“Huoling Shengji granule” for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial

Frontiers in Aging Neuroscience · 10 authors, 9 centres

AI SUMMARY

FIDELITY 92%

POPULATIONPatients aged 45–70 years with clinically definite, probable, or probable-laboratory-supported ALS (revised El Escorial criteria), disease duration ≤3 years, FVC ≥70% predicted, ALSFRS-R each item ≥2 (dyspnea/orthopnea/respiratory insufficiency must be 4), and TCM syndrome of spleen qi insufficiency and kidney yang deficiency.

INTERVENTIONHuoling Shengji Granule (HLSJ) 20 g twice daily plus placebo riluzole tablet twice daily for 48 weeks.

COMPARISONPlacebo HLSJ granule twice daily plus riluzole 50 mg tablet twice daily for 48 weeks.

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TL;DR

This protocol describes a phase II trial testing Huoling Shengji Granule (HLSJ), a traditional Chinese medicine formula, against riluzole in 144 ALS patients over 48 weeks. The primary outcome is change in the ALSFRS-R score, with secondary outcomes including the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). This is the first attempt to evaluate a TCM for ALS using a rigorous, evidence-based randomized controlled design.

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**Background:** Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Only riluzole, edaravone, and AMX0035 have shown modest benefits. Traditional Chinese medicine (TCM) is widely used by ALS patients, but evidence is lacking. Huoling Shengji Granule (HLSJ), a six-herb formula (Radix Astragali, Epimedium herb, Radix Rehmanniae, Fructus Corni, Atractylodes macrocephala Koidz, Poria cocos in a 6:5:5:4:3:3 ratio), is designed to tonify qi, strengthen the spleen, warm the kidney, and invigorate yang. Preclinical studies in SOD1^G93A^ mice showed that medium-dose HLSJ prolonged mean survival and disease course, prevented motor neuron loss, reduced glial activation, and suppressed inflammation. A previous 12-week clinical study in 64 ALS patients found no significant difference in Advanced Norris Scale scores between HLSJ decoction and riluzole, but HLSJ improved TCM syndrome scores. This protocol describes a phase II trial to evaluate HLSJ's efficacy and safety over 48 weeks.

**Methods:** This is a multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design trial conducted at 11 specialized ALS centers in Mainland China. A total of 144 patients will be enrolled (64 per group, assuming 10% dropout, to achieve 80% power with alpha=0.05 for a 2.0-point superiority margin in ALSFRS-R change with SD=4.0). Inclusion criteria: age 45–70 years, clinically definite/probable/probable-laboratory-supported ALS per revised El Escorial criteria, disease duration ≤3 years, FVC ≥70% predicted, each ALSFRS-R item ≥2 (dyspnea/orthopnea/respiratory insufficiency must be 4), and TCM syndrome of spleen qi insufficiency and kidney yang deficiency. Exclusion criteria include familial ALS, gastrostomy, other neurological diseases, prior riluzole/edaravone within 3 months, abnormal liver function (ALT/AST >1.5×ULN), and others. Patients are randomized 1:1 via block randomization (IWRS) to HLSJ (20 g twice daily) plus placebo riluzole, or placebo HLSJ plus riluzole (50 mg twice daily) for 48 weeks. The trial includes 14 visits (V0–V13) with site visits every 12 weeks and phone calls every 4 weeks. Primary outcome: change in ALSFRS-R from baseline to Week 48. Secondary outcomes: changes in ALSFRS-R at Weeks 12, 24, 36; Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) at Weeks 12, 24, 36, 48; FVC% at Weeks 12, 24, 36, 48; 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) at Weeks 12, 24, 36, 48; Symptom Scores of Chinese Medicine Syndrome (SSCMS) at Weeks 12, 24, 36, 48; and rate/time to endpoint events (death, tracheostomy, permanent-assisted ventilation >22 h/day for >14 days). Safety is assessed via adverse events (graded per CTCAE v5.0), vital signs, lab tests, and ECG. Statistical analysis follows intention-to-treat principles using ANCOVA for the primary outcome (covariate: baseline ALSFRS-R), with LSMEAN and 95% CI. Superiority is claimed if the lower limit of the 95% CI for the difference (HLSJ minus riluzole) is >0. Missing primary data will be imputed using last observation carried forward. Secondary outcomes will be analyzed with Wilcoxon tests or Cochran–Mantel–Haenszel statistics. Time-to-event data will use Kaplan–Meier and log-rank tests. Subgroup analyses by onset type (bulbar vs. limb) are planned.

