Skip to content

Advertisement

BMC Complementary and Alternative Medicine

What do you think about BMC? Take part in

Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

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

  • Kegang Cao1,
  • Fang Han1,
  • Anji Lin2,
  • Wenming Yang3,
  • Jianjun Zhao4,
  • Hui Zhang5,
  • Yanbing Ding6,
  • Wei Xie7,
  • Yinping Xu8,
  • Tingmin Yu9,
  • Xinzhi Wang10,
  • Xiaosu Yang11,
  • Jiying Zhou12,
  • Qun Hou13,
  • Lihua Yu14 and
  • Ying Gao1Email author
Contributed equally
BMC Complementary and Alternative MedicineBMC series – open, inclusive and trusted201616:356

https://doi.org/10.1186/s12906-016-1321-8

Received: 6 February 2016

Accepted: 25 August 2016

Published: 13 September 2016

Abstract

Background

The primary objective of this study was to assess whether Zhengtian Capsule was non-inferior to flunarizine in efficacy and safety profile for prevention of migraine in adults.

Methods

This was a double-dummy, double-blind, multicenter, positive drug (flunarizine), parallel randomized controlled, non-inferior clinical trial. Patients (n = 360) were randomized in a 1:1 to receive either Zhengtian Capsule or flunarizine, including 12 weeks’ intervention and 4 weeks’ follow-up. 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). The secondary outcome measures included migraine attack frequency, the number of migraine days, pain evaluated by visual analogue scale (VAS) score, duration of migraine attacks, the times of using analgesics, patient-reported outcome (PRO) measure of migraine and the scores of short-form 36 Health Survey Scale (SF-36). Weight variation in both groups was also evaluated. Adverse events were monitored throughout the trial.

Results

Zhengtian Capsule was non-inferior to flunarizine in responder rate at week 12 and follow-up period (P = 0.002, P < 0.001). There was fewer migraine days in Zhengtian Capsule group at follow-up period compared with flunarizine (P = 0.001). For the total duration of migraine attacks, there was significant group difference at week 4 which favored the control group (P = 0.009). For the total score of PRO scale, there was statistical difference between the two groups at follow-up period (P = 0.021). There were also group differences between the two groups in the dimensions of somatization symptoms at week 4 (P = 0.022) and functional status at week 12 and follow-up period (P < 0.001, P < 0.001). However, there were no significant differences between the two groups in migraine attack frequency, VAS scores reduction, consumption of acute pain drugs and the dimension scores of SF-36 at any time interval of the treatment period (P > 0.05). No severe adverse events occurred in the trial. Flunarizine was found associated with a weight gain.

Conclusion

Zhengtian Capsule was non-inferior to flunarizine with regard to the primary endpoint. In addition, it could reduce migraine days and improve the functional status and somatization symptoms of migraine patients with good safety profile.

Trial registration

This trial was registered at Chinese Clinical Trial Register (ChiCTR), ChiCTR-TRC-13004412.

Keywords

Zhengtian CapsuleFlunarizineMigraineRandomized controlled trialNon-inferior

Background

Migraine is a common disabling primary headache disorder characterized by recurrent unilateral location, throbbing quality, moderate or severe intensity, associated with symptoms such as nausea, vomiting, photophobia and phonophobia, usually aggravated by routine physical activities [1]. According to the Global Burden of Disease Survey 2010 (GBD2010), migraine was estimated a global prevalence of 14.7 %, ranked as third most common diseases in the world in both males and females [2]. Generally, it has been reported that female migraine sufferers tend to outnumber male sufferers by nearly 3 to 1 [35]. Migraine is burdensome and costly. On account of substantial impairment on work or school productivity, it negatively impacts human capital accumulation and brings about a heavy socioeconomic burden [68]. Migraine is also a disease that contributes to major disability thus leading to low life quality. It was ranked as the seventh-highest specific cause of disability worldwide [2, 9]. In addition, it is associated with a number of comorbidities, including psychiatric disease, sleep disturbances, stroke and other chronic pain disorders [1012]. The status quo in China is similar to the world average [13, 14]. Due to its high prevalence and disabling feature, migraine has become an important target issue for public health interventions.

Migraine is divided into acute episode and chronic remission period. Accordingly, the treatment is divided into abortive treatment and preventive treatment. The former intends to return the patient to full function within 2 h, whereas, the latter with a goal of improving the health-related quality of life in patients with migraine. For acute treatment, there are specific and nonspecific treatment methods. Triptans and dihydroergotamine are effective specific medications, nonsteroidal anti-inflammatory drugs, opioids and barbitals are effective nonspecific medications [15]. For the preventive treatment, there are angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACEI), antiepileptic drugs (AEDs), antidepressant drugs, calcium channel blockers (CCB), beta-receptor blocker, etc. However, there exists some side effects which inhibit the widely use of these drugs [16, 17]. In this trial we use flunarizine as the positive comparator drug because it is widely used for migraine with proven efficacy and safety. Zhengtian Capsule is a dosage form modified from Zhengtian Pill, which is a Chinese Patent medicine proved effectively in treating migraine in previous studies [18, 19]. It is composed of 15 herbal compositions: Uncariae Ramulus Cum Uncis(Gou Teng), Ephedrae Herba(Ma Huang), Asari Radix Et Rhizoma(Xi Xin), Aconiti Lateralis Radix Praeparata(Fu Pian), Paeoniae Radix Alba(Bai Shao), Persicae Semen(Tao Ren), Cartham Flos(Hong Hua), Rehmanniae Radix(Di Huang), Angelicae Sinensis Radix(Dang Gui), Chuanxiong Rhizoma(Chuanxiong), Notopterygh Rhizoma et Radix(Qiang Huo), Angelicae Pubescentis Radix(Du Huo), Saposhnikoviae Radix(Fang Feng), Spatholobi Caulus(Ji Xue Teng), Angelicae Dahuricae Radix(Bai Zhi). Studies on Zhengtian Capsule with a multicenter, double blind, randomized controlled trial are rarely known. Hence, we conducted a multi-center, double-blind, double-dummy, randomized controlled, non-inferior clinical trial to determine whether or not Zhengtian Capsule was non-inferior in effectiveness and safety to flunarizine in the prophylaxis of migraine.

Methods

Study design

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:
$$ \begin{array}{c}n=\frac{{\left({z}_{1-\alpha }+{z}_{1-\beta}\right)}^2\times \left[{P}_1\left(1-{P}_1\right)+{P}_2\left(1-{P}_2\right)\right]}{{\left(\varepsilon -\delta \right)}^2}\\ {}=\frac{{\left(1.65+1.28\right)}^2\times \left[0.63\left(1-0.63\right)+0.52\left(1-0.52\right)\right]}{{\left(0.113-\left(-0.05\right)\right)}^2}\\ {}\approx 156\end{array} $$

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.

Setting and participants

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.

Diagnostic criteria

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].

Inclusion criteria

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.

Exclusion criteria

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.

Interventions

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.

Outcome measures

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 [2325]. 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.

Statistical methods

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.

In addition, responder rate was compared between the two groups using non-inferior test, with non-inferiority margin - 0.5. For the changes in migraine attack frequency, the number of migraine days, duration of migraine attacks, the times of using analgesics, VAS scores, PRO scores, weight changes and SF-36 dimension scores, analysis of covariance (ANCOVA) with baseline variables as covariates were used to compare the differences between the two groups at different time points. The level of significance was set at 0.05, if P < 0.05, there were statistical differences.

Results

Of all the 360 randomized patients, 357 of their data were included in FAS analyses (intention-to-treat analyses). There were two lost to follow up and one withdrew the informed consent in the treatment group. Therefore, 177 of 180 patients in treatment group and all patients in control group were included into FAS. In comparison, 312 patients were put into PPS, 153 from the treatment group and 159 from the control group. In the process of the entire study, 48 patients dropped out, a rate of 13.33 % (27 from the treatment group 15 %, 21 from the control group 11.67 %). Among these, 21 patients lost to follow-up (12 from the treatment group, nine from the control group), four patients withdrew the informed consent (three from the treatment group, one from the control group), three patients dropped out for adverse events (two from the treatment group, one from the control group), 13 patients dropped out because of overstepping the time window (eight from the treatment group, five from the control group), seven dropped out for other reasons. The reasons for the dropouts are detailed in Fig. 1.
Fig. 1

Flow diagram of the study progress about enrollment, randomization, intervention, and completion of the trial

