Correlation of laboratory safety variables with disease course in the REFALS phase 3 study of levosimendan in people with ALS
Nelson Kibinge1, Alex Dickens1, Angela Genge2, Nicholas Maragakis3, Susanne Petri4, Leonard Van den Berg5, Ammar Al-Chalabi6, Valtteri Aho1, Kira Holmström1, Merit Cudkowicz7
1Orion Pharma, 2Mcgill University, 3Johns Hopkins University School of Medicine, 4Medizinische Hochschule Hannover, 5University Medical Centre Utrecht, 6King'S College London, 7Massachusetts General Hospital
Objective:

To evaluate how clinical chemistry measurements from the REFALS phase 3 trial (NCT03505021) correlate with ALS disease course in order to further elucidate their potential as biomarkers of disease.

Background:

Reliable biomarkers of ALS disease progression would be greatly beneficial in future clinical trials. In the phase 2 clinical trial LEVALS of levosimendan use in participants with ALS, a number of laboratory variables, such as the muscle biomarkers creatinine and creatine kinase, oxidative stress and tissue damage as well as liver function indicators demonstrated changes over time that may reflect progression of ALS. These and other markers can now be explored in a more extensive 48 week phase 3 clinical study.

Design/Methods:

The REFALS study enrolled 496 adult participants with ALS world wide. Participants were randomized (2:1 allocation) to oral levosimendan 1-2mg daily or placebo for 48 weeks in a double-blind, parallel group design. Clinical chemistry measurements were performed at multiple timepoints over the 48 week study period. Biomarker correlates of patients’ disease status and progression (e.g. disease duration, changes in Revised ALS Functional Rating Scale (ALSFRS-R) and slow vital capacity (SVC)) will be determined using longitudinal and multivariate models.

Results:

Data were analyzed from 492 participants, who received the study treatment, and were on average 26 months from symptom onset, with 81% spinal onset, mean sitting SVC 76.5% and ALSFRS-R 36.0 points at baseline. Results on clinical chemistry analytes, such as Troponin T, creatinine and creatine kinase, and their correlation to ALS disease characteristics will be presented in detail.

Conclusions:

The REFALS trial has provided a unique opportunity to study the potential of routine clinical chemistry measurements as markers to follow ALS disease pathology, which could be useful for managing patients in future clinical trials.