Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia: A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation

Phase 2

Terminated

Conditions: Alzheimers Disease, Familial
Dementia
Alzheimers Disease

Interventions: Drug: Gantenerumab

Registration Number: NCT06424236

Lead Sponsor: Washington University School of Medicine

Brief Summary: The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.

Detailed Description: Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression.

After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), eligible participants from the placebo, solanezumab, and gantenerumab treatment groups in double-blind period were invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months).

This study collected brain scans, blood, and spinal fluid tests (also called biomarkers), as well as safety, clinical and cognitive testing. The goal is to determine if gantenerumab has favorable effects on these tests to determine if and how much treatment may prevent or delay the symptoms of AD.

Update:

Based on the results of the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were substantially clinically benefiting from gantenerumab high-dose treatment before the trial reached completion as the Gant program was being stopped.

An interim efficacy analysis of the DIAN-TU-001 OLE was performed to:

1. determine if gantenerumab OLE treatment and/or long-term treatment results in clinical benefit and determine the extent of amyloid removal compared to the double-blind period.

2. determine the potential effects of gantenerumab on clinical and cognitive measures to support decision-making regarding next steps for the DIAN-TU-001 OLE.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 73

Inclusion Criteria

Between 18-80 years of age
Individuals who know they have an Alzheimer's disease-causing mutation
Individuals who have participated in the double-blind period
In the opinion of the investigator and sponsor, treatment is not contraindicated for safety
Capable of receiving drug and appropriate clinical safety assessment
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
Alcohol or drug dependence currently or within the past 1 year
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Gantenerumab Open Label Extension	Gantenerumab	Gantenerumab: Subcutaneously every 4 weeks, at escalating doses; at target, dosing was every 2 weeks

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The composite PiB partial volume corrected C-SUVR was used as the biomarker endpoint for amyloid deposition using PET. The C-SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex, and temporal cortex of brain regions was analyzed. Higher ratio indicate worse disease stage. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by CDR - sum of boxes. The CDR-SB score is considered a more detailed quantitative general index of cognition and function than the global CDR score. The CDR - sum of boxes is the sum score of 6 domains of cognitive function (memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care), with the score of each domain ranging from 0 (no impairment) to 3 (severe impairment). The total score ranges from 0 (no impairment) to 18 (severe impairment). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by CDR - global score. The score ranges from 0 (minimum) to 3 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by FAS. This scale measured instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS was to assess change in an individual's functional activities, relative to previously attained abilities, that were caused by cognitive dysfunction. The score ranges from 0 (minimum) to 30 (maximum). Higher score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156	Baseline (Day 1) and Weeks 24, 52, 76, 104, 128 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by MMSE. The MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment. The score ranges from 0 (minimum) to 30 (maximum). Lower score indicates worse performance. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by Tau PET SUVR. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by CSF pTau-181. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by CSF NfL. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by CSF Amyloid Beta1-42/40. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156	Baseline (Day 1) and Weeks 52, 104 and 156	The efficacy of gantenerumab in reducing disease progression was assessed by DIAN-TU OLE Cognitive Composite. The cognitive composite was calculated based on the below 4 components, 1. The wechsler adult intelligence scale-revised digit span (backward recall). Score ranges from 0 (minimum) to 7 (maximum). 2. The category fluency (animals) value. Score ranges from 0 to unlimited. 3. The wechsler adult intelligence scale digit symbol substitution test. Score ranges from 0 (minimum) to 93 (maximum). 4. The MMSE. Score ranges from 0 (minimum) to 30 (maximum). Lower scores of each component indicate worse performance. The cognitive composite is a normalized z score and has score range - 4.11 to unlimited as one of the components has score range 0 to unlimited. Lower score indicates worse performance. Baseline was defined as last non-missing measurement prior to OLE study drug administration.

Trial Locations

Locations (17): Emory University
🇺🇸
Atlanta, Georgia, United States
University of Alabama in Birmingham
🇺🇸
Birmingham, Alabama, United States
University of California San Diego Medical Center
🇺🇸
La Jolla, California, United States
Indiana University School of Medicine
🇺🇸
Indianapolis, Indiana, United States
Washington University in St. Louis
🇺🇸
Saint Louis, Missouri, United States
University of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
Butler Hospital
🇺🇸
Providence, Rhode Island, United States
University of Washington
🇺🇸
Seattle, Washington, United States
Neuroscience Research Australia
🇦🇺
Randwick, New South Wales, Australia
Mental Health Research Institute
🇦🇺
Melbourne, Victoria, Australia
The McCuster Foundation of Alzheimer's Disease Research
🇦🇺
Nedlands, Western Australia, Australia
CHU de Toulouse - Hôpital Purpan
🇫🇷
Toulouse, Haute Garonne, France
Groupe Hospitalier Pitie-Salpetriere
🇫🇷
Paris cedex 13, Paris, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷
Rouen, Seine Maritime, France
University of Puerto Rico, School of Medicine
🇵🇷
San Juan, Puerto Rico
Hospital Clínic I Provincial de Barcelona
🇪🇸
Barcelona, Spain
The National Hospital for Neurology and Neurosurgery
🇬🇧
London, Greater London, United Kingdom