Characteristics of demography and baseline

The demographic and baseline clinical characteristics of the two groups were comparable at baseline as shown in Table 1. There were no statistical significances in FAS between the two groups (P > 0.05).
Table 1

Baseline characteristics of migraine patients (FAS)

Parameters

Treatment group (n = 177)

Control group (n = 180)

P value

sex(Male/Female)

54/123

63/117

0.366

Age(year)

39.70 ± 12.81

38.99 ± 11.56

0.654

weight

59.74 ± 9.22

60.94 ± 10.07

0.301

Course (months)

95.76 ± 86.82

91.61 ± 81.87

0.695

Migraine days

4.02 ± 2.16

4.09 ± 1.73

0.181

Migraine attacks

3.37 ± 1.16

3.53 ± 1.11

0.099

Total duration(h)

31.87 ± 36.47

30.26 ± 27.90

0.936

VAS scores

5.63 ± 1.31

5.63 ± 1.27

0.661

Analgesic consumption(times)

1.34 ± 1.66

1.35 ± 1.87

0.726

Total scores of PRO

34.34 ± 5.82

34.94 ± 5.63

0.189

Headache

12.50 ± 1.983

12.71 ± 1.89

0.237

Somatization symptoms

10.53 ± 2.47

10.50 ± 2.51

0.910

Psychological state

4.71 ± 1.46

4.89 ± 1.49

0.195

Functional status

5.77 ± 1.51

5.92 ± 1.49

0.348

PF

92.91 ± 7.07

92.97 ± 8.08

0.527

RP

63.07 ± 37.51

64.56 ± 37.56

0.257

BP

53.71 ± 13.78

52.97 ± 13.98

0.636

GH

60.91 ± 16.93

61.86 ± 17.19

0.531

VT

72.52 ± 13.87

72.31 ± 14.71

0.781

SF

77.07 ± 13.18

75.24 ± 14.56

0.630

RE

70.42 ± 36.22

64.13 ± 39.73

0.371

MH

72.93 ± 14.41

71.39 ± 15.87

0.766

MCS

73.23 ± 14.83

70.77 ± 17.60

0.620

PCS

67.65 ± 14.31

68.09 ± 14.68

0.596

Responder rate

The responder rates in the treatment group and control group were 21.47 % VS 21.11 % after 4 weeks (P = 0.108), 34.46 % VS 38.89 % after 8 weeks (P = 0.455), 59.89 % VS 49.44 % after 12 weeks (P = 0.002) and 54.80 % VS 38.33 % at follow-up period (P < 0.001). After 12 weeks’ treatment and during follow-up period, Zhengtian Capsule was non-inferior to flunarizine (Table 2).
Table 2

Comparison of responder rate (FAS)

Responder rate

Treatment group (n = 177)

Control group (n = 180)

P value

4 W

38(21.47 %)

38(21.11 %)

0.108

8 W

61(34.46 %)

70(38.89 %)

0.455

12 W

106(59.89 %)

89(49.44 %)

0.002*

Follow-up period

97(54.80 %)

69(38.33 %)

<0.001*

Note: Non-inferiority margin was −0.5

*P < 0.05 for data comparison between groups after treatment

Migraine attacks

Migraine attacks have significantly decreased in the treatment group from 3.37 ± 1.16 at baseline to 1.37 ± 1.30 during follow-up period, whereas from 3.53 ± 1.11 to 1.55 ± 1.30 in the control group. However, no group differences were seen at any time points (Table 3).
Table 3

Differences from baseline in efficacy variables at different time points (FAS)

Variable

Treatment group (n = 177)

Control group (n = 180)

P value

Migraine attacks

 4 W

2.66 ± 1.40

2.66 ± 1.20

0.864

 8 W

2.04 ± 1.30

1.93 ± 1.19

0.153

 12 W

1.57 ± 1.46

1.42 ± 1.12

0.460

 Follow-up period

1.37 ± 1.30

1.55 ± 1.30

0.398

Migraine days

 4w

2.98 ± 1.74

2.91 ± 1.41

0.994

 8w

2.25 ± 1.72

2.13 ± 1.42

0.588

 12 w

1.73 ± 1.78

1.58 ± 1.34

0.093

 Follow-up period

1.46 ± 1.55

1.68 ± 1.50

0.001*

VAS scores

 4w

4.94 ± 1.26

4.79 ± 1.14

0.990

 8w

4.34 ± 1.31

4.22 ± 1.23

0.404

 12 w

3.58 ± 1.05

3.26 ± 1.47

0.141

 Follow-up period

3.87 ± 1.25

3.85 ± 1.41

0.852

Total Duration(h)

 4w

19.70 ± 19.69

19.18 ± 19.24

0.009*

 8w

14.68 ± 21.83

12.41 ± 14.41

0.753

 12 w

11.71 ± 24.83

8.69 ± 12.89

0.526

 Follow-up period

7.55 ± 13.76

7.31 ± 11.74

0.140

Analgesic consumption (times)

 4w

0.96 ± 1.30

1.01 ± 1.59

0.229

 8w

0.86 ± 1.65

0.76 ± 1.42

0.862

 12w

0.70 ± 1.52

0.51 ± 1.07

0.360

 Follow-up period

0.51 ± 1.37

0.41 ± 1.29

0.652

Note: *P < 0.05 for data comparison between groups after treatment

Number of migraine days

As compared to baseline, migraine days decreased throughout the study period in both groups. The difference in the number of migraine days between the two groups was significant at follow-up period (P = 0.001) (Table 3).

VAS scores

After treatment, the VAS scores in the two groups declined month by month compared with the baseline. During the treatment course, the VAS scores decreased from 5.63 ± 1.31 to 3.87 ± 1.25 throughout the study period in the treatment group, whereas from 5.63 ± 1.27 to 3.85 ± 1.41 in the control group. However, there were no statistical differences between the two groups at any 4-week of time interval (Table 3).

Total duration of migraine attacks

There was a significant decrease in total duration of migraine attacks per 4 weeks in both groups, and there was significant group difference at week 4 which favored the control group (P = 0.009) (Table 3).

Analgesic consumption

In both groups, frequency of using acute pain drugs at each time point was markedly reduced compared to baseline. However, there were no significant differences between the two groups at week 4, week 8, week 12 and follow-up period (P > 0.05) (Table 3).

The scores of patient reported outcome (PRO) scale of migraine

During the study period, the total scores of PRO were descending gradually in both groups. At follow-up period, there was statistical difference between the two groups (P = 0.021). For the dimension score of functional status, there were group differences between the two groups at week 12 and follow-up period (P < 0.001, P < 0.001). For the dimension score of somatization symptoms, there was group difference at week 4 after treatment (P = 0.022) (Table 4).
Table 4

Comparison of the scores of PRO for migraine (FAS)

 

Treatment group (n = 177)

Control group (n = 180)

P values

Total score

 4w

29.68 ± 5.87

30.18 ± 5.86

0.767

 8w

26.97 ± 6.72

26.79 ± 7.26

0.455

 12 w

22.90 ± 6.63

23.80 ± 7.27

0.301

 Follow-up period

21.61 ± 6.47

23.41 ± 6.80

0.021*

Headache

 4w

10.88 ± 2.07

11.05 ± 2.24

0.725

 8w

9.56 ± 2.62

9.52 ± 2.76

0.643

 12 w

8.54 ± 2.78

8.23 ± 2.88

0.246

 Follow-up period

7.95 ± 2.73

8.31 ± 2.98

0.283

Somatization symptoms

 4w

9.46 ± 2.66

9.48 ± 2.48

0.022*

 8w

8.83 ± 2.67

8.57 ± 2.72

0.340

 12 w

7.62 ± 2.51

7.72 ± 2.65

0.660

 Follow-up period

7.52 ± 2.49

7.61 ± 2.38

0.745

Psychological state

 4w

4.26 ± 1.36

4.43 ± 1.45

0.650

 8w

3.97 ± 1.36

4.14 ± 1.56

0.565

 12w

3.51 ± 1.29

3.81 ± 1.39

0.086

 Follow-up period

3.42 ± 1.24

3.72 ± 1.29

0.101

Functional status

 4w

5.08 ± 1.41

5.22 ± 1.52

0.697

 8w

4.61 ± 1.58

4.55 ± 1.63

0.442

 12 w

3.23 ± 1.36

4.04 ± 1.59

P < 0.001*

 Follow-up period

2.71 ± 1.16

3.77 ± 1.46

P < 0.001*

*P < 0.05 for data comparison between groups aftertreatment

SF-36

After 12 weeks’ treatment, most of the sub-dimensions of the SF-36 scores have improved in both groups. However, no significant differences were observed between the two groups (P > 0.05) (Table 5).
Table 5

Comparison of the dimension scores of SF-36 (FAS)

Dimension

Treatment group

Control group

P value

PF

92.99 ± 9.96

93.972 ± 9.18

0.268

RP

74.00 ± 34.36

74.44 ± 34.75

0.648

BP

71.85 ± 16.90

73.87 ± 17.17

0.171

GH

67.55 ± 15.71

66.70 ± 16.54

0.381

VT

75.96 ± 13.80

76.03 ± 14.48

0.892

SF

81.85 ± 14.59

83.40 ± 15.17

0.127

RE

78.72 ± 35.07

81.29 ± 32.52

0.174

MH

75.66 ± 13.54

74.24 ± 14.39

0.407

MCS

78.05 ± 16.18

78.74 ± 16.02

0.299

PCS

78.57 ± 13.61

78.03 ± 15.12

0.594

Weight changes

Notably, we found patients taking flunarizine had a weight gain, whereas those taking Zhengtian Capsule were not evident. A significant difference between the two groups was observed in the change of weight gain from baseline and week 8 (P < 0.001), week 12 (P < 0.001) (Table 6).
Table 6

Comparison of weight changes (FAS)

Weight

Treatment group (n = 177)

Control group (n = 180)

P value

4w

59.88 ± 9.17

61.15 ± 10.01

0.290

8w

59.89 ± 9.13

61.51 ± 9.99

P < 0.001

12 w

60.27 ± 9.08

61.97 ± 10.00

P < 0.001

Follow-up period

60.31 ± 9.05

61.46 ± 10.07

0.871

Safety and tolerability

In total, there were 46 (12.8 %) patients experienced adverse events in the process of the trial, 21 (11.86 %) from the treatment group, 25 (13.89 %) from the control group (P = 0.636). The adverse events were drowsiness, canker sore, upper respiratory tract infection, elevated ALT, et al. There was no need of special clinical dispose. No significant serious adverse events appeared in both groups. In addition, the compliance was similar in two groups and there was no statistical difference (P = 0.654).

Discussion

In the present randomized controlled trial, Zhengtian Capsule and flunarizine were compared with respect to effectiveness and safety profile. We have shown that Zhengtian Capsule was non-inferior to flunarizine in responder rate at week 12 and follow-up period.

To our knowledge, this was the first active-controlled randomized trial of Zhengtian Capsule on migraine prevention which was consistent with Guidelines for Controlled Trials of Drugs in Migraine (second edition) [21]. In this trial, Zhengtian Capsule showed similar efficacy and safety with flunarizine, which was being recommended as a first-line drug for preventive treatment of migraine by European Federation of Neurological Societies (EFNS) [30].

Previous studies have shown that migraineurs accordantly report a lower quality of life in physical health, mental health, social functioning and academic performance compared with those non-migraineurs [31]. A large percent of migraine patients were presented functional symptoms [32] and associated somatic symptoms [33]. Negative affect is a common trigger of migraine which plays an important role in the occurrence and development of migraine [34]. In our trial, Zhengtian Capsule was found to have a strength in improving patients’ functional status and somatization symptoms thus improving the life quality of migraineurs.

Although there was no significant difference between the two groups regarding the incidence of adverse events in the current study and no severe adverse events occurred, there was unfavorable gained weight in the flunarizine group in our findings. This result was in agreement with the findings of previous trials by Sørensen PS [35], Luo N [36] and Wang LP [37]. Zhengtian Capsule, on the other hand, was not significantly affect body weight, complete blood count, or liver and kidney functions which suggested that this herbal drug is safe to use. Although the results of the present study need to be confirmed in future larger clinical trials, Zhengtian Capsule holds promising potential as an effective and practical means to prevent migraine.

The strengths of our study lies in the following aspects. Firstly, the sample size was large and patients’ selection biases were avoided with the randomization and blinding method. Secondly, in view of ethic we included an active control group instead of placebo control. Additionally, the design was consistent with Guidelines for Controlled Trials of Drugs in Migraine (second edition) and the outcome measures we used were reliable. Nevertheless, the present study has some limitations that warrant consideration. Most of the outcome measures used in our trial were based on patient’s subjective feelings and there weren’t many objective indicators. Besides, a daily dose of 5 mg flunarizine was a relatively low dose compared with the previous studies [38, 39] which may have led to a modest improvement in the efficacy outcome measures of migraine. Ten milligram flunarizine may guarantee a more rapid efficacy [40]. Therefore, we should bear these in mind when interpreting our findings.

Conclusion

In summary, Zhengtian Capsule was non-inferior to flunarizine with regard to the primary endpoint. In addition, it could reduce migraine days and improve the functional status and somatization symptoms of migraine patients with good safety profile. This Chinese Patent Medicine may therefore be an option for the prophylactic treatment of migraine.

Abbreviations

ACEI: 

Angiotensin converting enzyme inhibitor

AEDs: 

Antiepileptic drugs

ANCOVA: 

Analysis of covariance

ARB: 

Angiotensin receptor blockers

BP: 

Body pain

CCB: 

Calcium channel blockers

CPM: 

Chinese patent medicine

CRF: 

Case Report Form

EFNS: 

European Federation of Neurological Societies

GCP: 

Good clinical practice

GH: 

General Health

LOCF: 

Last observation carried forward

MA: 

Migraine with a typical aura

MCS: 

Mental component summary

MH: 

Mental health

MO: 

Migraine without aura

PCS: 

Physical component summary

PF: 

Physical functioning

PRO: 

Patient-reported outcome

Qn: 

Quaque nocte

RE: 

Role emotional

RP: 

Role physical

SF: 

Social functioning

SF-36: 

Short-form health survey scale

Tid: 

Three times a day

VAS: 

Visual analog scale

VT: 

Vitality

Declarations

Acknowledgments

The authors appreciate the approval of Hua Run San-Jiu pharmaceutical Co.LTD for medication supply.

Funding

This study was supported by Project of National Great New Drug Research and Development (No.2009zx09502-028) and the National Natural Science Foundation of China (No. 81273688).

Availability of data and materials

The data supporting the conclusions of this article are contained in the paper.

Authors’ contribution

FH and KGC contributed equally to this work. All the authors participated in the preparation of the manuscript. KGC conceived the idea and designed the study. FH has been involved in drafting the manuscript and revising it for important intellectual content. AJL, WMY, JJZ, HZ, YBD, WX, YPX, TMY, XZW, XSY, JYZ and QH participated in data acquisition.LHY helped with statistical analysis and interpretation of data. YG conceived the study and helped to ensure the accuracy and integrity of any part of the study. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

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.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Neurology, Dongzhimen Hospital, Beijing University of Chinese Medicine
(2)
Department of Neurology, Xiamen Hospital of Traditional Chinese Medicine
(3)
Department of Neurology, The First Subsidiary Hospital of Anhui College of Traditional Chinese Medicine
(4)
Department of Neurology, The Affiliated Hospital to Changchun University of Chinese Medicine
(5)
Department of Traditional Chinese Medicine, the Central Hospital of Xuhui District
(6)
Department of Neurology, Hubei Hospital of Traditional Chinese Medicine
(7)
Department of Traditional Chinese Medicine, Nanfang Hospital of Southern Medical University
(8)
Department of Acupuncture, Beijing Pinggu District Hospital of Traditional Chinese Medicine
(9)
Department of Neurology, the Second Hospital of Jilin University
(10)
Department of Neurology, the First Affiliated Hospital of Henan University of Traditional Chinese Medicine
(11)
Department of Neurology, the Xiangya Hospital Central South University
(12)
Department of Neurology, the First Affiliated Hospital of Chongqing University of Traditional Chinese Medicine
(13)
Department of Neurology, Zhejiang Hospital of Traditional Chinese Medicine
(14)
Department of Emergency Medicine, the Third Hospital affiliated with Beijing University of Traditional Chinese Medicine

References

  1. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders (beta version). Cephalalgia. 2013;33(9):629–808.View ArticleGoogle Scholar
  2. Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2013;380(9859):2163–96.View ArticleGoogle Scholar
  3. Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia. 2007;27(3):193–210.View ArticlePubMedGoogle Scholar
  4. Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache J Head Face Pain. 2015;55(1):21–34.View ArticleGoogle Scholar
  5. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1278–99.View ArticlePubMedGoogle Scholar
  6. Ayzenberg I, Katsarava Z, Sborowski A, Chernysh M, Osipova V, Tabeeva G, et al. Headache-attributed burden and its impact on productivity and quality of life in Russia: structured healthcare for headache is urgently needed. Eur J Neurol. 2014;21(5):758–65.View ArticlePubMedGoogle Scholar
  7. Rees DI, Sabia JJ. The effect of migraine headache on educational attainment. J Hum Resour. 2011;46(2):317–32.View ArticleGoogle Scholar
  8. Steiner TJ, Scher AI, Stewart WF, Kolodner K, Liberman J, Lipton RB. The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia. 2003;23(7):519–27.View ArticlePubMedGoogle Scholar
  9. Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. Cephalalgia. 2013;33(5):289–90.View ArticlePubMedGoogle Scholar
  10. Pompili M, Di Cosimo D, Innamorati M, Lester D, Tatarelli R, Martelletti P. Psychiatric comorbidity in patients with chronic daily headache and migraine: a selective overview including personality traits and suicide risk. J Headache Pain. 2009;10(4):283–90.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Morgan I, Eguia F, Gelaye B, Peterlin BL, Tadesse MG, Lemmaet S, et al. Sleep disturbances and quality of life in Sub-Saharan African migraineurs. J Headache Pain. 2015;16(1):18.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Li L, Schulz UG, Kuker W, Rothwell PM. Oxford Vascular Study. Age-specific association of migraine with cryptogenic TIA and stroke: population-based study. Neurology. 2015;85(17):1444–51.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Yu S, Liu R, Zhao G, Qiao X, Feng J, Fang Y, et al. The prevalence and burden of primary headaches in China: a population-based door-to-door survey. Headache. 2012;52(4):582–91.View ArticlePubMedGoogle Scholar
  14. Yu S, He M, Liu R, Feng J, Qiao X, Yang X, et al. Headache yesterday in China: a new approach to estimating the burden of headache, applied in a general-population survey in China. Cephalalgia. 2013;33(15):1211–7.View ArticlePubMedGoogle Scholar
  15. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society Evidence Assessment of Migraine Pharmacotherapies. Headache. 2015;55(1):3–20.View ArticlePubMedGoogle Scholar
  16. Roberto G, Raschi E, Piccinni C, Conti V, Vignatelli L, D’Alessandro R, et al. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia. 2015;35(2):118–31.View ArticlePubMedGoogle Scholar
  17. Ozpelit E, Ozpelit ME, Akdeniz B, Göldeli O. Ergotamine-induced takotsubo cardiomyopathy. Am J Ther. 2016;23(2):e597–600.View ArticlePubMedGoogle Scholar
  18. Cao K, Yu L, Gao Y, Fan Y, Zhao J, Zhang X, et al. Efficacy of Zhengtian Pill for migraine prophylaxis: a randomized, multicenter, double-blind, placebo-controlled, parallel-group study. Eur J InternMed. 2014;6(3):259–67.Google Scholar
  19. Wang Y, Yuan CX, Shang HC, Ren M, Yuan J. Randomized, double-blind and double-dummy, multi-center clinical study of Zhengtian Pill for patients with migraine. Chin Tradit Patent Med. 2012;34(5):791–4.Google Scholar
  20. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders:2nd edition. Cephalalgia. 2004;24 Suppl 1:9–160.Google Scholar
  21. Tfelt-Hansen P, Block G, Dahlöf C, Diener H-C, Ferrari MD, Goadsby PJ, et al. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia. 2000;20(9):765–86.View ArticlePubMedGoogle Scholar
