Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.
BACKGROUND
Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy.


METHODS
The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465.


RESULTS
204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727).


CONCLUSIONS
48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients.


BACKGROUND
Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals.
Katsuno
Masahisa
M
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Banno
Haruhiko
H
Suzuki
Keisuke
K
Takeuchi
Yu
Y
Kawashima
Motoshi
M
Yabe
Ichiro
I
Sasaki
Hidenao
H
Aoki
Masashi
M
Morita
Mitsuya
M
Nakano
Imaharu
I
Kanai
Kazuaki
K
Ito
Shoichi
S
Ishikawa
Kinya
K
Mizusawa
Hidehiro
H
Yamamoto
Tomotaka
T
Tsuji
Shoji
S
Hasegawa
Kazuko
K
Shimohata
Takayoshi
T
Nishizawa
Masatoyo
M
Miyajima
Hiroaki
H
Kanda
Fumio
F
Watanabe
Yasuhiro
Y
Nakashima
Kenji
K
Tsujino
Akira
A
Yamashita
Taro
T
Uchino
Makoto
M
Fujimoto
Yasushi
Y
Tanaka
Fumiaki
F
Sobue
Gen
G
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007564:Japan; D016729:Leuprolide / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009133:Muscular Atrophy / Q000188:drug therapy*; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D016729:Leuprolide