Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

Abstract

Objective: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS).

Methods: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91.

Results: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes.

Conclusions: RhEPO 40,000 IU fortnightly did not change the course of ALS.

Keywords: ALS; MOTOR NEURON DISEASE.

Figure 1

Flow chart of the EPOS trial. CONSORT flow diagram. Flow diagram showing the progress of patients throughout the EPOS trial. ALS, amyotrophic lateral sclerosis rhEPO; recombinant human erythropoietin.

Figure 2

Italian centres participating in the EPOS trial with a number of patients enrolled in brackets.

Figure 3

Primary outcome analysis. Survival probability in terms of death, tracheotomy and 23 h non-invasive ventilation for 14 consecutive days during the 12 months of the EPOS trial, with the corresponding p value of the log-rank test.

Figure 4

Adverse event analysis. Survival probability in terms of adverse events causing withdrawal during the 12 months of the EPOS trial, with the corresponding p value of the log-rank test.

Figure 5

Secondary outcome analysis. Progression of ALSFRS-R (A) and slow vital capacity (sVC) (B) in the two treatment groups since the baseline visit through the 12-month trial period, with the corresponding p value of the repeated measure analyses.

Figure 6

Haematological effects of recombinant human erythropoietin (rhEPO) mean values of haemoglobin (A) and hematocrit (B) in the two treatment groups since baseline visit through the 12-month trial period. At baseline, haemoglobin and haematocrit values overlapped, whereas they were significantly higher (p<0.01) in the rhEPO group than in the placebo group at 3, 6, 9 and 12-month follow-up.