereafter
干预措施: Alum (Other)
Cohort II (CNP520)
CNP520 (50 mg) capsules taken orally once daily
干预措施: CNP520 (Drug)
结局指标
主要结局
Time to Event (Diagnosis of Mild Cognitive Impairment or Dementia, Due to Alzheimer's Disease (AD))
时间窗: Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII
Event was defined as the first confirmed diagnosis of MCI due to Alzheimer's disease (AD) or dementia due to AD (whichever occurred first) after adjudication by the progression adjudication committee (PAC) as triggered either by an investigator diagnosis or an increase in the Clinical Dementia Rating (CDR) global score. An event had to be confirmed by the PAC at two consecutive visits. In case no confirmed event was observed for a participant, the observation was censored, and the censoring date was defined as the last date where the diagnostic classification was assessed. The Study was terminated and only confirmed events collected up to the data cut-off point were counted. Due to the early termination of the study only a small number of events were observed and time-to-event could not be analyzed. Kaplan-Meyer (KM) estimates were provided to estimate probability that a subject would have an event prior to the specified visit.
Change in the Alzheimer's Prevention Initiative Composite Cognitive (APCC) Test Score
时间窗: CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment
APCC is a composite score derived from the specific scores from the Repeatable Battery for the Assessment of Neurological Status (RBANS), Mini-Mental State Examination (MMSE) and the Raven's Progressive Matrices. The APCC score is a weighted score with ranges from from 0 to 100 where higher scores correspond to better cognitive performance.
次要结局
- Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 40 (Aβ40)(Baseline to last assessment)
- Change in Cerebrospinal Fluid (CSF) Levels of Amyloid Beta 42 (Aβ42)(Baseline to last assessment)
- Change in the Index Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).(CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Change in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Score(CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Change in Neurofibrillary Tangle Burden as Measured by Standardized Uptake Ratio (SUVR) of PET Scans With Tau Radiotracer (Where Available)(Baseline to last assessment)
- Cohort I : Annualized Change in Amyloid Deposition as Measured by Centiloids of Positron Emission Tomography (PET) Scan With Amyloid Radiotracer(Baseline up to approximately Week 104)
- Cohort I : Change in Cognition as Measured by APCC and CDR-SOB Scores and Antibody Response(Month 6 to Month 60)
- Cohort I: Peak Concentration (Cmax) of CAD106 Induced Abeta-specific Antibody Titers(Week 9, 13, 15, 26 and quarterly thereafter (trough values))
- Change in the Total Scores of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).(CI = Baseline to Weeks 26, 52,78 104 and Baseline to last assessment; CII = Baseline to Weeks 26, 52, 78, 104 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Change in the Everyday Cognition Scale (ECog-Subject) Total Scores(CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Change in the Everyday Cognition Scale (ECog-Informant) Total Scores(CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Number of Participants With Newly Occurring Safety MRI Abnormalities (ARIA-E, ARIA-H,White Matter Disease and Any Other MRI Abnormalities)(Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII)
- Annualized Percent Change on Volume of Brain Regions(CI = Baseline to Weeks 26, 52 and Baseline to last assessment; CII = Baseline to Weeks 26, 52 and Baseline to Last on-treatment and Baseline to Last off-treatment)
- Change in Cerebrospinal Fluid (CSF) Levels of Total Tau and Phosphorylated Tau(Baseline to last assessment)
- Change in Serum Neurofilaments(Baseline to Week 26 and week 52, CI baseline to last assessment. CII baseline to last on-treatment and to last off-treatment)
- Number of Suicidal Ideation or Behavior Events(Baseline to end of exposure for a maximum of 1455 days for CI and 907 days for CII)
- Cohort I: Area Under the Concentration Curve (AUC) of CAD106 Induced Abeta-specific Antibody Titers(Week 9, 13, 15, 26 and quarterly thereafter (trough values))