| Title: |
An open-label Phase 2a study to assess the safety and tolerability of trimetazidine in patients with amyotrophic lateral sclerosis |
| Authors: |
van Eijk, Ruben P A; Steyn, Frederik J; Janse van Mantgem, Mark R; Schmidt, Angela; Meyjes, Myrte; Allen, Sally; Daygon, Dara V; Loeffler, Jean-Philippe; Al-Chalabi, Ammar; van den Berg, Leonard H; Henderson, Robert D; Ngo, Shyuan T |
| Contributors: |
FightMND; The Netherland ALS Foundation |
| Source: |
Brain Communications ; volume 7, issue 1 ; ISSN 2632-1297 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2024 |
| Description: |
Metabolic imbalance is associated with amyotrophic lateral sclerosis progression. Impaired glucose oxidation and increased reliance on fatty acid oxidation contribute to reduced metabolic flexibility and faster disease progression in amyotrophic lateral sclerosis. We sought to evaluate the safety and tolerability, and explore the pharmacodynamic response of trimetazidine, a partial fatty acid oxidation inhibitor, on oxidative stress markers and energy expenditure in amyotrophic lateral sclerosis. The study was conducted between June 29, 2021 and May 24, 2023. People living with amyotrophic lateral sclerosis, recruited in Australia and the Netherlands, received open-label oral trimetazidine for 12 weeks after an initial 4-week lead-in period. The primary outcome measures were safety and tolerability, as well as the change from baseline in oxidative stress markers malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Secondary outcome measures were change from baseline in energy expenditure, amyotrophic lateral sclerosis functional rating scale—revised, and slow vital capacity (SVC). Linear mixed effects were used to estimate the mean difference in MDA and 8-OHdG between the on- and off-treatment periods. This trial is registered under ClinicalTrial.gov National Clinical Trial (NCT) number NCT04788745 and European Union Drug Regulating Authorities Clinical Trials (EudraCT) number 2020-005018-17. Twenty-one participants received trimetazidine; 19 (90%) completed the treatment period. Trimetazidine was well tolerated; there were 57 adverse events reported, of which 7 (11%) were deemed potentially drug-related, including hot flushes (2), nausea (2), paraesthesia (2) and fatigue (1). MDA was numerically lower during treatment [−0.29 uM; 95% confidence interval (CI) −0.90 to 0.33, P = 0.36]; 8-OHdG was significantly lower during treatment (−0.12 nM; 95% CI −0.23 to −0.01, P = 0.0245). The decrease in oxidative stress markers was accompanied by a reduction in resting energy expenditure (95 kcal, 95% ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/braincomms/fcaf063 |
| DOI: |
10.1093/braincomms/fcaf063/61811287/fcaf063.pdf |
| Availability: |
https://doi.org/10.1093/braincomms/fcaf063; https://academic.oup.com/braincomms/advance-article-pdf/doi/10.1093/braincomms/fcaf063/61811287/fcaf063.pdf; https://academic.oup.com/braincomms/article-pdf/7/1/fcaf063/61811287/fcaf063.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.207EC67D |
| Database: |
BASE |