Study Protocol of Memantine to Preserve Memory and Neurocognition following Craniospinal Irradiation: A Phase 3 Randomized Controlled Trial (MEMENTO)

Introduction Craniospinal irradiation (CSI) forms an integral role in the management of primary brain tumors like embryonal tumors (medulloblastoma), non-seminomatous germ cell tumors, metastatic ependymoma, etc. The cranial component with radiation of whole brain and boost can lead to decline in neurocognitive function. Memantine is an NMDA receptor antagonist with an established role in reducing radiation-induced neurocognitive decline in patients treated with whole brain radiotherapy, but the benefit in pediatric and adults treated with CSI remains unclear. Methods This is a phase 3 open-label, randomized controlled trial. Pediatric and young adults (5 to 39 years) treated with CSI will be eligible for the study. Patients will be randomized in 1: 1 accounting for stratification factors such as age, CSI dose, location of tumor boost, and use of chemotherapy. Patients in the experimental arm will receive memantine 5mg once daily for 1 week, 5 mg twice daily for 1 week, and finally escalated to 10 mg twice daily for 6 months. The primary endpoint will be cognitive deterioration-free survival (CDFS) at 2 years, with secondary endpoints being safety and compliance of memantine, slope of decline of neurocognitive scores, and survival. To demonstrate the improvement of 2-year CDFS of 75% in memantine arm compared to 50% in standard arm, 84 patients need to be evaluated (alpha 0.05 and power 80%). Considering an attrition of 20%, a total of 101 patients will be randomized. Discussion If trial results are positive memantine will be established as a new standard of care to be used with CSI. Trial registration The trial is registered on ClinicalTrials.gov (study identifier NCT06275035) and Clinical Trial Registry India (CTRI/2024/02/062273).