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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04998305

Enrollment

Registered

2021-08-10

Start date

2022-09-30

Completion date

2024-07-26

Last updated

2025-05-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Amyotrophic Lateral Sclerosis, Muscle Cramp

Brief summary

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.

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.

Interventions

DRUGTJ-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.

DRUGPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

20 Years to 84 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Visual Analog Scale (MCS-VAS) Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.

Secondary

Measure	Time frame	Description
Self-reported Cramp Pain Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.
ALSFRS-R Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.
Overall Muscle Cramp Scale (MCS) Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.
ALSAQ-5 (Quality of Life Questionnaire) Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.
Goal Attainment Scale (GAS) Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.
Clinical Global Impression of Changes (CGIC) Score	Assessed at Baseline, Week 2, Week 5, Week 8 and Week 11; Week 2 reported	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
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 will be randomized to the following treatment sequences: TJ-68, placebo, placebo, TJ-68 (1 week WO between each treatment period)	6
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 will be randomized to the following treatment sequences: placebo, TJ-68, TJ-68, placebo (1 week WO between each treatment period)	5
Total	11

Baseline characteristics

Characteristic	Treatment Sequence TJ-68-Placebo-Placebo-TJ-68	Total	Treatment Sequence Placebo-TJ-68-TJ-68-Placebo
Age, Continuous	63 years STANDARD_DEVIATION 8.15	62.9 years STANDARD_DEVIATION 7.38	62.8 years STANDARD_DEVIATION 7.29
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	2 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	4 Participants	8 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	10 Participants	5 Participants
Region of Enrollment United States	6 participants	11 participants	5 participants
Sex: Female, Male Female	4 Participants	8 Participants	4 Participants
Sex: Female, Male Male	2 Participants	3 Participants	1 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 11	0 / 11
other Total, other adverse events	3 / 11	5 / 11
serious Total, serious adverse events	0 / 11	2 / 11

Outcome results

Primary

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.