Objective
Our study aims to assess the clinical effect of SQG on vascular endothelial dysfunction
in patients with stage I or Ⅱ hypertension, to provide a reliable experimental basis
for the early prevention and treatment of target organ damage in hypertension, and
to observe whether TCM plus western medicine can obtain better curative effect than
western medicine alone.
Design
This study will be a randomized, double-blind, double-simulation controlled trial, and participants will be recruited from China-Japan Friendship Hospital by
using notices at the hospital and newspaper advertisements.
In this clinical trial, patients with stage I or Ⅱ hypertension will be analyzed to
determine the safety and efficacy of SQG, and basic analysis will be conducted in terms of the examination results. The study
participants will voluntarily sign an informed consent and all examinations and tests
will be carried out based on the the clinical trial plan. Eligible subjects will be
chosen based on specific inclusion and exclusion criteria. Participants will be randomized
before the first treatment. Three hundred subjects with stage I or II hypertension
will be randomly assigned to three groups (in a 1:1:1 ratio): group A(treatment with SQG and placebo of Cozaar), group B(treatment with Cozaar and SQG placebo), and group C(treatment with SQG and Cozaar). Recruited patients will receive an 8-week treatment (SQG and placebo of SQG will be given twice a day in the morning and evening, 10g every
time, and the Cozaar and placebo of Cozaar will be administrated at 50mg every morning). The SQG and its placebo used in this study were produced n China in accordance with
the China Pharmacopoeia standard of quality control. Upon completion of the 8-week treatment, follow-up tests will be conducted at weeks
2,4,6 and 8 after randomization (Figure 1). This study has been registered with the
‘Chinese Clinical Trial Registry’, the People's Republic of China, which is a registry
in the WHO Registry Network (ChiCTR1800016427).
Recruitment
Patients with hypertension, recruited at clinic and ward of China-Japan friendship
hospital through advertisements and referrals, will be screened. The principle investigator(PI),
together with an attending physician well trained, will identify potentially eligible
patients based on the eligibility criteria. Then, a researcher will tell the patient
the whole schedule of the study including the aim, procedures, possible side effects
of the study SQG and benefits in details face to face. If the patient agrees to take part in the study,
he must sign an informed consent before randomization.
The inclusion, exclusion and withdraw criteria will be seen at the Fig.2.
Ethics
Our protocol(version identifier: V1.0 (2018.3.30)) has been approved by the clinical research ethics committee of China-Japanese Friendship
Hospital(Approval No.2018-59-K43), where the study will take place. And we have also
registered at Chinese Clinical Trial Registry(ChiCTR1800016427), complies with the
principles of the Declaration of Helsinki[16] and the principles of Good Clinical
Practice[17]. Every participant will sign an informed consent before enrollment and
they have right to withdraw from the trial at any time.
Randomization
The random series is generated by Statistical Analysis System(SAS, Version 9.4)by
statisticians in the Scientific Research Department of China-Japanese Friendship Hospital.
Three hundred participants will be randomly assigned to three groups to obtain the
clinical trial plan corresponding to the random number. Both researchers and participants
can’t know the treatment.
Blinding
One sealed opaque envelope with random series in it was prepared.
Three hundred sealed opaque envelopes were prepared, each containing information of
this participant: group name, treatment, possible adverse events and emergency measures.
The envelope should be kept by a special person, rather than the researcher, participant,
the clinical trial pharmacist, data manager or statistician, neither of who knows
the location or the treatment. The drug and placebo were similar in every group. The
manufacturer labeled the random codes on the packaging, and the code labeling conformed
to the principles of GCP.
Intervention
Eligible participants will be randomly assigned to three groups to obtain the clinical
trial plan corresponding to the random number. Group A will be given SQG and placebo
of Cozaar for 8 weeks，SQG will be taken orally in 50ml hot water twice a day,10g every
time, and placebo of 50mg Cozaar will be taken in every morning. Group B will be given
Cozaar and placebo of SQG and group C will be given SQG and Cozaar, administrated
in the same way as aforementioned.
SQG(production batch number: 181201), placebo of SQG(production batch number: 181201),
and placebo of Cozaar(production batch number: 181001)were produced and packed in
a single batch by Jiangxi Puzheng Pharmaceutical Co., Ltd.(Social unified code: 91360823744294486X).
The test results of drug quality were consistent with the Chinese Medicine Standards
of the State Food and Drug Administration (SFDA). The SQG was composed of original
drug flow paste 200 kg and dextrin 180 kg. The placebo of SQG was composed of caramel
5 kg, dextrin 120 kg and original drug flow paste 25 kg. The main components of Cozaar
placebo were dextrin. Cozaar were bought through Pharmaceutical Branch of China Pharmaceutical
Holdings Beijing Co., Ltd(Social unified code：91110101101297579G).
Outcome measures
Primary outcome
The primary outcome is the efficacy rate connected with blood pressure and flow-mediated
dilation(FMD). Efficacy rates will be compared among the three groups. Effective standard
need to satisfy the blood pressure effectively and FMD value decreased by 2%.
The measurement of blood pressure in consulting room：
1. Participants will be asked to rest quietly for at least 5 minutes before starting
to measure upper arm blood pressure in the sitting position. The upper arm should
be placed at the heart level.
2. Use an upper arm medical electronic sphygmomanometer to measure blood pressure.
3. Using standard cuffs (22-26 cm long and 12 cm wide), large cuffs should be used
for obese people or those with a large arm circumference (>32 cm).
4. The blood pressure of both upper arms should be measured at the first visit, and
the upper arm should be measured on the side with higher blood pressure readings.
5. When measuring blood pressure, repeat the measurements 1-2 minutes apart and record
the average of the two readings. If the difference between the two readings of systolic
or diastolic blood pressure(SBP or DBP) is more than 5mmHg, it should be measured
again, and the average of the three readings should be recorded.
6. Pulse rate should be measured while blood pressure is measured.
Flow-mediated dilation (FMD):
FMD will be detected by vascular endothelial function detector(Brand model:UNEXEF38G),
which was determined by temporary interruption and recovery of forearm blood flow.
Ultrasound was used to measure the increase of brachial artery diameter caused by
sudden increase of blood flow, which took about 10 minutes. Vasodilators including
calcium antagonists, nitrates, angiotensin-converting enzyme inhibitors and beta-blockers,
were discontinued for 18-24 hours before examination.
Effective of blood pressure according to guidelines Guiding Principles for Clinical Research of New Chinese Medicines[18], should meet the following 1 of the 3 items: (1) The decrease of diastolic blood
pressure is less than 10 mmHg, but it has reached the normal range. (2) The diastolic
blood pressure is decreased by 10-19 mmHg, as compared with that before treatment,
but it did not reach the normal range. (3) Systolic blood pressure is decreased by
more than 30 mmHg before treatment
Secondary outcomes
The secondary outcomes of this trial are as follows:
Target organ damage assessment: Echocardiogram, creatinine, heart rate variability(HRV),
ankle brachial index (ABI) and pulse wave velocity (PWV) were observed before and
after treatment.
Symptom improvement assessment: Syndrome evaluation was conducted by Hypertension symptom scale and TCM syndrome integral scale, sleep quality was evaluated by Pittsburgh sleep quality
index scale, anxiety and depression were assessed by Self-Rating Anxiety Scale(SAS)
and Self-rating depression scale(SDS), and life quality was assessed by The Short
Form-36Health Survey(SF-36).
Cardiovascular risk factors assessment: Blood glucose, blood lipid, BMI, homocysteine
and uric acid (UA) were tested before and after treatment.
Vascular endothelial function: The levels of ET-1, TXA2, NO, PGI2, Ang-Ⅱ angiotensin
converting enzyme(Ang-II) and high-sensitivity CRP(hs-CRP) in blood were measured
before and after treatment. The effect of the trial drug on vascular endothelial function
was explored through the regulation mechanism of nerve-endocrine-immune system.
Laboratory tests
Creatinine, blood glucose, blood lipids, homocysteine, uric acid (UA), ET-1, TXA2,
NO, PGI2, Ang-II, hs-CRP will be monitored periodically at the Clinical Laboratory,
China-Japanese Friendship Hospital Beijing, China.
Serum ET-1, TXA2, PGI2, NO levels will be measured by Human ET-1 ELISA kit, TXA2 ELISA
kit, PGI2 ELISA kit and Nitric Oxide (NO) assay kit in the Research Center, China-Japanese
Friendship Hospital Beijing, China.
Data collection and management
Each participant will get CRF for collecting relevant data. There will be an evaluation
for every participant every 14 days during the trial(day -17 ± 0, day 14 ± 2 days,
day 28 ± 5days, day 42 ± 5 days and day 56 ± 5days). Every evaluation includes physical
examination, symptom improvement record, the use and recovery and distribution of
the test drugs, combined medication record, adverse events record. Blood samples,
24-hour blood pressure monitoring and echocardiogram will be collected only at the
first and last time. Trials(SPIRIT) flow-chart of the trail can be found in Fig.3.
Data will be input into clinical data management system(CDMS) with the website(http://www.cardiar.com/zryygxy) by two research staff. The CDMS will be managed by Beijing Cardiar Technology Co.,
Ltd.(Social unified code：91110 10655 68170 240). All data supporting the conclusion
of this trail will be available in this system. There will be a password to control
access. To ensure the data integrity and easy to store, we will use data rules, valid
values and scope checks. Missing data and specific errors will be found by our system.
The changes of document will be available but the changes trails will be audited.
Auditing trial conduct will be carried out by Beijing Inruida Pharmaceutical Technology
Co., Ltd.(Social unified code: 91110105MA00H1U54L), and the during process will be
independent from investigators and the sponsor. All personnel involved in data entry
and management sign a confidentiality agreement to prevent data leakage and the participant’s
personal information will be fully protected. Original CRF will be kept for 5 years
after the end of this trials.
Adverse events (AEs)
Adverse events are defined as accidents or any signs of discomfort, symptoms or diseases.
These adverse events include hypertensive emergencies, bleeding, hematoma, syncope,
severe pain and local infection. If any adverse events occur during the observation
period, all details should be written down on the CRF, and the clinical research must
report the adverse events to the research leader, sponsor, the ethics committee within
24 hours. Ethics committee need to give treatment advices according to the corresponding
adverse events.
Statistical analysis
Sample size calculation
There was an superiority trial between group B(treatment with Cozaar and placebo of
SQG) and group C(treatment with SQG and Cozaar), and there was an non-inferiority
trial between the group A(treatment with SQG and placebo of Cozaar) and group B(treatment
with Cozaar and placebo of SQG). The sample size was estimated based on clinical research
literature and preliminary clinical basis of blood pressure and FMD of hypertensive
subjects. Given a type-Ⅰ error rate of α=0.05 and a type-Ⅱ error rate of β=0.2. The
effective rate of the group C was estimated at 90%, and the group B at 70%. The calculation
result was 78 patients each group by PASS 11 software, 156 patients for three groups.
After considering the expulsion rate and the requirement of minimum case number of
the GCP(A randomized controlled clinical trial requires at least 100 patients each
group). We estimated 100 patients in group B and group C. Group A will become an exploratory
trail with the above two groups, 100 patients initially identified. Above all, we
decided to recruit 300 patients during the trail.
Data analysis
Data entry and management will be completed by an independent data administrator to
ensure data accuracy. A professional statistician will perform the data analysis for
the results. We will use the intent-to-treat principle to analyze the efficacy and
safety of SQG. For continuous variables, the independent two-sample Student’s t test
will be used for comparisons between the two study groups, and the paired test will
be used for intra-group comparisons. The χ2 test will be used for categorical variables.
When continuous data distribution is not normal, the Wilcoxon test will be used. P
< 0.05 is considered to be statistically significant, and all tests are two-tailed.