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Randomized Controlled Trial
. 2025 Sep;72(3):485-492.
doi: 10.1002/mus.28459. Epub 2025 Jun 23.

Placebo-Controlled, Randomized Double-Blind N-Of-1 Trial to Study Safety and Potential Efficacy of TJ-68 for Improving Muscle Cramps in Patients With Amyotrophic Lateral Sclerosis: A Pilot Study

Hiroshi Mitsumoto  1 , Ken Cheung  2 , Björn Oskarsson  3 , Grace E Jang  1 , Howard F Andrews  4 , Stephen Johnson  5 , Jaimin S Shah  6 , Joseph Americo Fernandes Jr  7 , Jinsy A Andrews  1 , Maya Rao  8 , Martin McElhiney  9
Affiliations
Randomized Controlled Trial

Placebo-Controlled, Randomized Double-Blind N-Of-1 Trial to Study Safety and Potential Efficacy of TJ-68 for Improving Muscle Cramps in Patients With Amyotrophic Lateral Sclerosis: A Pilot Study

Hiroshi Mitsumoto et al. Muscle Nerve. 2025 Sep.

Abstract

Introduction/aims: Muscle cramps are a common symptom in amyotrophic lateral sclerosis (ALS). Ameliorating muscle cramps may improve quality of life in devastating diseases like ALS. A traditional Japanese medicine (Kampo, TJ-68) is widely prescribed in Japan for muscle cramps. However, it is not available in the USA. This study evaluated the safety, tolerability, and efficacy of TJ-68 in ALS.

Methods: This study was a double-blind, randomized, placebo-controlled crossover trial, consisting of four periods, conducted at three centers in the USA. Safety was evaluated using multiple measures. The primary efficacy outcome was the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity (item #5 of the Muscle Cramp Scale (MCS)). The secondary outcomes included the remaining items of the MCS and the Clinical Global Impression of Changes (CGIC), among others. The study was planned to enroll 22 participants with ALS within 2 years.

Results: The enrollment was slow and was completed with 11 participants. There were no serious safety issues and TJ-68 was well tolerated. Although the primary outcome measure did not reach statistical significance (p = 0.35), several secondary measures showed significant results: MCS #1 triggering of cramps (p = 0.01), MCS #2 cramp frequency (p = 0.03), MCS Additional 1 change of motor behaviors (p = 0.02), and CGIC assessed by the evaluator (p = 0.009). Other outcome measures did not reach statistical significance.

Discussion: The study revealed that N-of-1 trial design can detect changes in a small sample size, and TJ-68 appeared to be safe. Larger studies are needed to confirm the efficacy of TJ-68.

Keywords: ALS; N‐of‐1 trials; TJ‐68 (Shakuyakukanzoto); muscle cramp scale (MCS); muscle cramps.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests. Hiroshi Mitsumoto, MD, DSc has received support from SPF, ALS Association, MDA Wings, Tsumura & Co., Mitsubishi‐Tanabe Pharma, private donation, and Wesley J. Howe Professorship. Ken Cheung, PhD has received support from Tsumura & Co. for the current study. Björn Oskarsson, MD: has received support from Tsumura & Co, serves as a consultant for MediciNova Inc. and Mitsubishi, and has research funding from NINDS, Biogen, MediciNova, Cytokinetics, Mitsubishi, Calico, Sanofi, and TARGET ALS. Grace E. Jang, BA has received support from Tsumura & Co. Howard Andrews, MS, PhD directs the Data Management Center at Columbia University, which received support from Tsumura & Co. for data management. Stephen Johnson, MD has received research support from the ALS Association. Jaimin Shah, MD has received research support from the Muscular Dystrophy Association and clinical trial support from the Healey Center Corbus Pharmaceuticals, and Argenx. Joseph Americo Fernandes Jr., MD, has received research support from MGH philanthropy (Clene, Seelos, UCB, Biohaven, Prilenia, Denali Therapeutics, Calico Life Sciences) Columbia University (Tsumura & Co), Clene, and PTC Therapeutics. Jinsy A, Andrews MD, MS has received research funding to her institution from Amylyx, Biogen, Cytokinetics, MGH Foundation/Ra Pharma, Biohaven/Clene/Prilenia/Calico (Platform Trial) Corcept, and NIH/NINDS; has served as a consultant for AL‐S Pharma, Amylyx, Apellis, Biogen, Cytokinetics, Denali, Quralis, Neurosense, Regeneron, and Sanofi. Maya Rao, MD has no conflicts of interest. Martin McElhiney, PhD has no conflicts of interest.

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