a study of cad106 and cnp520 versus placebo in participants at risk for the onset of clinical symptoms of alzheimer's disease

Conditions: Alzheimers Disease

Summary: 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.

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.

Eligibility criteria:
key inclusion criteria: * 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. key exclusion criteria: * 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.

Keywords: randomization placebo controlled parallel-group apoe4 homozygotes preclinical alzheimers disease (ad) aβ lowering cnp520 cad106 elderly brain amyloid bace-1 inhibitor prevention unimpaired cognition