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Safety and Efficacy of Herbal Medicine for Acute Intracerebral Hemorrhage (CRRICH): A Multicenter Randomized Controlled Trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024932
Article Type: Research
Date Submitted by the 25-Jun-2018 Author:
Complete List of Authors: Zeng, Liling; The Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine Wang, Jing; Neurology Department, Shenzhen Longhua New District Center Hospita, Shenzhen Tang, Guanghai; Shenyang No.2 traditional Chinese medical hospital, Shenyang, Liaoning Zhong, Jianbin ; Boji-affiliated Hospital of Sun Yat-sen University Xia , Zhangyong ; Liaocheng People's Hospital, Liaocheng clinical school of Taishan Medical University Li, Jiexia; Conghua City’s hospital of Chinese Medicine Chen, Guangsheng ; Boluo County People's Hospital Zhang, Yongbo ; Shouguang City People's Hospital Luo, Saihua; Lianjiang People's hospital Huang , Gan ; Yangjiang Hospital of Chinese Medicine Zhao, Qianshan; Jiangmen Wuyi Hospital of Chinese Medicine Wan, Yue ; Zhongshan Hospital of Hubei Province Chen , Chaojun; Guangzhou Hospital of Integrated traditional and west medicine Zhu, Kaiyun ; Panyu Hospital of Chinese Medicine Qiao , Hanzi; Guangdong Provincial hospital of Chinese medicine, Neurology Wang, Jian ; First Affiliated Hospital to Changchun University of Chinese Medicine Huang, Tao ; Guangdong Provincial hospital of Chinese medicine, Neurology Liu, Xian; Guangdong Provincial hospital of Chinese medicine, Neurology Zhang, Qixin ; Guangdong Provincial hospital of Chinese medicine, Neurology Lin, Rongming ; Guangdong Second Hospital of traditional Chinese Medicine Li, Haijun ; Guangdong Provincial hospital of Chinese medicine, Neurology Gong, Baoying ; Guangdong Provincial hospital of Chinese medicine, Neurology Chen, Xiuyan ; Guangdong Provincial hospital of Chinese medicine, Neurology Zhou, Yuexiang; Guangdong Provincial hospital of Chinese medicine, Neurology Wen, Zehuai; Guangdong Provincial Hospital of Chinese Medicine, Key
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1 2 3 Unit of Methodology in Clinical Research 4 Guo, Jianwen; Guangdong Provincial hospital of Chinese medicine, 5 Neurology 6 intracerebral hemorrhage, Herbal medicine < THERAPEUTICS, 7 Keywords: 8 randomized controlled trials, hematoma enlargement, CRRICH 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 55
1 2 3 4 Safety and Efficacy of Herbal Medicine for Acute Intracerebral 5 6 Hemorrhage (CRRICH): A Multicenter Randomized Controlled 7 8 9 Trial 10 11 Liling Zeng, Jing Wang, Guanghai Tang, Jianbin Zhong, Zhangyong Xia, Jiexia Li, 12 13 Guangsheng Chen, Yongbo Zhang, Saihua Luo, Gan Huang, Qianshan Zhao, Yue Wan, 14 15 Chaojun Chen, Kaiyun Zhu, Hanzi Qiao, Jian Wang, Tao Huang, Xian Liu, Qixin Zhang, 16 For peer review only 17 Rongming Lin, Haijun Li, Baoying Gong, Xiuyan Chen, Yuexiang Zhou, Zehuai Wen, 18 19 Jianwen Guo* 20 21 Jianwen Guo, MD,Neurologist. 22 23 Guangdong Provincial Hospital of Chinese Medicine, Guangdong University of Chinese 24 Medicine 25 26 111 Da De Rd., Yuexiu District, Guangzhou, Guangdong Province, 27 28 PRC, 510120 29 30 Telephone 86 20 81867705 31 32 FAX 86 20 81867705 33 34 35 Author affiliations (Liling Zeng, Jianwen Guo, Haijun Li, Qixin Zhang, Tao Huang, 36 37 Xian Liu, Baoying Gong, Xiuyan Chen, Yuexiang Zhou, Zehuai Wen, Hanzi Qiao) The 38 Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, 39 Guangdong Provincial Hospital of Chinese Medicine,Guangzhou, China; (Jing 40 Wang)Shenzhen Longhua New District Center Hospita, Shenzhen, China.; (Jian Wang) 41 42 Changchun Chinese Medicine University affiliated hospital,Changchun,China; 43 (Zhangyong Xia) Liaocheng People's Hospital, Liaocheng clinical school of Taishan 44 Medical University, Liaocheng, China; (Jiexia Li)Conghua City’s hospital of Chinese 45 Medicine, Conghua, China; (Guangsheng Chen)Boluo County People's Hospital, 46 Huizhou , China;(Qianshan Zhao)Jiangmen Wuyi Hospital of Chinese Medicine, 47 48 Jiangmen, China; (Chaojun Chen)Guangzhou Hospital of Integrated traditional and 49 west medicine, Guangzhou, China; (Yongbo Zhang)Shouguang City People's 50 Hospital,Shouguang,China; ( Gan Huang)Yangjiang Hospital of Chinese Medicine, 51 Yangjiang, Guangdong, China; (Kaiyun Zhu)Panyu Hospital of Chinese Medicine， 52 53 Guangzhou, China;(Saihua Luo)Lianjiang People's hospital, Lianjiang, China; 54 (Guanghai Tang)Shenyang No.2 traditional Chinese medical hospital, Shenyang, China; 55 (Jianbin Zhong)Boji affiliated Hospital of Sun Yat sen University, zengcheng, China; 56 (Yue Wan)Zhongshan Hospital of Hubei Province, Wuhan, Hubei, China；Guangdong 57 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 55 BMJ Open
