TJ-68 Clinical Trial in Patients With Amyotrophic Lateral Sclerosis (ALS) and Muscle Cramps

A Phase 1/2 Two-center, Double-blind, Randomized, Placebo-controlled Multi-period Crossover (N-of-1) Study to Evaluable the Feasibility, Safety, and Efficacy of TJ-68 in Patients With Amyotrophic Lateral Sclerosis (ALS) and Muscle Cramps

The primary objective of the study is to demonstrate the safety and potential efficacy of TJ-68 for improving muscle cramps in participants with ALS based on a two-site, randomized, placebo-controlled double-blind multi-period crossover (N-of-1) study design.

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis; Muscle Cramp
• Intervention / Treatment: Drug: TJ-68; Drug: Placebo

Detailed Description

In Japan, TJ-68 is a common Kampo medicine prescribed by Japanese physicians to manage muscle cramps or pain of diverse origins. In the USA, there are no effective medications to control muscle cramps and no approved medications to specifically treat muscle cramps. Quinine sulfate and Mexiletine have shown some effect with additional safety considerations. The fact that TJ-68 has been commonly used for the treatment of muscle cramps in Japan and the lack of available medications for cramps in ALS represent the fundamental rationale for this proposal.

This is a phase 1/2, two-site, double-blinded, randomized, placebo-controlled, multi-period crossover clinical trial for individuals with ALS and muscle cramps. Participants will be enrolled in the study for 11 weeks and receive TJ-68, also known as Shakuyakukanzoto - a kampo, herbal medicine - to assess its effect in relieving muscle cramps. This clinical trial employs N-of-1 study design in which all participants will receive TJ-68 and placebo at certain points, serving as their own controls.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosed with ALS, PMA or PLS based on the El Escorial ALS Diagnostic Criteria or based on more recently revised Gold Coast ALS diagnostic criteria
• Experiences at least one muscle cramp in any muscle per day
• Age 20 to 84 years old
• Forced vital capacity is 45% of normal or greater in a seated position
• Able to swallow liquid via the mouth or be given via a feeding tube
• Caregiver available to assist with speaking or writing on behalf of the participant if they are not able to speak or write due to the disease
• Able to comprehend and willing to give (sign) the informed consent
• Willing to commute to the study site for the frequent visits, including a screening visit (study visits at the end of week 2, 5, 8 and 11)
• Taking a stable dose of Riluzole (Rilutek), Edaravone (Radicava), and/or sodium phenylbutyrate/taurursodiol (Relyvrio) for at least a month before randomization and not expected to require dose titration or initiation of these medications during the study period
• Willing to discontinue over-the-counter (OTC) products containing any peony root, Glycyrrhiza, or both
• Willing to discontinue Mexiletine, Quinine sulfate, or Ranolazine during the study period
• Willing to avoid food, beverages, and medications that may induce or inhibit metabolism of enzyme of transporters.
• Willing to refrain from initiation or dose adjustment of baclofen, gabapentin, pregabalin, and/or memantine during the study period (stable dosing of these medications is allowed).
• Willing to practice contraceptive measures for male and female patients.

Exclusion Criteria:

