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Efficacy and safety of the Chaixiong Qiwei granule for tension-type headache: study protocol for a randomised controlled trial
  1. Wei Shen1,
  2. Xueming Fan1,
  3. Guojing Fu1,
  4. Hongxi Liu2,
  5. Xiao Liang1,
  6. Jingjing Wei1,
  7. Linjuan Sun1,
  8. Lu Zhang1,
  9. Xiansu Chi1,
  10. Yunling Zhang1
  1. 1Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China
  2. 2Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
  1. Correspondence to Dr Yunling Zhang; yunlingzhang2004{at}163.com

Abstract

Introduction Tension-type headache (TTH) is the most prevalent headache disorder worldwide. Although current treatments for TTH are beneficial, they are not without adverse effects. Chaixiong Qiwei granule (CXQW) is an experienced prescription medicine for TTH management. This study will evaluate the efficacy and safety of CXQW for the treatment of TTH.

Methods and analysis This study will be a multicentre, randomised, double-blind, placebo-controlled trial. A total of 148 eligible participants will be divided into the intervention (CXQW treatment) and control (placebo treatment) groups. The primary outcome will be the reduction in the number of headache days (headache-days reduction) within 9–12 weeks after randomisation, while secondary outcomes will include the number of headache days, headache intensity, responder rate, drug consumption for acute treatment, quality of life and symptoms related to traditional Chinese medicine use based on a symptom-observation table. This protocol describes the design of the randomised controlled trial.

Ethics and dissemination The study design was approved by the Institutional Review Board of Human Research at Xiyuan Hospital, China Academy of Chinese Medical Sciences (No. 2020XLA030-2).

Trial registration number ChiCTR2100042514.

  • tension-type headache
  • chronic pain
  • clinical trial
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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • This study evaluates the clinical effectiveness and safety of Chaixiong Qiwei for the treatment of tension-type headache and provides a new treatment method for this type of headache.

  • This study establishes an evaluation system for the treatment of tension-type headaches based on traditional Chinese medicine characteristics.

  • This multicentre trial will include participants from Beijing and Hebei; therefore, geographical limitations may exist.

  • Individual differences among participants and the subjectivity of headaches may lead to various drug efficacies.

Introduction

Tension-type headache (TTH) is the most prevalent neurological disorder1 and is typically characterised by bilateral pressure or tightening pain of mild-to-moderate intensity.2 Headaches play a prominent role in the ranking of disability-adjusted life-years in young and middle-aged people.3 A previous study demonstrated that TTH affected 38% of the general population,4 with a greater prevalence among women than men.5 TTH is categorised into three subtypes, namely: infrequent episodic, frequent episodic and chronic TTH.6 In clinical practice, frequent episodic TTH may evolve into chronic TTH7 and is associated with a high frequency of pain attacks that adversely affect the patient’s quality of life8 and pose a significant socioeconomic burden on medical institutions and society.9 Although the pathogenesis of TTH remains unclear, most studies tend to consider peripheral and central sensitisation as important causes of pain in TTH.10 Headache management predominantly focuses on clinical symptoms and can be classified as acute or preventive treatment.11 Non-steroidal anti-inflammatory drugs are widely used to treat acute headache, whereas prophylactic pharmacotherapy is typically administered to patients with high pain rates, such as those with frequent episodic and chronic TTH.12 However, the frequent and excessive use of analgesics potentially leads to a greater risk of patient toxicity and the development of medication-overuse headaches.13 Moreover, the efficacy of preventive drugs is often limited by associated adverse effects.14 Therefore, considering the transformational relationship between frequent episodic and chronic TTH, more effective medication are required.

Traditional Chinese medicine (TCM) is widely used in Asia to relieve pain.15 A previous study reported that botanicals are beneficial for the treatment of headaches16 and have a more positive effect than placebos in reducing headache frequency, days, duration and intensity, with fewer adverse events.17 Kakkonto, a Japanese kampo medicine, is also found to have the effect of relieving pain and improve peripheral sensitisation to act as an acute treatment for TTH.18 Non-pharmacological therapies, such as acupuncture and electroacupuncture, are also the effective strategies for TTH19 20; however, large-scale controlled trials are lacking. Previous studies suggest that Chuanxiong rhizoma (Chuanxiong), Radix bupleuri (Chaihu), Paeoniae radix alba (Baishao),and Angelicae sinensis radix (Danggui) are the four core prescriptions for the treatment of TTH.21 On this basis, combined with relevant clinical practice experience, we proposed the Chaixiong qiwei granule (CXQW) for the treatment of TTH. CXQW is composed of 10 g Radix bupleuri (Chaihu), 10 g Chuanxiong rhizoma (Chuanxiong), 10 g Leonuri fructus (Chongweizi), 10 g Bombyx batryticatus (Jiangcan), 10 g Sophora japonica linn (Huaihua), 6 g Scutellariae radix (Huangqin) and 15 g Paeoniae radix alba (Baishao) (table 1). Modern phytochemical studies have demonstrated that Radix bupleuri contains several active components, including saponins, volatile oils and polysaccharides,22 that are effective to relieve pain symptoms.23 In addition, volatile oil from Chuanxiong rhizoma significantly elevated the pain threshold of mice during a hot-plate test24 and decreased headache frequency, duration, days and pain severity in patients with migraine.25 Furthermore, Bombyx batryticatus has sedative hypnotic and neurotrophic roles.26 Scutellariae radix, includes baicalin and baicalein and has analgesic, anti-inflammatory and neuroprotective effects that reduce abnormal skin pain in patients with headaches.27 Paeoniae radix alba has anti-inflammatory, analgesic, hepatoprotective, antioxidant activities and outstanding advantages in headache treatment.28 In a previous self-controlled study (unpublished data), CXQW reduced headache duration (p<0.01) and relieved headache intensity (p<0.01). This patented application was accepted by the China National Intellectual Property Administration in 2022 (No. 202210254280.3). Therefore, a multicentre, randomised controlled trial has been planned to evaluate the therapeutic efficacy and safety of CXQW for the treatment of TTH and to generate new ideas and possible alternative TCM therapies for the clinical management of TTH.

Table 1

Components of CXQW

Methods and analysis

Study design

The proposed study is a multicentre, randomised, double-blind, placebo-controlled clinical trial that will be conducted at five hospitals, including one main centre (Xiyuan Hospital, China Academy of Chinese Medical Sciences) and four cooperation centres (Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing Chinese Medicine Hospital Pinggu Hospital, Beijing Huairou Hospital of TCM and Botou Hospital of TCM). This randomised, double-blind, placebo-controlled clinical trial will be conducted by a principal investigator, YZ. After obtaining written informed consent, the 148 participants will be randomly assigned to the intervention or control groups at a ratio of 1:1. This trial will comprise a 12-week intervention period and a 4-week follow-up period, in which participants will be monitored and evaluated via blood, urine and electrocardiography safety examinations. The study has been designed following the Standard Protocol Items for Clinical Trials with TCM29 and the guidelines for controlled trials of drugs for TTH.30 An overall flow diagram of the research procedure is shown in figure 1.

Figure 1

Flow chart of the study design. CXQW, Chaixiong Qiwei granule; FAS, full-analysis set; PPS, per-protocol analysis set; SAS, safety assessment set; TCM, traditional Chinese medicine.

Study population

Participant recruitment

Recruitment strategies will include advertisements on social media, print brochures and hospital outpatient consultations. Patients who consent to participate in the trial will be screened and diagnosed by the associate chief physicians and subsequently enrolled in the study on the provision of written informed consent. No restrictions will be enforced on the source of the patients (outpatients or inpatients). Patient enrolment commenced on 23 June 2021 and ended on 2 February 2023.

Inclusion criteria

  1. Patients meeting the diagnostic criteria for frequent episodic TTH.31

  2. Patients whose initial onset age was <50 years.

  3. Patients with a disease course >3 months and headache duration >5 days in the previous month.

  4. Patients aged 18–65 years.

  5. Patients who provided written informed consent.

Exclusion criteria

  1. Patients with TTH combined with migraine, cluster headache, other headache causes.

  2. Headache caused by systemic diseases, such as cardiovascular, acute infectious, blood, endocrine and metabolic diseases, allergic reactions and/or poisoning, among others.

  3. Headache caused by facial diseases, such as glaucoma, otitis media, sinusitis or pericoronitis of the wisdom teeth, among others.

  4. Headache caused by intracranial organic lesions, such as intracranial infections, brain tumours and subarachnoid haemorrhages, among others.

  5. Anxiety, Hamilton Anxiety Scale score ≥14 points.

  6. Depression, Hamilton Depression Scale score ≥17 points.

  7. Patients with abnormal liver and kidney function, exceeding two times or more the normal value.

  8. Patients identified as alcohol or drug dependent in the preceding 6 months.

  9. Patients with neurological diseases that potentially affect cognitive function, such as Alzheimer’s disease, severe Parkinson’s disease and encephalitis, among others.

  10. Women preparing for pregnancy and lactation or pregnant women.

  11. Patients who are allergic to the ingredients of the herbs used in this study.

  12. Patients participating in other clinical trials.

  13. Patients who could not comply with the study protocol.

Withdrawal criteria

  1. The development of new circumstances that render the participant unsuitable for continuing the trial.

  2. Participants who fail to continue due to the occurrence of serious adverse reactions during the study.

  3. Taking ibuprofen capsules for more than 15 days per month (patients can temporarily take Ibuprofen capsules when the headache is severe: 300 mg/capsule, one capsule/time, two times/day when pain persists; the oral dose and pain relief time will have to be recorded in detail).

  4. Participants will be excluded in cases of serious complications or deteriorations, and emergency measures will be taken during the study.

Drop-out criteria

Participants who fail to complete the intervention period of the trial, regardless of the time and reasons, will be considered drop-out cases. Reasons will be recorded in case report forms (CRFs) and included in data analysis. A participant will be removed if he/she:

  1. Exhibits poor compliance.

  2. Undergoes special physiological changes that render them unsuitable for further study.

  3. Drops out voluntarily.

  4. Does not use the intervention drugs according to the study protocol.

Randomisation and allocation concealment

A statistical expert appointed by the Good Clinical Practice (GCP) Centre of Xiyuan Hospital, China Academy of Chinese Medical Sciences, will be responsible for the blinded randomisation. An independent expert who is not involved during the intervention period will use SAS software (V.9.4; SAS Institute) to generate drug sequences and randomise allocation forms numbered 1–148. Details of the software program and randomisation scheme will be concealed at the GCP Centre of Xiyuan Hospital. Prior to the beginning of the trial, the blinded drugs and corresponding emergency envelopes will be distributed to each centre in consecutive number segments, and the drugs will be allocated to the enrolled patients based on the chronological order of recruitment.

Blinding

This trial will use the double-blind method. The statistical expert will initially verify the consistency of the appearance and packaging of the research drugs in each group and subsequently label on the outer packages with the drug number. Emergency envelopes sealed with a random number corresponding to the drug used in this study will be provided, with each participant assigned to an envelope. Unless special circumstances arise, researchers will not reveal the contents of the envelopes. Only when an emergency situation arises, and disclosure of the drug identity by the recruited participants is considered to facilitate the management of adverse events, will the investigators have the right to uncover the drugs. In addition, to enable blinding, 5% CXQW will be added to the placebo to assume the appearance, dose, colour, taste and smell of the CXQW.

Interventions

Eligible participants will be randomly divided into two groups: an intervention group (CXQW, 71 g per granule, twice per day) and a control group (placebo therapy involving the same treatment course, drug usage and dosage). The Chinese herbal granules are all provided by Beijing Tcmages Pharmaceutical. The observation period will be 16 weeks, including 12 weeks of drug therapy and 4 weeks to follow-up. None of the eligible participants will be allowed to take drugs with analgesic properties other than the trial drugs and TCM formulations with ingredients and effects similar to those of CXQW. The use of acupuncture and massages will also be restricted. However, concomitant treatments for comorbidities, such as hypertension, diabetes mellitus, hyperlipidaemia and other chronic conditions, as well as acute headache treatment with ibuprofen, will be permitted.