1 2 3 Second Hospital of traditional Chinese Medicine(Rongming Lin) 4 5 6 ABSTRACT 7 8 9 Objective: To evaluated the safety and efficacy of herbal medicine for 10 11 the treatment of acute intracerebral hemorrhage (AICH) within a 6 h time 12 13 14 window. 15 16 For peer review only 17 Study design: A randomized, multicenter, double blind, 18 19 placebo controlled study performed in 14 hospitals in China. 20 21 22 23 Participants and Interventions: Patients with AICH were randomly 24 25 assigned to receive a placebo, the ICH 1 formula (8 herbs, including the 26 27 28 removing blood stasis (RBS) herbs hirudo and tabanus) or the ICH 2 29 30 formula (6 herbs without the RBS herbs hirudo and tabanus) within 6 h 31 32 of ICH onset. 33 34 35 36 Outcomes: The primary safety outcome was the hematoma enlargement 37 38 (HE)rate at 24 h and on 10 days after treatment. The secondary outcome 39 40 41 endpoint was incidence of poor prognosis (mortality or modified Rankin 42 43 Scale (mRS) score ≥5) assessed on 90 days after symptom onset. 44 45 46 Results: A total of 324 subjects were randomized between October 2013 47 48 49 and May 2016: 105 patients received placebo; 108 patients received the 50 51 ICH 1 formula; and 111 patients received the ICH 2 formula. The HE 52 53 54 rates at 24 h were 7.8% in the placebo group, 12.3% in the ICH 1 group, 55 56 and 7.5% in the ICH 2 group, and the HE rates on day 10 were 1.1% in 57 2 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 55
1 2 3 4 the placebo group, 1.1% in the ICH 1 group, and 3.1% in the ICH 2 5 6 group, with no significant differences between the groups (P>0.05). The 7 8 9 mortality rates were 3.8% in the placebo group, 2.8% in the ICH 1 group, 10 11 and 0.9% in the ICH 2 group,and the incidences of poor prognosis were 12 13 7.1% in the placebo group, 6.0% in the ICH 1 group, and 4.8% in the 14 15 16 ICH 2 groupFor at 3 peer months, with review no significant only differences between the 17 18 groups (P>0.05). However, the overall frequency of adverse events in the 19 20 21 ICH 1 group (12.1%) was higher than that in the placebo and ICH 2 22 23 groups (5.8% and 2.8%, respectively, P<0.022). The 3 cases of serious 24 25 26 adverse events were all in the ICH 1 group. 27 28 29 Conclusions: Ultra early administration of RBS herbal medicine, within 30 31 6 h of ICH onset, for AICH patients did not exert significantly beneficial 32 33 34 effects on clinical outcomes, but increased the risk of bleeding, such as 35 36 gastrointestinal bleeding, and hematoma growth. 37 38 39 Clinical Trial Registration: URL:http//www.ClinicalTrials.gov. 40 41 42 Unique identifier: NCT01918722. 43 44 45 Keywords: intracerebral hemorrhage; herbal medicine; randomized 46 47 48 controlled trials; hematoma enlargement; CRRICH 49 50 51 Word count: 4568 52 53 54 55 56 57 3 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 55 BMJ Open
1 2 3 4 Strengths and limitations of this study 5 6 7 ▪ The CRRICH trial is the largest Multicenter clinical trial to examine the 8 9 safety and efficacy of a Chinese compound formula in patients with 10 11 12 HICH. 13 14 15 ▪ This study highlights the possibility that the early use of RBS herbal 16 For peer review only 17 medicine in HICH could increase the risk of bleeding, which spurs further 18 19 20 research on the safety of Chinese medicines. 21 22 23 ▪ there were no available data to elucidate the mechanism of AEs or 24 25 26 serious AEs. 27 28 29 30 31 32 Introduction 33 34 35 Hypertensive intracerebral hemorrhage (HICH) accounts for 36 37 [1] 38 approximately 15% of all acute strokes which is the third most common 39 40 cause of death in most Western countries, following coronary heart 41 42 [2, 3] 43 disease and cancer. HICH has been the leading cause of death in 44 [4] 45 China in recent years, being responsible for approximately one third of 46 47 [5] the total number of deaths from stroke worldwide. 48 49 50 51 Available specific medical and surgical treatments do not improve 52 53 prognosis substantially,[7, 8] and intracerebral hemorrhage (ICH) still 54 55 56 accounts for a higher proportion of stroke in Chinese people compared 57 4 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 55
