Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial.
Neuroinflammation through the cytokine, tumor necrosis factor-alpha (TNF-alpha) is thought to play an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We conducted a preliminary phase II trial of thalidomide, which reduces levels of TNF-alpha pre-transcriptionally and post-transcriptionally in vivo and has been shown to prolong disease duration and extend the lifespan of transgenic animal models of ALS. Patients who met diagnostic criteria for ALS received thalidomide at escalating doses to a target dose of 400 mg/day. The primary endpoints in the trial were the ALS Functional Rating Scale (ALSFRS) and pulmonary function testing (PFT) curves after nine months of thalidomide treatment that were compared to historical controls. Secondary endpoints were: survival stratified for newly diagnosed and progressive disease, toxicity, quality of life, and serum cytokine measurements. Twenty-three patients were enrolled, but only 18 were evaluable for the primary outcome. There was no improvement in the ALSFRS or PFT compared to historical controls. Thalidomide had several side-effects in our ALS patients. There was no significant shift in cytokine profile after treatment compared to baseline. In conclusion, treatment of ALS with the TNF-alpha inhibitor, thalidomide, does not appear to effectively modulate disease progression and can cause adverse effects.
Stommel
Elijah W
EW
Department of Medicine (Section of Neurology), Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, USA. elijah.w.stommel@hitchcock.org
Cohen
Jeffrey A
JA
Fadul
Camilo E
CE
Cogbill
Christopher H
CH
Graber
David J
DJ
Kingman
Linda
L
Mackenzie
Todd
T
Channon Smith
Jacqueline Y
JY
Harris
Brent T
BT
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D011788:Quality of Life; D011795:Surveys and Questionnaires; D013792:Thalidomide / Q000627:therapeutic use*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D016207:Cytokines; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide