Enhancing Chronic Migraine Preventive Therapy: Laser Acupuncture as an Add-On Treatment for Patients With Unsatisfactory Pharmacological Effect, a Pilot Randomized Controlled Trial
Phase: NA
Conditions: Chronic Migraine
Sponsor: Taichung Veterans General Hospital

Study Protocol and Statistical Analysis Plan 
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Last update date: 01/ January/ 2022 
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Title: 
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Enhancing Chronic Migraine Preventive Therapy: Laser Acupuncture as an Add-On 
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Treatment for Patients with Unsatisfactory Pharmacological Effect, a Pilot Randomized 
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Controlled Trial 
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Huan-Yun Wu1, Chi-Sheng Wang2*†, Yuan-Chen Liu1, Ching-Chun Chung1, Wan-Ling Chen1, Chia-
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I Tsai1,3, Chiann-Yi Hsu4, Chi-Hsiang Chou2,3,5*† 
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1. Department of Traditional Chinese Medicine, Taichung Veterans General Hospital, Taiwan 
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2. Division of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taiwan 
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3. Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing 
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University, Taichung, Taiwan. 
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4. Biostatistics Task Force, Taichung Veterans General Hospital, Taichung, Taiwan 
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5. Department of Neurology, National Yang Ming Chiao Tung University School of Medicine, 
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Taipei, Taiwan. 
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* Correspondence: 
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1. 
Chi-Sheng Wang, at: Division of Neurology, Neurological Institute, Taichung Veterans 
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General Hospital, Taiwan.  
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Taichung Veterans General Hospital, No. 1650, Taiwan Boulevard, Sec. 4, Taichung City 
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40705, Taiwan 
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Tel. +886 4 23592525 #3325 
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e-mail: sam7227632@gmail.com 
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Fax: +886-4-23584403 
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2. 
Chi-Hsiang Chou, at: Department of Post-Baccalaureate Medicine, College of Medicine, 
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National Chung Hsing University, Taichung, Taiwan. Tel. +886 4 22840421, e-mail 
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bryanchouysvh@gmail.com 
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Objective 
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We aimed to investigate the efficacy and safety of laser acupuncture (LA) as an add-on preventive 
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therapy on chronic migraine (CM). 
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Methods 
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A single-blind randomized controlled trial was conducted from January 2022 to November 2023. 
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CM patients with unsatisfactory pharmacological effects were randomly assigned in a 1:1 ratio to 
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receive either LA or sham treatment over a course of 8 sessions spanning 4 weeks. The co-primary 
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outcomes were changes in monthly migraine days (MMD) and acute headache medications usage 
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days per month from baseline. Evaluations were taken at baseline (12 weeks before randomization), 
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at 4th week (treatment completed), 8th week and 12th week from baseline. 
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Study Protocol and Statistical Analysis Plan 
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Trial Design and Participants 
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Our study is a hospital-based (Taichung Veterans General Hospital), single-blind randomized 
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controlled trial. Between January 2022 to September 2023, patients over 20 years old with CM 
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managed pharmacologically with unsatisfactory effect were included. CM was diagnosed by 
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neurologists based on the criteria of International Classification of Headache Disorders, 3rd edition 
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(ICHD-3). Participants were randomly assigned in a 1:1 ratio to receive either LA or sham treatment. 
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Participants were randomized by computer software (Excel 2016 for Windows). All the participants 
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and our collaborative case-manager were blinded to treatment types. Clinical assessments were taken 
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at baseline, with headache defined in diary for 12 weeks before randomization, and other clinical 
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assessments at the time of randomization, at the 4th (treatment completed), 8th and 12th week from 
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baseline. After completing the LA protocol or sham treatment, participants were observed via 
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clinical follow-up examinations and through questionnaires. In addition, participants received 
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anthropometric measurements, including body-mass index (BMI) and blood pressure by case-
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manager at the time of randomization. Medication histories of patients were recorded, including 
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acute headache medications and preventive medications. 
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Clinical assessments were as follows: (1) headache diary; (2) headache characteristics and (3) 
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the Migraine Disability Assessment (MIDAS). The headache diary was completed by each 
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participant. Items recorded were headache duration, frequency, location, severity (using Numeric 
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Rating Scale [NRS]), acute headache medications usage, presence of aura or not, menstrual relation, 
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concomitant symptoms. Questionnaires were acquired by a trained and certified case-manager, who 
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was blinded to treatment types.  
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All participants provided written informed consent prior to enrolment. The study protocol was 
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approved by the ethics committee of the Institutional Review Board at Taichung Veterans General 
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Hospital (approval number: CF22082B). 
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Trial Inclusion and exclusion criteria 
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The inclusion criteria included: (1) patients aged >20 years old and had CM managed 
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pharmacologically, including preventive and/or acute migraine medications, and in addition, those 
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who had refused preventive agent despite recommendation of the neurologist; (2) patients who had 
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unsatisfactory effect of current pharmacological treatments, defined as they self-reported16; and (3) 
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patients who had a minimum of one-year history of migraine with or without aura. 
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Exclusion criteria included: (1) patients who had received another LA therapy or traditional 
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acupuncture at baseline; (2) migraine onset after the age of 50; (3) cognitive or psychological 
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impairment interfering with the participant’s ability to receive LA protocol and describe symptoms; 
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and (4) patients with missing data at baseline or during the follow-up period.  
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In our trial, the primary analytical approach utilized is intention-to-treat (ITT) analyses. 
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Simultaneously, we have also performed per-protocol (PP) analyses. The factors listed below was 
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defined as protocol violations which would be excluded from the per-protocol analysis: (1) patients 
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who had records of changing preventive medications during the follow-up period; (2) patients who 
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received another LA therapy or traditional acupuncture during the follow-up period. 
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Protocol of laser acupuncture and sham control 
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We selected identical acupoints in both the treatment and sham control groups. Patients in the 
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LA group sequentially received laser stimulation energy of 4.5 J for 30 seconds at each of the 
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following acupoints: bilateral Cuanzhu (BL2), Fengchi (GB20), Taiyang (EX-HN5), Shuaigu (GB8), 
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Hegu (LI4), Taichong (LR3) and midline Yintang (EX-HN3). Control patients received sham 
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treatment with no laser output. Each treatment course lasted for about 10 minutes. The treatment 
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protocol was conducted over a course of 8 sessions that spanned 4 weeks. During treatment, patients 
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were asked to wear eye goggles and noise-canceling headphones to inhibit visual and auditory 
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perception. 
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Selected acupoints were localized according to the WHO Standardized Acupuncture Point 
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Location guidelines. The laser application procedures were performed by the same experienced 
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physician who was a well-trained and a licensed Chinese medicine practitioner in Taiwan. 
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2.4 Trial outcomes 
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The co-primary efficacy outcomes were (1) changes from baseline in monthly migraine days 
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(MMD), and (2) changes from baseline in acute headache medications usage days per month 
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between baseline and each of the three follow-up time points (4th, 8th and 12th weeks) after 
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randomization.  
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We classified 4 secondary efficacy outcomes in our study, which were ≥ 30% reduction in 
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migraine days between baseline and each follow-up time point, and changes in the following 
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parameters: (1) headache duration; (2) headache severity (based on NRS) and (3) MIDAS score. 
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The safety outcome was defined as any adverse event (AE) that had occurred during LA or 
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sham treatment, and during the follow-up period. Serious AEs were defined as those that resulted in 
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patients withdrawing from the trial. We recorded any patient-reported AEs, including but not limited 
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to nausea, dizziness, local paresthesia, local heat sensation, fatigue, somnolence, and ecchymosis. 
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Trial physicians also inquired patients on the incidence of any AE during treatment and at every 
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follow-up point. 
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2.5 Treatment Credibility 
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To evaluate the reliability of treatment blinding and ascertain the credibility of the assigned 
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treatment groups, a credibility questionnaire was administered at each follow-up assessment. Within 
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the questionnaire, patients were queried about their perceptions regarding whether they had 
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undergone laser acupuncture following the principles of traditional Chinese medicine (TCM) or 
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received sham treatment. At the end of the study, participants were surveyed about the treatment 
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logical and their likelihood of recommending the received treatment to others. 
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2.6 Statistical Analyses and Sample Size Calculation 
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The baseline characteristics and clinical outcomes described are based on the ITT population, 
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which included participants who had completed the LA or Sham treatment protocol. In addition, we 
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also performed another clinical outcome analysis based on the PP population which are available in 
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the supplement. 
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Descriptive statistics were presented as mean ± standard deviation (SD), and as number and 
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percentage. We used Fisher’s exact test and chi-squared test to analyze categorical variables. We 
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used post hoc power analyses based on the primary efficacy, changes from baseline in MMD at 12th 
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weeks, to assess the adequacy of our sample size. All tests were two-sided. Statistical significance 
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was set at P value less than 0.05 (p < 0.05). All analyses were done using the statistical package SAS 
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version 9.4 for Windows. 
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