Overview

This trial is active, not recruiting.

Conditions alzheimers disease, dementia, alzheimers disease, familial
Treatments gantenerumab, solanezumab, matching placebo (gantenerumab), matching placebo (solanezumab)
Phase phase 2/phase 3
Sponsor Washington University School of Medicine
Collaborator Eli Lilly and Company
Start date December 2012
End date September 2019
Trial size 210 participants
Trial identifier NCT01760005, 1U01AG042791, 2013-000307-17, DIAN-TU-001, R01AG046179, REec-2014-0817, The Alzheimer's Association

Summary

The purpose of this study is to assess the safety, tolerability, biomarker and cognitive efficacy of gantenerumab and solanezumab in subjects who are known to have an Alzheimer's disease-causing mutation by determining if treatment with the study drug improves cognitive outcomes and disease-related biomarkers.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose treatment
Arm
(Experimental)
gantenerumab RO4909832
Subcutaneously at escalating doses every 4 weeks
(Experimental)
solanezumab LY2062430
400 mg intravenous infusion every 4 weeks
(Placebo Comparator)
matching placebo (gantenerumab)
subcutaneous injection of placebo every 4 weeks
(Placebo Comparator)
matching placebo (solanezumab)
intravenous infusion of placebo every 4 weeks

Primary Outcomes

Measure
Assess cognitive efficacy of gantenerumab and solanezumab in individuals with mutations causing dominantly inherited AD as measured by change in the DIAN-TU cognitive composite score. Comparisons will not be made between the two drug treatments.
time frame: Baseline and Week 52, 104, 156, and 208

Secondary Outcomes

Measure
Gantenerumab: Cerebral amyloid imaging using [11C]PiB-PET.
time frame: Baseline and Weeks 52, 104, and 208
Solanezumab: Total Abeta 1-42 (Aβ42) in CSF.
time frame: Baseline, Week 104
Change in amyloid deposition as measured by [11C]PiB-PET-C-SUVR [when not the biomarker endpoint]
time frame: Baseline, Week 208
Change in CSF amyloid-beta peptide concentrations [when not the biomarker endpoint]
time frame: Baseline, Week 208
Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group
time frame: Baseline, Week 208
Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI)
time frame: Baseline, Week 208
Change in FDG-PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured
time frame: Baseline, Week 208

Eligibility Criteria

Male or female participants from 18 years up to 80 years old.

Inclusion Criteria: - Between 18-80 years of age - Individuals who know they have an Alzheimer's disease-causing mutation or are unaware of their genetic status and have a 50% chance of having an autosomal dominant Alzheimer's disease (ADAD) mutation (e.g. parent or sibling with a known AD-causing mutation) - Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset - Cognitively normal or with mild cognitive impairment or mild dementia, Clinical Dementia Rating (CDR) of 0-1 (inclusive) - Able to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron Emission Tomography (PET), and complete all study related testing and evaluations. - For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide). - Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments. - Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion. Exclusion Criteria: - History or presence of brain MRI scans indicative of any other significant abnormality - Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin or body which would preclude MRI scan. - History or presence of clinically significant cardiovascular disease, hepatic/renal disorders, infectious disease or immune disorder, or metabolic/endocrine disorders - Anticoagulants except low dose (≤ 325 mg) aspirin. - Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the past six months. - History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years. - Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial. - Subjects unable to complete all study related testing, including implanted metal that cannot be removed for MRI scanning, required anticoagulation and pregnancy.

Additional Information

Official title A Phase II/III Randomized, Double-Blind, Placebo-Controlled Multi-Center Study of 2 Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease
Description The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with autosomal dominant Alzheimer's disease have very high penetrance (near 100%). This study will target individuals who are either known to have a disease-causing mutation or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and with each mutation (Ryman et al., 2014), an age at onset is determined for each affected parent or mutation. This study will enroll subjects who are either asymptomatic and are within a specific window of time of expected age of onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease. The ability to identify individuals destined to develop Alzheimer's disease (AD) within the next 10-15 years with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Although there are differences between dominantly inherited AD and the more common age-associated sporadic disease, the results of the early intervention in this study will have implications for future studies and treatments in sporadic AD. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Many of the subjects in this study will not yet have any cognitive symptoms of AD; they will be "asymptomatic" carriers of mutations that cause Autosomal Dominant Alzheimer's disease and would be expected to perform normally on standard cognitive and functional testing. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation or not, some of the at-risk individuals enrolled in this study will not have the disease causing mutations; they will be "mutation negative". It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be pressured into genetic testing to learn their genetic status in order to be eligible for the trial). These mutation negative individuals will be assigned to the placebo group; subjects and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be double blinded for placebo and for mutation status, except for mutation positive subjects who are aware of their genetic status. Two different therapies will be tested in order to increase the likelihood that an effective treatment will be discovered. They were selected for this trial based on mechanism of action and available data on efficacy and safety profile. The study design includes a pooled placebo arm shared by all treatment groups. Mutation positive subjects will be randomized to one of the four study arms (gantenerumab:gantenerumab placebo:solanezumab:solanezumab placebo) in an overall 3:1:3:1 ratio for active drug:placebo. Mutation negative subjects will all receive placebo. Importantly, subjects and study staff will not be blinded as to which treatment group each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo arms. Biomarker data will be analyzed for prespecified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. The primary cognitive endpoint will be the same for both treatment arms. Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study drug engages its biological targets. This biomarker approach is particularly important in this study as most study subjects will be cognitively normal at the time of enrollment and most will remain cognitively normal during the first 2 years of the study. The cognitive composite is designed to assess subtle cognitive changes that may be detectable before the onset of dementia. The four year cognitive endpoint will allow for analysis of these subtle cognitive changes.
Trial information was received from ClinicalTrials.gov and was last updated in October 2016.
Information provided to ClinicalTrials.gov by Washington University School of Medicine.