1 2 3 [6] 4 with that in white populations. Therefore, traditional Chinese medicine 5 6 (TCM) physicians in China widely use removing blood stasis (RBS) 7 8 9 herbs for the treatment of HICH, which was proven previously to provide 10 [9] 11 some benefit for HICH patients in a meta analysis. RBS herbal 12 13 medicine maybe promotes hematoma absorption and improves recovery 14 15 [10, 11] 16 of neurologicalFor impairment peer review, which is already only included by a 17 18 guidelines for the management of spontaneous intracerebral 19 20 [24] 21 hemorrhage .However, sufficient evidence of long term benefits and 22 23 risks of superacute stage is lacking. RBS herbals, such as hirudo, that act 24 25 26 as a thrombin inhibitor with anticoagulant pharmacological effects, may 27 28 cause re bleeding risk in clinical practice.[12] A total of 90% of hematoma 29 30 31 growth, which plays an important role in prognosis, occurs within a 6 h 32 [13] 33 time window. Therefore, confirmation of the safety and efficacy of 34 35 RBS herbal medicines in the treatment of early stage HICH is urgently 36 37 38 needed. 39 40 41 We performed a retrospective study that demonstrated that RBS 42 43 [14] 44 herbal medicine for HICH patients was safe and effective. However, 45 46 little additional evidence of the safety and efficacy of this treatment exists. 47 48 We designed a multicenter, three group, prospective, randomized, 49 50 51 double blinded and placebo controlled clinical trial on hematoma 52 53 enlargement in HICH patients treated with RBS herbal medicine within a 54 55 56 6 h time window from symptom onset (CRRICH) to evaluate its safety 57 5 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 55 BMJ Open
1 2 3 4 and efficacy in HICH patients and to provide a high level of evidence for 5 6 clinical practice. 7 8 9 Methods 10 11 12 13 Study Design 14 15 16 The CRRICHFor trialpeer was a multicenter,review randomized, only double blinded, 17 18 placebo controlled, parallel group study to assess the safety and efficacy 19 20 21 of RBS herbal medicine in HICH patients. This trial is registered at 22 23 clinicaltrials.gov (NCT01918722), and the research design proposal has 24 25 [15] 26 been published. 27 28 29 Participants 30 31 32 Patients with a Glasgow Coma Scale [GCS] score ≥6 were enrolled 33 34 if they were ≥18 years of age and had a clinical diagnosis of ICH 35 36 37 confirmed with computed tomography within 6h of onset. All participants 38 39 signed an informed consent form. Patients who suffered secondary ICH 40 41 42 resulting from trauma, brain tumor, blood diseases, arteriovenous 43 44 malformation or aneurysm were excluded. A detailed patient history was 45 46 47 recorded. S3 Table in the online Data Supplement provides a full list of 48 49 study inclusion and exclusion criteria during the screening period. 50 51 52 Randomization and Blinding 53 54 55 56 Patients were randomized to receive placebo, ICH 1, or ICH 2 in 57 6 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 55
1 2 3 4 a 1:1:1 ratio with a stratification and block size of 6 using the PROC 5 6 PLAN process in SAS software version 9.13.Stratified block and 7 8 9 randomization were concealed using a sequentially numbered opaque 10 11 envelope. Persons involved in the study, including the investigators, 12 13 patients and data analysts, were blinded to treatment assignment during 14 15 16 double blindedFor treatment peer until thereview end of follow up. only Only the data 17 18 administrators were permitted access to unblinded data. 19 20 21 22 Procedures 23 24 Enrollment, Intervention and Follow-up 25 26 27 Patients were recruited from October 2013 through May 2016 at 14 28 29 hospitals in China (S1 Table in the online only Data Supplement). The 30 31 32 study consisted of a screening and randomization period (≤6 h 33 34 post stroke), a 10 day double blinded treatment period and a 3 month 35 36 37 follow up period (S1 Figure in the online only Data Supplement). 38 39 Participants were randomly assigned to one of three treatment groups at a 40 41 42 ratio of 1:1:1 during the double blinded treatment: (1) Group ICH 1 43 44 received the ICH 1 formula, which consisted of 8 herbs including RBS 45 46 medicines [Hirudo, Tabanus, Rhubarb, Typha angustifolia L, Fructus 47 48 49 trichosanthis, Panax notoginseng, Acorus tatarinowii, and Chinemys 50 51 reevesii (Gray)]; (2) Group ICH 2 received the ICH 2 formula, which 52 53 54 consisted of 6 herbal medicines without RBS herbs [Rhubarb, Typha 55 56 angustifolia L, Fructus trichosanthis, Panax notoginseng, Acorus 57 7 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 55 BMJ Open