Study outcomes

During the 12-week intervention and 4-week follow-upperiods, all eligible participants will be evaluated based on predesigned outcome measures, including one primary and six secondary outcome indicators. Details of variables to be measured and the schedule of enrolment, intervention and assessment are shown in table 2.

Table 2

Study schedule

Primary outcome

The primary outcome of the study will be the reduction of the number of headache days. The number of headache days within 4 weeks prior to randomisation will be reported by the participants and compared with the number of headache days within 9–12 weeks after the intervention, which will be recorded in a predesigned headache diary. Headache-days reduction will be the difference between the number of headache days before and after the intervention.

Secondary outcome

  1. The number of headache days: The number of headache days will be recorded daily by participants using a headache diary. These numbers will be collected by the researchers each month. Recorded data will include headache onset date, cause, intensity, duration, nature, location, concomitant symptoms and use of CXQW or placebo.

  2. Headache intensity: Headache intensity will be evaluated using an 11-point Visual Analogue Scale, with 0 representing no headache, 5 representing a moderate headache and 10 representing a severe and unendurable headache. The participants will self-evaluate their headache intensity based on their subjective feelings, and a doctor will subsequently evaluate the intensity by observing the participant’s performance and behaviour when completing the report. A superior doctor will make a final judgement in cases where the scores of the two evaluations are inconsistent.

  3. Responder rate: The rate will be considered effective if the number of headache days decreases by more than 50% after the intervention compared with the number of headache days within 4 weeks before randomisation.30

  4. Drug consumption for acute treatment: The number of headache days involving treatment with ibuprofen capsules will be recorded, including dosage, duration and days of headache after medication.

  5. Quality of life: The 12-Item Short Form Health Survey, which comprises 12 items that evaluate the quality of life of eligible participants, including physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health, will be administered to participants. The higher the score, the better the quality of life.

  6. Observation of TCM symptoms: TCM symptoms will be observed using a participant-symptom table that was designed based on our early clinical experience and previous literature study of TTH,32 and it includes 26 symptoms with TCM characteristics, which will be recorded from multiple perspectives by uniformly trained neurologists.

Safety evaluation

Safety evaluations, including the monitoring of vital signs (body temperature, blood pressure, breathing and heart rate), laboratory examinations (blood routine, urine routine and liver renal function, including alanine aminotransferase, aspartate aminotransferase, total bilirubin and gamma-glutamyl transferase as well as blood urea nitrogen, urine creatinine and uric acid) and electrocardiography, will be implemented before and after the intervention. Any adverse reactions or events will be carefully analysed, and necessary measures will be adopted to minimise possible detriment to participants. Relevant records will be documented in the CRFs to assess causality with the interventions, including the duration, recurrence and disappearance of symptoms.

Adverse events

The adverse event is any adverse event of medical origin that occurs to a subject as a result of or during the administration of an investigational drug, whether or not causally related to the administration of the investigational drug or course of treatment.

First, any adverse event should be documented truthfully. Second, the severity should be judged. And finally, the causal relationship of the adverse event to the drug should be judged. Regardless of its severity and whether or not it is related to the study drug, an adverse event should be recorded on the appropriate page in the CRF, taken seriously and carefully analysed from the first day of the clinical research protocol after the visit or signing of the informed consent form until the end of the last follow-up visit planned for the study protocol. The investigator should take immediate measures to protect the safety of the subject, retest the event in 24 hours and within 7 and 14 days as appropriate, and record its persistence, regression and disappearance. In addition, any serious adverse event/reaction must be handled immediately and reported to the Medical Ethics Committee of the organisation or the main research unit in accordance with GCP regulations by completing the ‘serious adverse event report form’. In case of emergency, the patient should be blinded immediately and treated according to the drug and the symptoms. Meanwhile, the results should be notified to the clinical supervisor, and the researcher should record the date, treatment and results on the CRF and sign it.

