Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS

Abstract

Our objective was to assess the effects of acetyl-L-carnitine (ALC) with riluzole on disability and mortality of amyotrophic lateral sclerosis (ALS). Definite/probable ALS patients, 40-70 years of age, duration 6-24 months, self-sufficient (i.e. able to swallow, cut food/handle utensils, and walk), and with forced vital capacity (FVC) > 80% entered a pilot double-blind, placebo-controlled, parallel group trial and were followed for 48 weeks. ALC or placebo 3 g/day was added to riluzole 100 mg/day. Primary endpoint: number of patients no longer self-sufficient. Secondary endpoints: changes in ALSFRS-R, MRC, FVC and McGill Quality of Life (QoL) scores. Analysis was made in the intention-to-treat (ITT) and per-protocol (PP) population, completers and completers/compliers (i.e. taking > 75% of study drug). Forty-two patients received ALC and 40 placebo. In the ITT population, 34 (80.9%) patients receiving ALC and 39 (97.5%) receiving placebo became non-self-sufficient (p = 0.0296). In the PP analysis, percentages were 84.4 and 100.0% (p = 0.0538), respectively. Mean ALSFRS-R scores at 48 weeks were 33.6 (SD 10.4) and 27.6 (9.9) (p = 0.0388), respectively, and mean FVC scores 90.3 (32.6) and 58.6 (31.2) (p = 0.0158), respectively. Median survival was 45 months (ALC) and 22 months (placebo) (p = 0.0176). MRC, QoL and adverse events were similar. In conclusion, ALC may be effective, well-tolerated and safe in ALS. A pivotal phase III trial is needed.

The MITOS system predicts long-term survival in amyotrophic lateral sclerosis

“…For example, in one of the lithium trials,19 the composite outcome of severe loss of autonomy, defined as the time from inclusion to death/tracheotomy or at least two of three selected ALSFRS-R scores (ie, ≤1 for swallowing, ≤1 for walking, or ≤2 for respiratory insufficiency), was able to capture a percentage of events around 15% at 6 months and above 30% at 12 months. Similarly, in the acetyl- l -carnitine trial,4 the composite primary outcome of loss of self-sufficiency, defined as inability to swallow, cut food/handle utensils and walk, was observed in more than 80% of patients at 12 months.…”

“…Combined outcome measures including survival, tracheotomy, NIV and/or selected domains of the ALSFRS-R scale showed better performances compared to survival or mean ALSFRS-R decline alone in several studies 4 5 12 17 19 20. For example, in one of the lithium trials,19 the composite outcome of severe loss of autonomy, defined as the time from inclusion to death/tracheotomy or at least two of three selected ALSFRS-R scores (ie, ≤1 for swallowing, ≤1 for walking, or ≤2 for respiratory insufficiency), was able to capture a percentage of events around 15% at 6 months and above 30% at 12 months.…”

Valproate Treatment in an ALS Patient Carrying a c.194G>A Spastin Mutation and SMN2 Homozygous Deletion

“…However, recent suggestions that modifications of the epigenome might be of interest for understanding clinical variability in ALS [19, 35] might further justify the attempts of testing in the future other compounds able to modify histone acetylation or histone and/or DNA methylation [36]. In fact, in spite of the fact that ALS clinical heterogeneity might imply differences in the involved pathophysiology, a common downstream pathway converging on the regulation of mRNA expression has been repeatedly demonstrated since the discovery of TARDP43 and FUS/TLS mutations in ALS [37, 38].…”

Complementary and Alternative Therapies in Amyotrophic Lateral Sclerosis

“…A small (n=42 treated, 40 placebo) randomized double-blind placebo-controlled pilot study of acetyl-L-carnitine, showed an increase in median survival and slower ALSFRS-R and FVC decline in the patients taking L-carnitine 3g/day. No significant side effects were reported and the authors concluded that a phase III trial is needed to confirm these preliminary findings (60). …”