1 2 3 4 tatarinowii, and Chinemys reevesii (Gray)] in the same doses as ICH 1, 5 6 with the remaining dose filled with a placebo; and (3) Group placebo 7 8 9 received a placebo that included dextrin and farina. Each unit of TCM 10 11 medicine or placebo was dissolved in 200 ml of boiling water. Each 12 13 patient received 200 ml orally or through a nasogastric tube two times 14 15 16 daily for 10For days (S2 peer Table in thereview online only Data only Supplement). 17 18 19 Patients were followed up for 3 months after the 10 day 20 21 22 double blinded treatment period. Patients were hospitalized in stroke 23 24 units and received standard stroke care in accordance with local 25 26 guidelines, which included general supportive care, treatment of acute 27 28 29 complications, and rehabilitation. Astringents and other RBS drugs were 30 31 prohibited. Visits were scheduled at baseline, 24 h post stroke, at the end 32 33 34 of the treatment period, and a single visit was scheduled 3 months 35 36 post stroke (S1 Figure in the online only Data Supplement). Adverse 37 38 39 events (AEs), treatment compliance, and concomitant medication use 40 41 were reported during each visit. Participants were randomly assigned to 42 43 44 one of three treatment groups at a ratio of 1:1:1 during double blinded 45 46 treatment. 47 48 49 Primary and Secondary Outcomes 50 51 52 The hematoma enlargement rate, which is a radiographic outcome, 53 54 55 was the primary outcome in the study. Hematoma enlargement was 56 57 8 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 55
1 2 3 4 operationally defined as an increase in hematoma volume of >33% or 5 6 12.5 ml as measured on image analysis on the 24 h CT compared with the 7 8 9 baseline CT scan. Hematoma volume was measured using the ABC/2 10 [16] 11 Coniglobus formula at 24 h after onset. The same measurement was 12 13 performed on days 10 14 as a primary outcome measure. The following 14 15 16 secondary Forend points peer were assessed: review change in NIHSS only score at 3 months; 17 18 mortality at 3 months; and poor prognosis rate, which was defined as the 19 20 21 proportion of patients who died or were severely disabled based on an 22 23 mRS score ≥5 at 3 months.[17] Safety data focused on treatment emergent 24 25 26 AEs (TEAEs). TEAEs were defined as AEs that first occurred or 27 28 worsened (increased in severity) after the first dose of study drug. The 29 30 31 patient spontaneously reported TEAEs in response to an open ended 32 33 question from the contact person at each visit. Patients with a worsened 34 35 condition, prolonged hospitalization, and life threatening TEAEs were 36 37 38 reported as serious adverse events (TEsAEs). Abnormal laboratory values 39 40 that constituted a serious AE or led to the discontinuation of experimental 41 42 43 drugs were also reported as TEsAEs. S4 Table in the online only Data 44 45 Supplement provides a full list of all primary, secondary and safety end 46 47 48 points. 49 50 51 Statistical Analyses 52 53 54 All reported efficacy analyses were predefined and based on full 55 56 57 9 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 55 BMJ Open
1 2 3 4 analysis set (FAS) (patients who were randomized and received any study 5 6 medication) according to the intent to treat (ITT) principle. Supportive 7 8 9 analyses were performed in a predefined per protocol population set 10 11 (PPS), which included FAS patients who did not have one or more key 12 13 protocol deviations, including violations of inclusion and exclusion 14 15 16 criteria. TheFor last observation peer for review surviving patients only with missing outcome 17 18 data was carried forward. Patients who had died at the 90 day follow up 19 20 21 were assigned a Barthel index score of 0 and mRS score of 6, and the last 22 23 recorded NIHSS score was carried forward. Hematoma enlargement rate 24 25 26 at 24 h (primary end point), the rate of poor prognosis and the incidence 27 28 of total adverse events between the three groups were analyzed using the 29 30 2 31 χ test. The hematoma enlargement rate on days 10 14 (primary end point) 32 33 and mortality between the three groups were compared using Fisher’s 34 35 exact test. Mean differences in NIHSS score between groups were 36 37 38 analyzed using one way ANOVA. Demographic characteristics and 39 40 serious AEs were summarized using descriptive statistics. 41 42 43 44 Power and sample size were determined using relative hematoma 45 46 volume at 24 h as the primary outcome variable. A total of 285 47 48 participants were required at the final follow up to provide 90% power 49 50 51 with a two sided alpha level at 0.05 to test the primary effectiveness, 52 53 which was calculated using the PASS (Power Analysis and Sample Size) 54 55 56 software program (licensed by NCSS, LLC). A total of 360 participants 57 10 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 55
