A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation (DIAN-TU)
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|ClinicalTrials.gov Identifier: NCT05552157|
Recruitment Status : Suspended (Roche announced a decision to discontinue most of the company's global trials of gantenerumab. The DIAN-TU has paused the DIAN-TU-002 Primary Prevention Trial related to gantenerumab while considering other potential options for this platform trial.)
First Posted : September 23, 2022
Last Update Posted : January 12, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Alzheimers Disease Dementia Alzheimers Disease, Familial||Drug: Gantenerumab Drug: Matching Placebo (Gantenerumab)||Phase 2 Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||220 participants|
|Intervention Model:||Parallel Assignment|
|Intervention Model Description:||Part 1: Interventional/matching placebo; Part 2: Open Label Non-interventional run-in component Potential for future interventions to be added|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled, Two-part Adaptive Design, Platform Trial of Investigational Treatments for Primary Prevention of Disease Progression in Dominantly Inherited Alzheimer's Disease|
|Actual Study Start Date :||December 2, 2022|
|Estimated Primary Completion Date :||November 2029|
|Estimated Study Completion Date :||March 2034|
Experimental: Part 1: Gantenerumab
Active gantenerumab- blinded
Subcutaneously every 4 weeks at escalating doses
Other Name: RO4909832
Placebo Comparator: Part 1: Matching placebo (Gantenerumab)
Drug: Matching Placebo (Gantenerumab)
Subcutaneous injection of placebo every 4 weeks
Active Comparator: Part 2: Gantenerumab Open Label
Open label will start after last dose of Part 1
Subcutaneously every 4 weeks at escalating doses
Other Name: RO4909832
- Part 1: Difference in change from baseline in amyloid deposition as measured by [11C]PiB-PET average cortical composite between active drug and placebo groups. [ Time Frame: Baseline and Week 208 ]Comparison of the study drug to placebo on change from baseline to week 208 in amyloid deposition as measured by [11C]PiB-PET cortical composite SUVR, which is derived from the average of cortical regions of interest (superior frontal, rostral middle frontal, superior temporal, middle temporal, lateral orbito-frontal, medial orbito-frontal and precuneus).
- Part 2: Odds ratio between treated group and the external control group of being in the lower biomarker disease progression stage based on two-stage modeling of 6 biomarkers. [ Time Frame: Part 2 Week 208 ]The primary endpoint will be the odds ratio of being in the lower biomarker disease progression stage after treatment with study drug compared to the external control group (DIAN-OBS and DIAN-TU-001 placebo. Disease progression will be based on two-stage modeling of 6 biomarkers (CSF pT153/T153 ratio, CSF pT205/T205 ratio, CSF MTBR-tau299, MRI hippocampal volume, CSF NfL, and MRI precuneus thickness). These biomarkers represent tau and neurodegenerative pathobiological events in the disease cascade for temporally different periods of the pre-symptomatic phases of the disease.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||Yes|
- Informed consent form (ICF) is signed and dated by the participant and study partner, or by the participant's legally acceptable representative (LAR) if applicable, according to local regulations for the ICF and, if applicable, the DIAN-TU cognitive run-in (CRI) ICF and/or country-specific ICFs.
- Participant is at least 18 years old.
- Women of childbearing potential, if partner is not sterilized, must agree to use effective contraceptive measures (e.g., hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide) from Screening visit (V1) until 16 weeks after last dose of study drug.
Participants must fulfill mutation status and EYO criteria:
- Participant is a carrier of a mutation in an APP, PSEN1, or PSEN2 gene that is associated with DIAD or does not know their mutation status and has a 50% chance of having an AD-causing mutation (e.g., parent or biological sibling clinically affected with known AD-causing mutation in family).
- Participant is -25 to -11 EYO based on their mutation type or family pedigree (refer to Global Manual of Operations for calculation of EYO).
Note: If the at-risk parent is deemed a non-carrier through confirmed genetic testing at any time during the study, the participant will be withdrawn.
- Cognitive status of participant is normal (CDR 0).
- Participant's confirmed primary language is a DIAN-TU study-approved language.
- Participant has adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
- If participant is receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to CRI Entry visit and Screening visit (V1) except for medications taken for episodic conditions (e.g., migraine abortive therapy, antibiotics, and other medications for upper respiratory and gastrointestinal ailments).
- The participant has a study partner who in the PI's judgment can provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits that require study partner input for scale completion, and who signs the necessary ICF, if applicable.
- The participant agrees not to donate blood or blood products for transfusion from the time of Screening (V1) for a study drug arm, for the duration of the study, and for 1 year after the final dose of study drug. Donation of blood or blood products for transfusion is allowed during the CRI period.
- In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
- The participant is able and willing to complete all study-related testing, evaluations, and procedures.
- Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the study affect cognition or the participant's ability to complete the study. This would include disorders such as: recent or severe head trauma causing cognitive change, seizure disorder, neurodegenerative disease other than DIAD, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any other psychiatric condition/disorder which could significantly interfere with the participant's cooperative participation (e.g., prominent anxiety, agitation or behavioral problems). Disorders that are controlled medically or remote history of these disorders (e.g., history of febrile seizures in childhood) that are not likely to interfere with cognitive function and compliance with study procedures are not exclusionary.
- At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months, current major depression (as defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-V]), or increased suicide risk based on screening Columbia Suicide Severity Rating Scale (C-SSRS). Current stable mild depression or current use of antidepressant medications is not exclusionary.
- History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral hemorrhage (including atrial fibrillation and anticoagulation, documented transient ischemic attack [TIA] in the last 12 months). Low dose aspirin (≤ 325 mg daily) is not exclusionary.
- Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
- History of or Baseline visit brain MRI scan indicative of any other significant abnormality, including but not limited to > 5 definite microhemorrhages, history or evidence of a single prior hemorrhage > 1 cm3, 2 or more subcortical infarcts, evidence of a single prior cortical infarct > 1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (e.g., arachnoid cysts or brain tumors, such as meningioma), hydrocephalus (other than hydrocephalus ex vacuo). Minor or clinically insignificant imaging findings are not exclusionary. Participants with > 5 definite microhemorrhages or > 1 area of leptomeningeal hemosiderosis will be evaluated on a case-by-case basis by the site PI or designated sub-investigator and the PAL and medical director or designee.
- 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.
- Uncontrolled hypertension within 6 months prior to screening (e.g., sustained systolic blood pressure [BP] >160 mm Hg or diastolic blood pressure > 95 mm Hg).
- Myocardial infarction or other myocardial ischemic events within the last 2 years.
- Heart failure that results in limitation of physical activity (e.g., New York Heart Association [NYHA] functional classification stage 2 or higher).
- History of atrial fibrillation unless more than 1 year ago, and no structural lesions (e.g., atrial enlargement or cardiomyopathy) that would increase risk of stroke.
- 12-lead ECG: Clinically significant abnormalities including Bazett's corrected QT (QTc) interval greater than 450 msec for males and 470 msec for females; in participants above 65 years of age: 470 msec (atrioventricular [AV]-block I° allowed; right bundle branch block [RBBB] allowed).
- Alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal or Baseline total bilirubin ≥ 2 times the upper limit of normal.
- Creatinine clearance lower than 30 mL/min according to Cockcroft-Gault formula (if confirmed at re-test).
- Clinically significant abnormalities in urinalysis.
- History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B infection within the past year, history of Hepatitis C infection which has not been adequately treated or history of spirochete infection of the CNS, (e.g., syphilis, Lyme or borreliosis).
- Known allergies, hypersensitivity, or intolerance to study drug or its excipients (see current investigator's brochures [IB]) or sensitivity to study-drug specific PET imaging agents.
- Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 90 days prior to the CRI Entry and Baseline (V2) visit (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
- Current clinically significant abnormalities of thyroid function, or clinically significant deficiency in vitamin B12.
- Screening hemoglobin A1c (HbA1c) > 8% (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes). Participants may be rescreened after 3 months to allow optimization of diabetic control.
- Morbid obesity with significant comorbidities or that would preclude MRI imaging.
- Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (< 325 mg) aspirin is not exclusionary.
- Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
- Received any other investigational pharmacological treatment within 3 months of Screening or 5 half-lives, whichever is longer.
- Lack of sufficient venous access.
- Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
- History of cancer within the last 3 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer, or carcinoma in situ with no significant progression over the past 2 years.
- Any other medical condition that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical or mental status of the participant to a significant degree or put the participant at special risk.
- Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.
- Positive urine or serum pregnancy test or plans to become pregnant during the study.
- Currently breastfeeding. Participants must agree to refrain from breastfeeding from the time of signed ICF until 16 weeks after the last dose of study drug.
- Participants with the "Dutch" APP E693Q mutation.
- Unable to fully complete CRI Entry visit and baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility (e.g., mild dementia).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05552157
|Study Director:||Eric M McDade, DO||Washington University School of Medicine|
|Responsible Party:||Washington University School of Medicine|
|Other Study ID Numbers:||
5U01AG059798 ( U.S. NIH Grant/Contract )
|First Posted:||September 23, 2022 Key Record Dates|
|Last Update Posted:||January 12, 2023|
|Last Verified:||January 2023|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||Access to DIAN-TU trial data will follow the DIAN-TU data access policy, which complies with the guidelines established by the Collaboration for Alzheimer's Prevention [CAP REF].|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Dominantly Inherited Alzheimer's Disease
Dominantly Inherited Alzheimer Network
Autosomal Dominant Alzheimer's Disease
Early Onset Alzheimer's Disease
Central Nervous System Diseases
Nervous System Diseases
Physiological Effects of Drugs