Sample size

According to data from a previous study, it is predicted that the number of headache days in the intervention group will be reduced by 2.5 days and those in the control group by 1.5 days compared with the number of headache days at baseline, with an SD of 2.1. The inspection levels (α) of both sides are 0.05, and the degree of assurance (1–β) is 80%. The participants will be allocated to the intervention and control groups at a ratio of 1:1. The estimated sample size of each group is 59 participants. Based on a possible drop-out rate of 20%, 148 eligible participants will need to be included in this study.

Data monitoring and quality control

To ensure research quality, a multicentre, clinical monitoring mechanism will be established. Prior to participant recruitment, uniform preclinical training will be conducted, through which all staff, including physicians, data collectors and analysers, will be fully informed regarding the purpose and content of the study in an effort to standardise the CRF completion process during data collection. In addition, the supervisors at Xiyuan Hospital will offer guidance at each centre when the first participant is enrolled and will conduct periodic on-site inspections to ensure a consistent and accurate study process. During the clinical trial, the clinical monitor will conduct regular on-site inspection visits to ensure the quality of the CRFs.

Data management and statistical analysis

The statistical analysis plan will be specified before the data analyses. The statistical analyses will be undertaken by the GCP Centre of Xiyuan Hospital, China Academy of Chinese Medical Sciences. Only authorised study personnel are able to view and manage data. Three analysis sets will be used for statistical processing. According to the intention-to-treat principle, all randomly enrolled participants with more than one medication record and efficacy evaluation after intervention will be included in the full-analysis set (FAS). The missing values will be estimated using the last-observation-carried-forward method to replace the absent data. The per-protocol set (PPS) will include participants who fully comply with the study protocol and provide the relevant information as required by the study. Serious protocol violations may include, but are not limited to, interference in treatment (contraindication) and detachment. The analysis of demographic and baseline characteristics and curative assessments will be performed using the FAS and PPS approaches. The safety set will include all participants who would have received at least one treatment and safety evaluation after randomisation.

SPSS V.22.0 (V.22.0; IBM) will be used to complete the statistical analyses, and a two-sided test will be used, with a significance level of p<0.05. Quantitative data will be described using the basic statistical description method of numerical variable indicators. Normally distributed data will be reported as mean and SD will be calculated, while the median and quartile spacing will be calculated for non-normally distributed data. Categorical variables will be presented as frequencies and percentages of cases.

Primary and continuous secondary outcomes will be analysed using a linear mixed-effects model. Missing data will be imputed with multiple imputation under the assumption of random missing and non-random missing data, and a sensitivity analysis will be performed. To assess the secondary outcome of a ≥50% reduction in the mean number of TTH days per month, the stratified Cochran-Mant-Haenszel test will be used after imputing missing data as ‘no response’. Sensitivity analyses for this outcome will include the generalised linear mixed-effects models without the imputation of any missing data. The FAS and PPS analyses will be conducted separately. In cases where the conclusions of the two datasets are inconsistent, the two datasets will be evaluated and analysed. Other secondary outcomes will be analysed as evidence to support the conclusions drawn from the primary indicators.