1 2 3 4 were needed for primary outcome randomization assuming a dropout rate 5 6 of 20%, with 120 patients per treatment arm. The statistical package 7 8 9 STATA (version 13.1) was used for all statistical analyses. 10 11 12 Patient and Public Involvement statement 13 14 15 While we put forward the research question and outcome measures, 16 For peer review only 17 the patients’ priorities, experience, and preferences were fully considered 18 19 20 by a survey. Patients were involved in the recruitment to and conduct of 21 22 the study.The results would be disseminated to study participants by 23 24 25 posting a letter. The CRRICH trial was a randomised controlled trials, 26 27 patients themselves had fully assessed the burden of the intervention. 28 29 30 Patient advisers should also be thanked in the contributorship 31 32 statement/acknowledgements. 33 34 35 Funding statement and Ethical statement 36 37 38 39 The State Administration of Traditional Chinese Medicine of the 40 41 P.R.C. (SATCM) awarded Guangdong Provincial Hospital of TCM 42 43 (GPHTCM) SATCM Grant No: ZDJX2012074 and provided input 44 45 46 during the study period. This report was an independent study supported 47 48 by SATCM and performed by the GPHTCM in a SATCM–GPHTCM 49 50 51 partnership. The viewpoints stated in this manuscript are the authors’ and 52 53 may not represent the opinions of SATCM, GPHTH or the Public Health 54 55 56 Bureau. The SATCM and GPHTCM approved the decision to submit this 57 11 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 55 BMJ Open
1 2 3 4 paper for publication. Dr. Jianwen Guo had full access to all study data 5 6 and had final responsibility for the decision to submit for publication. 7 8 9 Each respective institutional review board or ethics committee 10 11 12 approved the study protocol, which followed established Good Clinical 13 14 Practice guidelines. All patients provided written informed consent to 15 16 For peer review only 17 participate in the study. An independent contract research organization, 18 19 S&R (Department of Science and Research of Guangdong Provincial 20 21 22 Hospital of Chinese medicine), managed the administration, coordination, 23 24 and monitoring of the study, including researcher training, study 25 26 inspection, data management and statistical analyses, with oversight by 27 28 29 the State Administration of Traditional Chinese Medicine of the P.R.C. 30 31 32 Results 33 34 35 Study Population 36 37 Patient recruitment began in October 2013, and the study ended in 38 39 40 May 2016. A total of 5589 individuals with ICH were screened (Figure 1). 41 42 The most frequent reasons for exclusion in descending order were time 43 44 45 window >6 hours, refusal to participate, secondary ICH (i.e., not HICH) 46 47 and other reasons. A total of 319 of the 324 randomized patients (105 48 49 50 placebo, 108 ICH 1, 111 ICH 2) received the assigned treatment 51 52 following the elimination of five patients (one patient for missing the 53 54 55 time window, one patient for kidney failure, one patient for secondary 56 57 12 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 55
1 2 3 4 ICH, one patient for surgery within 24 h and one patient withdrew 5 6 consent). Therefore, only the 319 participants who underwent 7 8 9 randomization and received study medication were included in the FAS 10 11 and safety analysis set based on ITT. Twenty three patients in the FAS 12 13 did not completely adhere to the protocol and dropped out during the 14 15 16 treatment period.For A peertotal of 296 review patients were included only in the PPS (see 17 18 Figure 1 for patient flow diagram). The mean dropout rate was <8%. 