A Phase 1/2 Study for Safety and Efficacy Evaluation of Treatment of Amyotrophic Lateral Sclerosis Using Autologous Bone-Marrow-Derived Stromal Cell

Abstract

Background: There is no effective treatment and many previous efforts using various neuroprotective agents did not prove successful in ALS. Recently, stem cell-based therapy is an emerging alternative therapeutic or disease-modifying strategy in ALS. Objectives: On the basis of the previous animal study and the pilot clinical study, we sought to evaluate the safety and feasibility of repeated intrathecal administrations of autologous bone marrow-derived MSCs in patients with ALS. Methods: This study was designed as a single-center, randomized, open label, parallel-group, phase 1/2 trial (HYUH IRB 2010-C-70, KFDA-2413, clinicaltrials.gov: ID NCT01363401). In phase 1 trial, eight patients were enrolled. After lead-in period for 3 months, autologous MSCs were isolated from bone marrow, expanded in vitro, and suspended in autologous CSF; seven patients received an intrathecal MSCs (1×106/kg) injection twice at an interval of 1 month via a standard lumbar puncture. After the first MSC injection, clinical and laboratory measurements were recorded to evaluate its safety. In phase 2 trial, 59 patients (treatment group: 32, control group: 27) were enrolled. All treatment group received procedures same as phase 1 trial. Primary outcome measures the decline rate of ALSFRS-R score from baseline to 4 months. Occurrences of AE and SAE, all clinical and laboratory findings were collected for safety analysis. Changing ratio of ALSFRS-R between lead-in period and 6 month after MSCs injection. The changes of Appel score, forced vital capacity (FVC) were secondary outcome. Results: No significant major adverse events were reported during phase 1 and 2 trials. MSCs injection was well tolerable except for occurrences of transient headache, myalgia, and back pain. These AEs were disappeared spontaneously or with simple analgesics within 1 or 2 weeks. In phase 2 trial, ALSFRS-R decline rate was significant lower in treatment group compared to control group during the first 4 and 6 months follow-up period .42±0.64/month vs. 1.17±0.81/month, p=0.0002, 0.58±0.68/month vs. 1.25±0.90/month, p=0.003). Appel score change 4 months after MSCs injection compared to baseline was showing statistically significant differences between treatment group and control group (10.44±9.24 vs. 17.96±11.78, p<0.0091). FVC change was not showing statistically significant difference between groups (2.82±2.51 %/month vs. 2.69±2.10 %/month, p=0.833).