  22. Fu C, Yu L, Zou Y, Cao KG, Zhao JJ, Gong HY, et al. Efficacy of chuanxiong ding tong herbal formula granule in the treatment and prophylactic of migraine patients: a randomized, double-blind, multicenter, placebo-controlled trial. Evidence-based Complement Altern Med. 2012;2012(6): 1325–1325Google Scholar
  23. Kesterke N, Egeter J, Erhardt JB, Jost B, Giesinger K. Patient-reported outcome assessment after total joint replacement: comparison of questionnaire completion times on paper and tablet computer. Arch Orthop Trauma Surg. 2015;135(7):935–41.View ArticlePubMedGoogle Scholar
  24. Stover A, Irwin DE, Chen RC, Chera BS, Mayer DK, Muss HB, et al. Integrating patient-reported outcome measures into routine cancer care: cancer patients’ and clinicians’ perceptions of acceptability and value. Egems. 2015;3(1):1169.PubMedPubMed CentralGoogle Scholar
  25. Brod M, Blum SI, Bushnell DM, Ramasamy A. Development and validation of the Diabetic Peripheral Neuropathic Pain Impact (DPNPI) measure, a patient-reported outcome measure. Qual Life Res. 2015;24(12):3001–14.View ArticlePubMedGoogle Scholar
  26. Norquist JM, Girman C, Fehnel S, DeMuro-Mercon C, Santanello N. Choice of recall period for patient-reported outcome (PRO) measures: criteria for consideration. Qual Life Res. 2012;21(6):1013–20.View ArticlePubMedGoogle Scholar
  27. Yu L, Cao K. Development of first draft of PRO scale of migraine. Chin Arch Tradit Chin Med. 2014;32(06):1331–4.Google Scholar
  28. Ai J, Cao K, Yu L, Gao Y. Clinical research of migraine pain remission based on patients-reported outcomes. Glob Tradit Chin Med. 2015;08(05):535–40.Google Scholar
  29. Cao K, Sun F, Gu Z, Liu Z, Hong Y, Chen L. Performance evaluation on patient reported outcome scale in migraine remission patients. World Clinic Drugs. 2014;35(01):15–9.Google Scholar
  30. Evers S, Afra J, Frese A, Goadsby PJ, Lind M, May A, Sandor PS, European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine- revised report of an EFNS task force. Eur J Neurol. 2009;16(9):968–81.View ArticlePubMedGoogle Scholar
  31. Smitherman TA, McDermott MJ, Buchanan EM. Negative impact of episodic migraine on a university population: quality of life, functional impairment, and comorbid psychiatric symptoms. Headache J Head Face Pain. 2011;51(4):581–9.View ArticleGoogle Scholar
  32. Villate S, Arroyo J, Bessolo E, Crespín F. Headache and functional symptoms. Revista De Neurologia. 2015;60(8):341–4.PubMedGoogle Scholar
  33. Morris Maizels MD, Raoul Burchette MS. Somatic symptoms in headache patients: the influence of headache diagnosis, frequency, and comorbidity. Headache. 2004;44(10):983–93.View ArticlePubMedGoogle Scholar
  34. Wang J, Huang Q, Li N, Tan G, Chen L, Zhou J. Triggers of migraine and tension-type headache in China: a clinic-based survey. Eur J Neurol. 2013;20(4):689–96.View ArticlePubMedGoogle Scholar
  35. Sørensen PS, Larsen BH, Rasmussen MJ, Kinge E, Iversen H, et al. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache. 1991;31(10):650–7.View ArticlePubMedGoogle Scholar
  36. Luo N, Wei D, Zhang A, Wang Y, Ding M, et al. A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. Pain Med. 2012;13(1):80–6.View ArticlePubMedGoogle Scholar
  37. Wang LP, Zhang XZ, Guo J, Liu HL, Zhang Y, et al. Efficacy of acupuncture for migraine prophylaxis: a single-blinded, double-dummy, randomized controlled trial. Pain. 2012;55(1):22–4.Google Scholar
  38. Deeb SM, Biary N, Bahou Y, Jaberi M, Khoja W. Flunarizine in Migraine: A double-blind placebo-controlled study (in a Saudi Population). Headache. 1992;32(9):461–62.View ArticlePubMedGoogle Scholar
  39. Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath V, Ludin HP, Nappi G, et al. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia. 2002;22(3):209–21.View ArticlePubMedGoogle Scholar
  40. Centonze V, Magrone D, Vino M, Caporaletti P, Attolini E, Campanale G, et al. Flunarizine in migraine prophylaxis: efficacy and tolerability of 5 mg and 10 mg dose levels. Cephalalgia Int J Headache. 1990;10(1):17–24.View ArticleGoogle Scholar

Copyright

© The Author(s). 2016

Advertisement