19 20 21 Table 1 presents the demographics and baseline characteristics of the 22 23 FAS, which were well balanced with no significant between group 24 25 26 differences. The mean age was 62.5±12.7 years (mean±SD, n=319); 27 28 65.5% of the patients were male, and 98.7% were ethnic Han. The 29 30 31 median GCS score was 15 (range, 3 to 15), and the mean NIHSS score 32 33 was 8 (range, 0 to 47). The deep gray matter was involved in 93.4% of 34 35 cases, and the lobar regions were involved in 6.6% of cases. The baseline 36 37 38 characteristics of the three treatment groups were similar. The mean 39 40 volume of the ICH at baseline for all patients was 11.0 ml (range, 0.3 to 41 42 43 86.7 ml), which was similar in the three groups (Table 1). The mean time 44 45 from onset of symptoms to admission was 3.36±1.49 h, and the mean 46 47 48 time from onset of symptoms to treatment was 4.10±1.38 h. Fourteen 49 50 percent of patients were treated within 3 h after symptom onset. Two 51 52 53 patients were treated outside the 6 h time window. The timing of the 54 55 treatment was similar in the three groups (Table 1). 56 57 13 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 55 BMJ Open
1 2 3 4 5 6 Figure 1. Enrollment and Follow up. AEs, adverse events; FAS, full analysis set; PPS, per protocol population set; 7 8 RBS, removing blood stasis;ICH denotes intracerebral hemorrhage; ICH 1 denotes herbal medicine with RBS 9 herbals hirudo and tabanus (8 herbals); ICH 2 denotes herbal medicine without RBS herbals hirudo or tabanus (6 10 herbals). 11 12 13 14 15 Table 1. Baseline Characteristics and Treatment Timing. 16 For peer review only 17 Variable Placebo (N=104) ICH 2 (N=108) ICH 1 (N=107) 18 19 62.84±12.23 20 Age (yr) 61.95±13.38 62.56±12.64 21 22 Sex n (%) Male 69(66.3) 69(63.9) 71(66.4) 23 24 Female 35(33.7) 39(36.1) 36(33.6) 25 26 Ethnic group n(%) 27 28 29 Ethnic Han 103(99.0) 105(97.2) 107(100.0) 30 31 Not ethnic Han 1(1.0) 3(2.8) 0(0) 32 33 Hemisphere hematoma n(%) 34 35 36 Left hemisphere 44(42.3) 53(49.1) 56(52.3) 37 38 Right hemisphere 59(56.7) 54(50.0) 51(47.7) 39 40 Supratentorial hematoma n (%) 41 42 Putamen or globus 43 69(66.3) 72(66.7) 64(59.8) 44 pallidus 45 46 Thalamus 19(18.3) 24(22.2) 28(26.2) 47 48 49 Lobar hemisphere 10(9.6) 7(6.5) 4(3.7) 50 51 None 6(5.8) 5(4.6) 11(10.3) 52 53 Subtentorial hematoma n (%) 54 55 56 57 14 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 55
1 2 3 Cerebellum 4(3.8) 2(1.9) 7(6.5) 4 5 Pons or midbrain 2(2.0) 4(3.7) 5(5.0) 6 7 8 None 98(94.2) 102(94.4) 95(88.8) 9 10 Intraventricular hemorrhage n(%) 11 12 Yes 17(16.3) 19(17.6) 25(23.4) 13 14 15 No 87(83.7) 89(82.4) 82(76.6) 16 For peer review only 17 GCS score‡ 14.18±1.86 13.77±2.34 13.76±2.06 18 19 NIHSS score 7.88±5.24 9.00±7.24 9.13±6.16 20 21 Volume of the 22 23 intracerebral 9.82±7.45 11.56±9.67 11.57±11.55 24 hemorrhage at 25 26 baseline 27 28 Systolic BP at time 29 of admission 171.34±28.04 174.14±23.72 172.04±22.53 30 31 (mmHg) 32 33 Time from onset to 4.31±1.38 4.02±1.35 3.97±1.39 34 35 treatment (h) 36 37 Time from onset to 3.61±1.54 3.08±1.47 3.05±1.63 38 admission (h) 39 40 * The values are expressed as counts and % within group, and plus–minus values are the mean±SD. Percentages 41 may not total 100 because of rounding. GCS, Glasgow Coma Scale (Scores range from 15 (normal) to 3 (deep 42 coma); NIHSS, National Institutes of Health Stroke Scale (Scores range from 0 (normal) to 42 (coma with 43 quadriplegia); BP, blood pressure. 44 45 Primary Outcome (Radiographic Outcomes) 46 47 48 49 A total of 319 baseline CT scans and 315 CT scans at 24 h were 50 51 available for analysis. The volume enlargement rates of ICH were 7.8% 52 53 in the placebo group, 12.3% in the group ICH 1 and 7.5% in the group 54 55 56 ICH 2. There was no significant difference between the three groups in 57 15 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 55 BMJ Open
1 2 3 4 the enlargement rate of hematoma volume at 24 h (P=0.409). The volume 5 6 enlargement rates of ICH on days 10 14 day were 1.1% in the placebo 7 8 9 group, 3.1% in the group ICH 2 and 1.1% in the group ICH 1. There was 10 11 also no significant difference between the three groups in the enlargement 12 13 rate of the hematoma volume on days 10 14 (P=0.625) (Table 2). 14 15 16 For peer review only 17 Secondary Outcomes (Clinical Outcomes) 18 19 20 Mortality at 3 months was approximately 2.6% in the three groups 21 22 (Table 2, Figure 2). Poor prognosis (i.e., the proportion of patients who 23 24 25 died or were severely disabled, mRS ≥5) did not differ significantly 26 27 between the three groups (Table 2). The distributions of outcomes on the 28 29 30 modified Rankin scale (Figure 3) were similar between the three groups. 31 32 The differences in the NIHSS scores at 3 months between the three 33 34 35 groups were not significant (Table 2). 36 37 38 39 40 Figure 2 Kaplan Meier Survival Curves. Group placebo with 4 cases dead, respectively at day 4,5,8,9; Group ICH 41 42 1 with 3 cases dead, respectively at day 4,5,9; Group ICH 2 with 1 case dead at day 3.A possible small benefit of 43 treatment with ICH 1,ICH 2 was evident from 10 to 90 days after treatment. 44 45 46 47 48 Figure 3 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin scale 49 evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). There were 50 no significant differences between the three groups. 51 52
53 54 55 Adverse Events 56 57 16 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 55
1 2 3 4 There were 35 AEs reported by investigators, and 22 AEs may have 5 6 been TEAEs. All AEs occurred during the double blinded treatment 7 8 9 period (within 2 weeks). TEAEs occurred in 13 (12.1%) ICH 1–treated 10 11 patients, 3 (2.8%) ICH 2–treated patients and 6 (5.8%) placebo treated 12 13 patients. The pattern of AEs was similar in the 3 groups, but the overall 14 15 16 frequency ofFor AEs between peer the threereview groups was significantlyonly different 17 18 (P=0.022)Table 2. Table 3 shows the TEAEs that occurred during the 19 20 21 study. The most frequent event was diarrhea, and its incidence was 22 23 similar in the 3 treatment groups (ICH 2 66.7%, ICH 2 100%, placebo 24 25 26 53.8%, P=0.392). Treatment was discontinued because of TEsAEs in 3 27 28 (1.9%) ICH 1–treated patients. The 3 cases with TEsAEs (2 cases of 29 30 31 gastrointestinal bleeding, 1 case of cerebral hernia) reported by 32 33 investigators occurred in ICH 1–treated patients. There was no consistent 34 35 pattern to this difference, and all serious AEs occurred within the 10 day 36 37 38 drug treatment period. There were no differences in the incidence or type 39 40 of serious AEs leading to death (data not shown). There was no 41 42 43 relationship between AEs, serious AEs, or mortality and poor outcome 44 45 (data not shown). 46 47 48 Table 2 Primary outcome and secondary outcomes 49 50 Between Group 51 Differences 52 Placebo ICH 2 ICH 1 53 54 P Value 55 56 57 17 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 55 BMJ Open
1 2 3 Primary outcome: enlargement rate in ICH volume at 24 h and day 14 4 5 At 24 h 8/104(7.8) 8/108(7.5) 13/107(12.3) 0.409 6 7 8 On days 10 14 1/92(1.1) 3/97(3.1) 1/91(1.1) 0.625 9 10 Secondary outcomes: 11 12 NIHSS# at 3 months 3.58±5.32 3.58±5.32 3.58±5.32 0.475 13 14 Mortality at 3 months 4/104(3.8) 1/108(0.9) 3/107(2.8) 0.328 15 16 Poor prognosisFor (mRS peer review only0.783 17 7/99(7.1) 5/105(4.8) 6/100(6.0) 18 ≥5) 19 20 Total TEAEs 6/104(5.8) 3/108(2.8) 13/107(12.1) 0.022 21 22 The values are expressed as n/N(%) within group or the mean±SD; # denotes the number of patients at 3 23 24 months: 104 in group Placebo, 107 in group ICH 2, and 105 in group ICH 1. 25 26 27 28 29 Table 3 treatment emergent adverse events 30 31 Placebo ICH 2 ICH 1 32 33 34 Vomiting 1/104(1.0) 0/108(0.0) 2/107(1.9) 35 36 Gastrointestinal 0/104(0.0) 0/108(0.0) 2/107(1.9) 37 bleeding* 38 39 Stomach ache 0/104(0.0) 0/108(0.0) 1/107(0.9) 40 41 42 Chest stuffy 1/104(1.0) 0/108(0.0) 0/107(0.0) 43 44 Cerebral hernia* 0/104(0.0) 0/108(0.0) 1/107(0.9) 45 46 The values are expressed as n/N(%) within group. All adverse events are listed in order of frequency from the 47 overall study period (90 days); adverse events were collected from investigator reports. The principal investigator at each site determined whether an adverse event or serious adverse event was related to the intervention. TEAEs, 48 treatment emergent adverse events. *indicates TEAEs. 49 50 51 52 53 54 Discussion 55 56 57 18 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 55
1 2 3 4 RBS administration within 6 h after symptom onset of ICH did not 5 6 significantly reduce hematoma growth and failed to improve survival or 7 8 9 functional outcome at 90 days. Conversely, the incidence of AEs 10 11 increased significantly. A significant increase was demonstrated in total 12 13 AE frequency and serious AEs. Three serious bleeding events occurred in 14 15 16 the RBS groupFor (ICH 1, peer with 2 RBSreview herbals), including only two cases of 17 18 gastrointestinal bleeding and one case of intracerebral re bleeding. All 19 20 21 three cases were fatal serious AEs (Table 2). These data suggest that RBS 22 23 treatment for ICH patients within 6 h of symptom onset is a safety 24 25 26 concern. However, no data were available to suggest a mechanism for 27 28 this effect. 