Zhengtian Capsule versus flunarizine in patients with migraine: a multi-center, double-blind, double-dummy, randomized controlled, non-inferior clinical trial

A multicenter, prospective, double-blind, double-dummy, positive drug parallel controlled, non-inferior clinical trial was conducted in our study. The study was carried out on 360 patients with migraine in 13 participating centers simultaneously. Since Zhengtian Capsule was previously reported rarely, the sample calculation of the study was determined in reference of Zhengtian Pill. The previous study showed that the responder rate of migraine attacks was 63.3 % in Zhengtian Pill and 52 % in flunarizine. We designed a non-inferiority testing. The sample size was estimated using standard methods for test of non-inferiority. Non-inferiority margin is - 5 %, alpha = 0.05, beta = 0.10. The computational formula was as follows:

To allow for a maximum drop-out rate of up to 15 %, 360 individuals should be enrolled in this study. We allocated a proportion of the two groups (1:1) and determined 180 patients for each group. There were a 3-month well documented retrospective history and a run-in period of 4 weeks without treatment. Then migraineurs who met the inclusion criteria were assigned to the experimental group and the control group randomly. The experimental group were treated with Zhengtian Capsule (0.9 g, three times a day) and flunarizine simulation (5 mg, quaque nocte). The control group were treated with flunarizine (5 mg, q.n) and Zhengtian Capsule simulation (0.9 g, tid). All the participants then underwent a therapeutic course of 12-week and 4-week of follow-up. There were totally five visits for each eligible patient conducted every 4-week interval: At baseline, week 4, week 8, week 12 and follow-up period respectively. Ibuprofen and other analgesic drugs were permitted during the process if necessary which were recorded in detail. Headache diary was handed out to each included patient, they were instructed to note the characteristics of the migraine attacks such as headache severity, functional disability, associated symptoms such as nausea, vomiting, photophobia, and phonophobia. The protocol and informed consent were reviewed and approved by the Ethics Committee of the Affiliated Dongzhimen Hospital of Beijing University of Chinese Medicine before commencing the trial. This study protocol was in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) ethical guidelines. Written informed consent was obtained from each subject prior to participation. The randomization sequence was computer generated in a 1:1 ratio by an independent statistician using SAS statistical software. There were accordant drug codes. All of the trial drugs were dispensed sequentially by a specified drug administrator in a separate reception room according to the sequence of inclusion of eligible patients. There were also sealed envelopes which served as emergency envelopes, when there were severe adverse events investigators would know which drug patients had received. All researchers, participants and statisticians were masked to treatment allocation throughout the trial.

Patients were recruited through advertising and outpatient departments of the 13 participating hospitals across China and through advertising. Four hundred eighteen patients were screened and 360 patients were randomized to treatment. The assessment was performed by principle investigators of the participating hospitals. The 13 participating hospitals were as follows: Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Xiamen Hospital of Traditional Chinese Medicine, the First Subsidiary Hospital of Anhui College of Traditional Chinese Medicine, the Affiliated Hospital to Changchun University of Chinese Medicine, the Central Hospital of Xuhui District, Hubei Hospital of Traditional Chinese Medicine, Nanfang Hospital of Southern Medical University, Beijing Pinggu District Hospital of Traditional Chinese Medicine, the Second Hospital of Jilin University, the First Affiliated Hospital of Henan University of Traditional Chinese Medicine, the Xiangya Hospital Central South University, the First Affiliated Hospital of Chongqing University of Traditional Chinese Medicine, Zhejiang Hospital of Traditional Chinese Medicine. All the patients had blood routine, urine routine, liver and renal function tests, electrocardiogram examinations, myocardial enzyme, myocardial injury markers, CT or MRI to exclude severe accompanying conditions before entrance to the trial.

Migraine without aura (MO) or with a typical aura (MA) both fulfilled the second edition of International Classification of Headache Disorders (ICHD-II) diagnostic criteria for migraine strictly [20].

A subject would be eligible for inclusion in the trial only if all the following criteria were fulfilled at baseline: (1) Diagnosed as MO or MA according to the diagnostic criteria specified by ICHD-II [20]. (2) Age of first onset ≤ 50 years old. (3) The patients had at least a 12-month history of migraine with or without aura as defined by the criteria of the 2004 International Headache Society. (4) Average migraine attacks per month were between 2 and 6 (including two times and six times) at baseline period. (5) Age between 18 and 65 years old.