• History of allergic reactions to peony root, Glycyrrhiza, or FD&C Yellow No. 5 (tartrazine)
• Takes any medication known to increase the risk of pseudoaldosteronism or hypokalemia, including corticosteroids and diuretics (except potassium sparing diuretics, such as spironolactone or amiloride)
• History of pseudoaldosteronism or hypokalemia or current use of potassium supplementation
• Screening potassium level 3.4 mEq/L or less
• Screening diastolic blood pressure (DBP) more than 90 mmHg or systolic blood pressure (SBP) more than 150 mmHg after sufficient rest
• Screening albumin below normal laboratory level either at the Columbia or Mayo Clinic laboratory
• Screening bicarbonate or carbon dioxide level less than 29 mmol/L, suggesting metabolic alkalosis
• Screening sodium level greater than 145 mmol/L, suggesting hypernatremia
• Unstable or active medical or neurological (other than ALS) diseases which require treatment
• Failure of Capacity Assessment
• Not able and/or willing to comprehend and sign the informed consent
• Not able to speak or write English to complete the primary outcome measure, MCS
• Taking any experimental medication or unapproved medications directed at treating muscle cramps
• Those who are pregnant or breast feeding
• Those who have renal or hepatic impairment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment sequence TJ-68-Placebo-Placebo-TJ-68; Employing an N-of-1, crossover design, each participant in the TJ-68 clinical trial will serve as his/her control. The participation will last for 11 weeks - four, 2-week treatment periods with 1-week washout (WO) period between each treatment period. Participants (n=13) will be randomized to the following treatment sequences: TJ-68, placebo, placebo, TJ-68 (1 week WO between each treatment period)	Drug: TJ-68; For two periods (one period = 2 weeks) during the 11-week participation, participants will take 2.5 g of TJ-68 for three times per day before meals. It will be administered by dissolving 2.5 g of TJ-68 powder in 1 oz. of lukewarm water.; Other Names: Shakuyakukanzoto; Drug: Placebo; For two periods (one period = 2 weeks) during the 11-week participation, participants will take 2.5 g of placebo for three times per day before meals. It will be administered by dissolving 2.5 g of the placebo powder in 1 oz. of lukewarm water.; Other Names: Placebo Tablet
Experimental: Treatment sequence Placebo-TJ-68-TJ-68-Placebo; Employing an N-of-1, crossover design, each participant in the TJ-68 clinical trial will serve as his/her control. The participation will last for 11 weeks - four, 2-week treatment periods with 1-week washout (WO) period between each treatment period. Participants (n=13) will be randomized to the following treatment sequences: placebo, TJ-68, TJ-68, placebo (1 week WO between each treatment period)	Drug: TJ-68; For two periods (one period = 2 weeks) during the 11-week participation, participants will take 2.5 g of TJ-68 for three times per day before meals. It will be administered by dissolving 2.5 g of TJ-68 powder in 1 oz. of lukewarm water.; Other Names: Shakuyakukanzoto; Drug: Placebo; For two periods (one period = 2 weeks) during the 11-week participation, participants will take 2.5 g of placebo for three times per day before meals. It will be administered by dissolving 2.5 g of the placebo powder in 1 oz. of lukewarm water.; Other Names: Placebo Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analog Scale (MCS-VAS) Score	This is designed to measure improvements in muscle cramps. MCS-VAS indicates the level to which muscle cramps affect overall daily activity. The score ranges from 0 to 10; 0 indicates no interference and 10 indicates severe interference with overall daily activity. MCS-VAS will be administered by a trained evaluator to reduce recall bias and lack of insight, which can limit subjective assessments. To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Muscle Cramp Scale (MCS) Score	Changes in trigger, frequency, severity, and location of muscle cramps will be measured by administering all of MCS questions. Motor behaviors which trigger muscle cramps and muscle cramps' effects on sleep quality will also be measured. The score for each component of MCS -- trigger, frequency, severity, location, behavior, and effect on sleep quality -- will range from 1 to 5, with the severity increasing from 1 to 5. The total score range is 6 to 30. All of the MCS components will be administered by a trained evaluator and evaluated by the investigator. To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported
Self-reported Cramp Pain Score	Cramp pain will be measured on a scale of 0 to 10 with 0 indicating no pain and 10 indicating severe pain. To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported
ALSFRS-R Score	Changes in functionality due to disease progression will be measured by administering ALSFRS-R to participants. ALSFRS-R includes 12 questions that can have a score of 0 to 4. A score of 0 on a question would indicate no function while a score of 4 would indicate full function. Total score range is 0 to 48. To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported
Clinical Global Impression of Changes (CGIC) Score	Changes in participant's feelings since the start of dosing will be measured by using a score of 1 to 7 with 1 indicating "very much improved" and 7 indicating "very much worse." To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported
ALSAQ-5 (Quality of Life Questionnaire) Score	Participants' motor functions and resulting quality of life will be measured by asking questions about their ability to perform certain tasks or feelings of hopelessness within the last two weeks. Participants can answer by saying never, rarely, sometimes, often, or always/cannot do at all. The ALSAQ-5 full score range is from 0 to 100, with 0 reflecting the best health state. To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported
Goal Attainment Scale (GAS) Score	Participant and the evaluator will collaborate and establish a goal. Progression of goal achievement will be measured over the course of participation and scored from -2 to +2 with -2 indicating "(achievement) much worse than expected" and +2 indicating "(achievement) much better than expected." To minimize carryover effects, results reflect the average of the scores taken at the second week of each treatment period.	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported

Collaborators and Investigators

• Sponsor: Hiroshi Mitsumoto
• Collaborators: Tsumura & Co., Tokyo, Japan
• Investigators: Principal Investigator: Hiroshi Mistumoto, MD, Dsc., Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2022
• Primary Completion (Actual): July 26, 2024
• Study Completion (Actual): July 26, 2024

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: August 2, 2021
• First Posted (Actual): August 10, 2021

Study Record Updates

• Last Update Posted (Actual): May 1, 2025
• Last Update Submitted That Met QC Criteria: April 14, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Central Nervous System Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Manifestations; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Spasm; Muscle Cramp
• Other Study ID Numbers: AAAT0610

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No