Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial.

INTRODUCTION/AIMS: Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS. METHODS: This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R). DISCUSSION: The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.

Dependence Clusters in Alzheimer Disease and Medicare Expenditures: A Longitudinal Analysis From the Predictors Study.

INTRODUCTION: Dependence in Alzheimer disease has been proposed as a holistic, transparent, and meaningful representation of disease severity. Modeling clusters in dependence trajectories can help understand changes in disease course and care cost over time. METHODS: Sample consisted of 199 initially community-living patients with probable Alzheimer disease recruited from 3 academic medical centers in the United States followed for up to 10 years and had ≥2 Dependence Scale recorded. Nonparametric K-means cluster analysis for longitudinal data (KmL) was used to identify dependence clusters. Medicare expenditures data (1999-2010) were compared between clusters. RESULTS: KmL identified 2 distinct Dependence Scale clusters: (A) high initial dependence, faster decline, and (B) low initial dependence, slower decline. Adjusting for patient characteristics, 6-month Medicare expenditures increased over time with widening between-cluster differences. DISCUSSION: Dependence captures dementia care costs over time. Better characterization of dependence clusters has significant implications for understanding disease progression, trial design and care planning.

A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease.

OBJECTIVE: Authors determined the impact of high-dose vitamin supplements on plasma homocysteine levels in patients with Alzheimer disease (AD). METHODS: Authors used an open-label trial of folic acid, vitamin B(12), and vitamin B(6), in combination for 8 weeks, with measurement of plasma homocysteine levels in the fasting state and after methionine-loading. A total of 69 subjects with AD were enrolled, including 33 who were taking standard multivitamin supplements; 66 were available at 8-week follow-up. RESULTS: The high-dose vitamin regimen was associated with a significant reduction in fasting and post-methionine-loading homocysteine. Reductions were greater in the subgroup not using multivitamins, but were also significant in the multivitamin users. CONCLUSION: High-dose vitamin supplementation reduces homocysteine levels in patients with AD. The effect of supplementation on rate of cognitive decline will be assessed later in a randomized, double-blind study.