A subject would not be eligible for inclusion in the trial if any of the following criteria applied at baseline: (1) Analgesics were used for acute headache >10 times per month. (2) For the previous 3 months before inclusion, migraine prevention drugs was taken, such as beta blockers, calcium channel blockers, anti-epileptic drugs, antidepressants and 5-HT receptor blockers, etc. (3) Alcohol or other drug abusers. (4) Combined with severe primary diseases such as cardiovascular, cerebrovascular, liver, kidney, hematopoietic system disease, etc. (5) Psychiatric patients. (6) Allergic to the trial drugs. (7) Pregnancy and lactation.

Participants in the experimental group were given Zhengtian Capsule and flunarizine simulation, while the control group were given flunarizine and Zhengtian Capsule simulation. The active drugs and simulations had identical appearance and were indistinguishable in taste, color, appearance and smell. Both of them were issued in a sealed box and provided by Hua Run San-Jiu Pharmaceutical Co.LTD. Zhengtian Capsule was taken 0.9 g at a time, three times a day after meal while flunarizine was taken 5 mg, quaque nocte. Ibuprofen and other analgesic drugs were permitted to use when necessary and should be well recorded. With other diseases such as infection, hypertension and diabetes, concomitant therapies that were allowed or on a restricted basis should be specified.

The primary outcome measure was responder rate (defined as the percentage of subjects in a treatment group with 50 % or greater reduction in attack frequency during treatment compared with the baseline period) [21]. Migraine attack temporarily relieved due to sleep or treatment relapsed within 48 h was defined as one single attack. Forty-eight hours of freedom between attacks of migraine permits identification of individual attacks.

The secondary outcome measures were migraine attack frequency, the number of migraine days, intensity for pain evaluated by VAS score, duration of migraine attacks, the times of using analgesics, PRO sacle of migraine and the SF-36 questionnaire. Weight changes were also measured. The VAS is a 10 cm continuous horizontal line that measures the severity of headache, it is a quantitative index for pain. Make the patients point out the number that can mostly represent the pain of his headache. Zero stands for no headache, ten stands for extreme headache. Score range 0 ∼ 4 stands for mild headache, score range 4 ∼ 7 stands for moderate headache, score range 7 ∼ 10 stands for severe headache [22]. The duration of each attack refers to the time from migraine onset to vanish, if the patient goes to sleep in pain, the time of vanishing is when he wakes up. Patient reported outcome (PRO) is a modern scientific approach widely used in evaluating outcomes of clinical trials based on patient centred evidence [23‐25]. A PRO is defined as any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else [26]. It highlights the importance of assessing the effectiveness of health care from the patients’ perspective.

Since there was no PRO sacle validated for migraine patients. Our previous study established a PRO sacle for remission period migraine patients with comprehensive contents and reasonable structure [27]. The four domains are headache, somatization symptoms, psychological state and functional status. It has been proved to imply treatment effect from multiple dimensions and with good reliability, validity and reaction degree [28, 29]. The PRO sacle also has a good connotation of traditional Chinese medicine with the concept of the holism of body and spirit as one of the basic Chinese medical theories. It has become a good complement to migraine clinical efficacy evaluation system and should not be ignored.

The SF-36 questionnaire assesses Health Related Quality Of Life in eight domains: Mental Health (MH), Role Emotional (RE), Social Functioning (SF), Vitality (VT), General Health (GH), Body Pain (BP), Role Physical (RP), Physical Functioning (PF). There are also two scales for mental and physical health, Mental Component Summary (MCS) score and Physical Component Summary (PCS) score.

In addition, the blood routine, urine routine, liver and kidney function tests, electrocardiogram, myocardial enzyme and myocardial injury markers were evaluated at the baseline and the treatment ended as safety evaluation endpoints. During the study, all adverse events were monitored and recorded on the case report form (CRF) including time of onset and resolution, severity and the relationship between adverse events and drugs analyzed by investigators.

SAS (Statistical package version 9.2) was used for Statistical analysis, which were prespecified using both per-protocol set (PPS) and full analysis set (FAS). PPS analyses were based on data from patients who had good compliance to complete the trial according to the criteria of protocol and who had taken 80–120 % amount of trial drugs. FAS analyses took the principle of intention-to-treat which were based on data from all the randomized patients who took at least one trial drug and the last observation carried forward (LOCF) approach was used to impute missing data. FAS is the main analysis set in this trial.