A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis.
OBJECTIVE
To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS.


METHODS
A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival.


RESULTS
Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis).


CONCLUSIONS
At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.
Cudkowicz
M E
ME
Neurology Clinical Trials Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. mcudkowicz@partners.org
Shefner
J M
JM
Schoenfeld
D A
DA
Brown
R H
RH
Johnson
H
H
Qureshi
M
M
Jacobs
M
M
Rothstein
J D
JD
Appel
S H
SH
Pascuzzi
R M
RM
Heiman-Patterson
T D
TD
Donofrio
P D
PD
David
W S
WS
Russell
J A
JA
Tandan
R
R
Pioro
E P
EP
Felice
K J
KJ
Rosenfeld
J
J
Mandler
R N
RN
Sachs
G M
GM
Bradley
W G
WG
Raynor
E M
EM
Baquis
G D
GD
Belsh
J M
JM
Novella
S
S
Goldstein
J
J
Hulihan
J
J
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D018737:Hand Strength; D006801:Humans; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D016016:Proportional Hazards Models; D012449:Safety; D016019:Survival Analysis; D013923:Thromboembolism / Q000139:chemically induced; D000077236:Topiramate; D017211:Treatment Failure; D014797:Vital Capacity / Q000187:drug effects
D000077236:Topiramate; D005632:Fructose