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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04998305
Recruitment Status : Not yet recruiting
First Posted : August 10, 2021
Last Update Posted : May 24, 2022
Sponsor:
Collaborator:
Tsumura & Co., Tokyo, Japan
Information provided by (Responsible Party):
Hiroshi Mitsumoto, Columbia University

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.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Muscle Cramp Drug: TJ-68 Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Estimated Study Start Date : June 2022
Estimated Primary Completion Date : October 2023
Estimated Study Completion Date : October 2023


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 Name: 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 Name: 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 Name: 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 Name: Placebo Tablet




Primary Outcome Measures :
  1. Change in Visual Analog Scale (MCS-VAS) Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    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.


Secondary Outcome Measures :
  1. Change in overall Muscle Cramp Scale (MCS) Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    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. All of the MCS components will be administered by a trained evaluator and evaluated by investigator.

  2. Change in self-reported cramp pain score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    Participants will complete weekly cramp diary and cramp pain scale. Cramp diary will assess frequency (0 to more than 10 cramps) and severity (mild, moderate, severe) of muscle cramps in various parts of the body (R/L leg, arm; torso; neck or above). Cramp pain will be measured on a scale of 0 to 10 with 0 indicating no pain and 10 indicating severe pain.

  3. Change in ALSFRS-R Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    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.

  4. Change in Clinical Global Impression of Changes (CGIC) Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    Changes in participant's feelings since the start of dosing will measured by using a score of 1 to 7 with 1 indicating "very much improved" and 7 indicating "very much worse."

  5. Change in ALSAQ-5 (Quality of Life Questionnaire) Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    Changes in 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.

  6. Change in Goal Attainment Scale (GAS) Score [ Time Frame: Baseline, Week 2, Week 5, Week 8 and Week 11 ]
    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."



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Ages Eligible for Study:   20 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 70 years old
  • Forced vital capacity is 60% 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), or both 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 Jacksonville laboratory
  • Screening bicarbonate or carbon dioxide level less than 19 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
  • Those who are pregnant or breast feeding
  • Those who have renal or hepatic impairment

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04998305


Contacts
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Contact: Hiroshi Mistumoto, MD, Dsc. 212-305-1319 hm264@cumc.columbia.edu
Contact: Grace Jang, BA 212-305-7037 gej2116@cumc.columbia.edu

Locations
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United States, New York
Columbia University Irving Medical Center
New York, New York, United States, 10032
Contact: Hiroshi Mitsumoto, MD, DSc.    212-305-1319    hm264@cumc.columbia.edu   
Contact: Grace Jang, BA    212-305-7037    gej2116@cumc.columbia.edu   
Sponsors and Collaborators
Hiroshi Mitsumoto
Tsumura & Co., Tokyo, Japan
Investigators
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Principal Investigator: Hiroshi Mistumoto, MD, Dsc. Columbia University
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Responsible Party: Hiroshi Mitsumoto, Wesley J. Howe Professor of Neurology, Columbia University
ClinicalTrials.gov Identifier: NCT04998305    
Other Study ID Numbers: AAAT0610
First Posted: August 10, 2021    Key Record Dates
Last Update Posted: May 24, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscle Cramp
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Spasm
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations