Thalidomide causes sinus bradycardia in ALS

Objective: Neuroinflammation contributes to motor neuron degeneration in ALS. Thalidomide (THL) shows potent anti-inflammatory properties and increased the life span in ALS transgenic mice. Therefore, thalidomide was suggested as therapeutic intervention for the treatment of ALS. We conducted a pilot, randomized trial of THL in patients with ALS to assess safety, feasibility, and preliminary estimates of treatment efficacy.

Methods: Patients were randomized to THL in combination with riluzole (n=18) or riluzole alone (n=19). THL was initiated at 100mg for 6 weeks. Thereafter, the dose was increased every week by 50mg until reaching the dose of 400mg/day and continued for 12 weeks.

Results: Within 12 weeks, 9 THL patients (50%) developed bradycardia defined as a heart rate below 60 beats per minute (bpm) and ranged from 46 to 59 bpm. Mean heart rate dropped by 17 bpm with THL treatment. Severe symptomatic bradycardia of 30 bpm occurred in one patient. A further patient died from sudden unexpected death. The study was terminated prematurely for safety concerns. The secondary outcome variables showed similar results for both groups.

Conclusion: Bradycardia was the most common adverse event of THL treatment in ALS. THL-related bradycardia does not appear to be ALS-specific. However, it is well conceivable that the unexpected frequency and severity of THL-induced bradycardia may be related to the subclinical involvement of the autonomic nervous system in ALS. The cardiac toxicity discourages further trials and compassionate use of THL in ALS.

ClinicalTrials. gov Identifier: NCT00231140