**Key Results:** This is a protocol paper; no results are reported. The trial is registered as ChiCTR2100044085. Recruitment started September 2021, enrollment completed May 2022, and all visits are scheduled to finish by May 2023.

**Clinical Implications:** If HLSJ demonstrates superiority over riluzole in slowing ALS progression (as measured by ALSFRS-R and ROADS), it would provide a new, well-tested TCM option for ALS patients. The use of ROADS as a secondary outcome may improve sensitivity and patient-reported assessment. This trial represents a rigorous, evidence-based evaluation of a TCM formula for ALS, potentially setting a standard for future TCM research in neurodegenerative diseases.

PICO

PPOPULATION

Patients aged 45–70 years with clinically definite, probable, or probable-laboratory-supported ALS (revised El Escorial criteria), disease duration ≤3 years, FVC ≥70% predicted, ALSFRS-R each item ≥2 (dyspnea/orthopnea/respiratory insufficiency must be 4), and TCM syndrome of spleen qi insufficiency and kidney yang deficiency.

IINTERVENTION

Huoling Shengji Granule (HLSJ) 20 g twice daily plus placebo riluzole tablet twice daily for 48 weeks.

OOUTCOME

Primary: change in ALSFRS-R score from baseline to Week 48. Secondary: changes in ALSFRS-R at Weeks 12, 24, 36; ROADS, FVC%, ALSAQ-40, SSCMS at Weeks 12, 24, 36, 48; rate and time to endpoint events (death, tracheostomy, permanent-assisted ventilation).

STUDY TYPE

RCT

SPECIALTY

neurology

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92% · A

ORIGINAL PAPER

PMC10203426

“Huoling Shengji granule” for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial

Frontiers in Aging Neuroscience

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ABSTRACT

Abstract Background There is still a large demand for effective treatments to delay disease deterioration in amyotrophic lateral sclerosis (ALS). Typical symptoms of ALS are considered “flaccidity syndrome” in traditional Chinese medicine (TCM). Huoling Shengji Granule (HLSJ) is a TCM formula used to treat flaccidity syndrome. Results of preclinical tests and a previous clinical study support HLSJ as a novel drug for ALS patients. This trial proposed to examine whether a 48-week course of HLSJ is effective and safe for ALS patients diagnosed with the Chinese medicine syndrome of spleen qi insufficiency and kidney yang deficiency. Methods and analysis In this phase II, multicenter, randomized, double-blind, riluzole parallel-controlled, superiority-design study, eligible participants had the equal opportunity to be assigned to receive either HLSJ or riluzole randomly. Eleven specialized ALS centers in Mainland China will recruit 144 patients for this trial. The primary and secondary outcomes included the change in the ALSFRS-R score and the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) from baseline to Week 48. Discussion Here, we endeavored to evaluate TCM for ALS using a standard evidence-based approach for the first time. In addition, the ROADS, a self-report linear-weighted questionnaire, was selected as a secondary outcome measure. We expect to offer a new reference for the outcome evaluation of ALS trials. Clinical trial registration: http://www.Chictr.org.cn , identifier ChiCTR2100044085. Keywords: amyotrophic lateral sclerosis, randomized controlled trial, traditional Chinese medicine, Huoling Shengji granule, flaccidity syndrome

CITATION EXPORT

Xiaolu Liu, Tingting Qin, Tao Li et al.. “Huoling Shengji granule” for amyotrophic lateral sclerosis: protocol for a multicenter, randomized, double-blind, riluzole parallel controlled clinical trial. Frontiers in Aging Neuroscience. (2023). https://doi.org/10.3389/fnagi.2023.1153973

AUTHORS

10 · 9 CENTRES

Xiaolu Liu, Tingting Qin, Tao Li, Lei Shan, Xiang Lei, Xin Xu, Bin Wen, Yi Feng, Ping Yin, Dongsheng Fan

1Department of Neurology, Peking University Third Hospital, Beijing, China
2Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
3Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China
4Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
5Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
6Foshan Kaichuan Pharmaceuticals Co., Ltd., Foshan, China
7Beijing Qi-Huang Technology Co., Ltd., Beijing, China
8Shanghai Pharma Rare Disease Medicine Co., Ltd., Shanghai, China
9Engineering Research Center of Modern Preparation Technology of TCM, Shanghai University of Traditional Chinese Medicine, Shanghai, China