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

Phase 1

Completed

Conditions: Muscle Cramp
Amyotrophic Lateral Sclerosis

Interventions: Drug: TJ-68
Drug: Placebo

Registration Number: NCT04998305

Lead Sponsor: Hiroshi Mitsumoto

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 11

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment sequence TJ-68-Placebo-Placebo-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: TJ-68, placebo, placebo, TJ-68 (1 week WO between each treatment period)
Treatment sequence Placebo-TJ-68-TJ-68-Placebo	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)
Treatment sequence TJ-68-Placebo-Placebo-TJ-68	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)
Treatment sequence Placebo-TJ-68-TJ-68-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: placebo, TJ-68, TJ-68, placebo (1 week WO between each treatment period)

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
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.
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.