Discussion

The Global Burden of Diseases, Injuries and Risk Factors 2016 study revealed that headaches area major emerging global public health concern.33 More than half of the 1.89 billion people with TTH worldwide report impaired social activities and working ability.33 However, due to the lack of attention from scientists, funding agencies and the pharmaceutical industry, treatments for TTH are lacking.34 Considering the insufficient treatment strategies included in the current guidelines and the common side effects cited in various studies, our research team conducted an in-depth study regarding the pathogenesis of TTH and distribution of TCM symptoms, and a systematic review of the efficacy and safety of TCM and acupuncture for the treatment of TTH.32 35 36 We believe that the current quality of clinical research regarding treatments for TTH is low, and high-quality clinical studies are needed to provide more adequate evidence for the treatment of TTH using TCM. Therefore, we designed a multicentre, randomised, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of CXQW as a prescription treatment for TTH. The key pathogenic mechanism of TTH is that the disease stays in Shaoyang, and phlegm and stasis are intertwined. Therefore, the proposed study evaluates the use of CXQW for the treatment of TTH over a 12-week intervention period. The clinical effectiveness and safety of CXQW for the treatment of TTH will be evaluated based on the reduction of the number of headache-days, headache days, headache intensity, responder rate, requirement of acute treatment, quality of life and observation of common TCM symptoms. These factors were used to establish an evaluation system for the treatment of TTH with TCM characteristics, providing evidence regarding new treatment methods. In addition, a TCM symptom table including 26 symptoms and the TCM tongue and pulse was created to carefully monitor changes in symptoms, accurately describe the efficacy of TCM, and provide a template for future studies regarding TTH.

Although this protocol uses a rigorous randomised controlled-trial design to evaluate the effectiveness of the drug, potential limitations may arise. First, the prevalence of TTH varies between regions due to differences in demographic characteristics, and this multicentre trial will include only participants from Beijing and Hebei. Therefore, geographical limitations may exist. Second, a lack of objective indicators for the evaluation of headache outcomes remains. Individual differences between participants and the subjectivity of headache may lead to the recording of various drug efficacies. Third, severe headaches may lead to poor patient compliance, thus potentially influencing the therapeutic effects. Patients will be required to maintain a detailed record of their medications during the intervention period. Patients who are not able to follow the clinical trial protocol regarding the use, visitation and follow-up of the drug will be withdrawn from the study if the investigators determine that the lack of protocol may affect the authenticity of the research results. Finally, the number of headache days within 4 weeks before randomisation will be recorded via participant recall, which may result in observation deviations due to memory errors.

Patient and public involvement

Patients and the public were not involved in the design and planning of the study. Patient and public representatives will be informed about the study. A summary of the findings will be made available to the patient and public representatives.

Ethics and dissemination

This study has been approved by the Institutional Review Board of Human Research of Xiyuan Hospital, China Academy of Chinese Medical Sciences (No. 2020XLA030-2). Beijing Chinese Medicine Hospital Pinggu Hospital has reconducted the ethics approval, and the ethics approval number is 2020-bjsfzx-hzkt-01. Beijing Hospital of Integrated Traditional Chinese and Western Medicine, Beijing Huairou Hospital of TCM and Botou Hospital of TCM have approved the ethics approval document and ethics review decision of the research leader committee, and have signed the certificate. In order to ensure the standardisation of the process and the safety of the participants’ information, all subjects will be informed of every detail of the trial and will sign a written informed consent form before participating in the trial. To protect the privacy of participants, the data forms and eCRFs involved in this study will be kept in secure storage in the coordination centre.

Ethics statements

Patient consent for publication

Acknowledgments

We would like to express our appreciation to the participants as well as the neurologists, experts, data collectors, statistical analysts, and physicians from each cooperation centre for their contributions. Furthermore, we acknowledge the patients with TTH who participated in this trial.

References

Footnotes

  • Twitter @676665709@qq.com

  • WS, XF and GF contributed equally.

  • Contributors YZ, WS, XF and GF designed this study. WS, XF and GF contributed equally to the study and drafted the manuscript. WS is responsible for this protocol. HL, XL, JW, LS, LZ and XC participated in the modification of the study protocol. WS and XF designed the method for statistical analyses. All authors contributed to the article and approved the final manuscript.

  • Funding This research was supported by the Capital Health Research and Development of Special (No. 2020-2-4173), Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (No. CI2021B006), Innovation Team and Talents Cultivation Programme of National Administration of Traditional Chinese Medicine (No. ZYYCXTD-C-202007) and the National TCM Leading Personnel Support Programme (NATCM Personnel and Education Department (2018)) (No.12).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.