2896 - Phase II Randomized Trial of Low-Dose Radiation Therapy plus Donanemab in Early Alzheimer's Disease: A Radiation-as-a-Drug Approach (RAD-CLEAR)

Background: Donanemab significantly slows clinical progression in early symptomatic Alzheimer's disease (AD) by clearing amyloid plaques. Preclinical studies demonstrate that low-dose radiation therapy (LDRT) reduces amyloid burden by 60-80%, modulates neuroinflammation, and improves cognition in AD models. The "radiation-as-a-drug" paradigm proposes that repeated low-dose exposures provide sustained immunomodulatory effects, potentially enhancing amyloid clearance when combined with anti-amyloid therapy.

Purpose/Objective(s): To evaluate safety, tolerability, and preliminary efficacy of combining upfront whole-brain LDRT with maintenance LDRT plus donanemab in newly diagnosed early-stage AD.

Materials/Methods:

Design: Multicenter, randomized, double-blind, placebo-controlled phase II trial. Approximately 120 participants randomized 1:1 to LDRT plus donanemab versus sham radiation plus donanemab for 18 months. Participants: Adults aged 60-85 years with early symptomatic AD (MCI or mild dementia), amyloid-positive and tau-positive on PET, MMSE 20-28, CDR global score 0.5-1.0. Interventions: - Experimental: Whole-brain LDRT 3 Gy/10 fractions (0.3 Gy per fraction) over 2 weeks, then maintenance 0.3 Gy monthly concurrent with donanemab infusions. Donanemab 700 mg for first 3 doses, then 1400 mg IV every 4 weeks for up to 72 weeks. - Control: Sham radiation plus donanemab on identical schedule. Primary Outcome: Change from baseline in integrated Alzheimer's Disease Rating Scale (iADRS) at 18 months. Secondary Outcomes: Change in CDR-SB, ADAS-Cog13, ADCS-iADL; time to amyloid clearance on PET; plasma biomarkers (p-tau217, p-tau181, GFAP, NfL); regional tau PET burden; ARIA incidence/severity; safety/tolerability; cognitive response rate. Statistical Analysis: Mixed-model repeated measures comparing iADRS change between groups. Sample size of 60/arm provides 80% power to detect 3.5-point difference (a=0.05, SD=7.0, 15% dropout). Rationale: RAD-CLEAR tests whether combining LDRT's anti-inflammatory and amyloid-modulating effects with donanemab's direct amyloid clearance produces synergistic benefit. Maintenance LDRT operationalizes "radiation-as-a-drug," providing continuous immunomodulation throughout treatment. If successful, this combination may accelerate amyloid clearance and produce greater clinical benefit than anti-amyloid therapy alone.

Results: TBD

Conclusion: TBD