A Study of Donanemab, RG6289, or the Combination of Donanemab and RG6289 in Presenilin 1 (PSEN1) E280A Mutation Carriers for the Treatment of Autosomal-Dominant Alzheimer's Disease

Sponsor
Banner Health
Study ID
NCT06996730
Phase
PHASE2/PHASE3
Status
Not Yet Recruiting

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Conditions

Eligibility Criteria

Sex
ALL
Age
25 Years - 65 Years
Healthy Volunteers
Accepted

Interventions

  • Donanemab — DRUG
    IV Infusion
  • RG6289 — DRUG
    Oral tablet
  • Donanemab placebo — DRUG
    IV placebo
  • RG6289 placebo — DRUG
    Oral tablet placebo

Study Details

The study will be conducted in 2 blinded parts (Part 1 and Part 2). In Part 1, study participants who are mutation carriers will receive active donanemab and non-mutation carriers will receive placebo-donanemab for up to 18 months (76 weeks), with a minimum treatment period of 9 months. Amyloid PET scans will be conducted at screening, 9, and 18 months in Part 1. Participants who are at or below 11 CL at screening or reach complete amyloid plaque clearance as measured by florbetapir F18 PET (defined as ≤11 CL) at 9 months will initiate Part 2. Participants who are ≤11 CL at screening may delay their entry into Part 2 for up to 6 months at the discretion of the Investigator. All remaining participants will start Part 2 after completing 18 months (76 weeks) in Part 1 independent of amyloid results. Non-carriers will receive placebo in both Parts 1 and 2. In Part 2, study participants who are mutation carriers will be randomized 1:1:1:1 in a full factorial design to receive either RG6289 + placebo-donanemab (RG6289 alone group), donanemab + placebo-RG6289 (donanemab alone group), the combination of RG6289 and donanemab (combination group), or placebo-RG6289 and placebo-donanemab (placebo group). All non-carriers will be assigned to the placebo group. CDR-GS at the end of Part 1 and the amyloid level using the last completed amyloid PET scan in Part 1 will be used for stratification. All study participants will participate in a double-dummy design for the duration of Part 2 receiving both an intravenous (IV) infusion at the required interval for the donanemab or matching placebo as well as a daily oral treatment of RG6289 or matching placebo. An exploratory outcome of Part 1 is a comparison of the amyloid clearance between this ADAD cohort and historical controls using propensity score matching. The primary outcome in Part 2 is change from the start of Part 2 through the end of Part 2 in brain amyloid load in PSEN1 E280A mutation carriers as measured by amyloid PET imaging. Other endpoints will include fluid and imaging biomarkers and measures of cognition and functioning. The maximum study duration for any individual participant will be 3 years, not including the screening or follow-up periods

Key Dates

Start date
Jan 15, 2026
Status verified
Aug 2025
Primary completion
Jun 1, 2030
Completion
Jun 1, 2030

Study Design

Enrollment
240 participants (estimated)
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT

Arms

  • Experimental: Part 1: Donanemab
    Donanemab will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers
  • Placebo Comparator: Part 1: Donanemab placebo
    Donanemab placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Non-Carriers
  • Experimental: Part 2: Donanemab + RG6289 placebo
    Donanemab plus RG6289 placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers
  • Experimental: Part 2: RG6289 + Donanemab placebo
    RG6289 plus donanemab placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers
  • Experimental: Part 2: RG6289 plus donanemab
    RG6289 plus donanemab will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers
  • Placebo Comparator: Part 2: RG6289 placebo plus donanemab placebo
    RG6289 placebo plus donanemab placebo will be administered per the schedule specified in the treatment arm for all assigned PSEN1 E280A Carriers and all PSEN1 E280A Non-Carriers

Primary Outcome Measure

Part 1: Change in amyloid load as measured by centiloid (CL) [F18]Florbetapir-PET as biomarker endpoint [ Time Frame: Part 1: Screening, Month 9, and Month 18 ]

Central Contacts

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