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.

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.

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