29 30 31 This result contrasts with the clinical benefit demonstrated in a 32 33 [9] 34 previous meta analysis , which included 9 randomized controlled 35 36 clinical trials with 798 individuals who demonstrated that RBS therapy 37 38 39 for acute ICH reduced brain hematoma and cerebral edema volumes, 40 41 improved the neural function and reduced the mortality and disability 42 43 44 rates with fewer AEs. The present trial revealed significant heterogeneity 45 46 compared with the studies included in the meta analysis possibly because 47 48 of differences in the intervention time window. This research is the first 49 50 51 prospective, multicenter, randomized, double blind, placebo controlled 52 53 study to assess the effect and safety of RBS in HICH patients within a 6 h 54 55 56 time window from symptom onset, unlike prior studies that examined 57 19 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 55 BMJ Open
1 2 3 4 these effects within a 24 h or later intervention time window. Earlier RBS 5 6 administration increased the risk of bleeding events (e.g., gastrointestinal 7 8 9 bleeding or intracerebral re bleeding) counteracted the benefit to some 10 11 extent. 12 13 14 The primary outcome of the rate of hematoma enlargement, which is 15 16 For peer review only [17] 17 an independent prognostic determinant of mortality and poor prognosis, 18 19 was also used to assess safety. The hematoma enlargement rates at 24 h in 20 21 22 the three groups in the CRRICH trial (placebo, ICH 2, and ICH 1) were 23 24 7.8%, 7.5%, and 12.3%, respectively, which were not significantly 25 26 different (Table 2). The mean hematoma enlargement rate was only 9.2%, 27 28 [27] 29 which was far lower than the mean level of 18 30%. The main reasons 30 31 of lower hematoma expansion incidence may include the following: (1) 32 33 34 the investigators’ inclination toward surgery in HICH patients with large 35 36 hemorrhage volumes within 24 h of onset, which resulted in the exclusion 37 38 39 of patients susceptible to re bleed in the study; and (2) patients with 40 41 terrible and unstable conditions who were prone to hematoma expansion 42 43 44 were excluded by investigators privately for fear that deterioration risk 45 46 would rise during study. 47 48 49 Hematoma growth is an independent determinant of death and 50 51 [18] 52 disability. Therefore, hematoma expansion may be an attractive 53 54 therapeutic target.[19, 20] However, no proven specific therapies or 55 56 57 20 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 22 of 55
1 2 3 4 treatments exist to prevent hematoma expansion or improve outcomes 5 6 after ICH. Sufficient evidence based medical research to prove that 7 8 9 mini traumatic surgeries and the present available medicines provide 10 [7, 8] 11 ideal treatment is lacking. 12 13 14 Herbal medicine in China has been used to treat ICH for at least 2,000 15 16 For peer review only 17 years, and RBS herbal medicines are listed in the 2010 Chinese 18 [21] 19 Pharmacopeia. Dr. Si reported the earliest available literature on HICH 20 21 [22] 22 with RBS herbal medicine therapy in 1981. Another RBS medicine, 23 24 Naoxuekang capsule, was approved as routine treatment for HICH 25 [21] 26 patients by the Chinese state food and drug administration . 27 28 29 (Naoxuekang capsule, register No. Z10960009). RBS herbal medicines 30 31 have been studied in HICH patients in more than 200 clinical studies in 32 33 34 the past 30 years, and it gradually became a regular therapy that reached a 35 36 consensus.[23] HICH management guideline in China cited this 37 38 [24] 39 treatment. However, safety evidence in the early stage of HICH is 40 41 lacking. Some studies demonstrated 30% of ICH patients suffered 42 43 [25] 44 continued bleeding within 6 h of onset . Some research has provided 45 46 low level evidence of the safety of RBS herbal medicine for superacute 47 48 cerebral hemorrhage, but whether RBS herbal medicine administration in 49 50 51 an early stage induced hematoma growth was not known because RBS 52 53 herbal medicine exhibits an anticoagulation effect.[26] Marketed RBS 54 55 56 drugs that are clinically recognized and widely used did not illustrate a 57 21 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 23 of 55 BMJ Open
1 2 3 4 specific application time window. Early administration of RBS drugs may 5 6 cause hematoma expansion and increase the risk of death and serious 7 8 9 disability. The CRRICH trial was a prospective, double blinded, 10 11 multicenter clinical trial that demonstrated that early administration of 12 13 RBS drugs did not increase hematoma growth but significantly increased 14 15 16 AEs. For peer review only 17 18 19 The CRRICH trial is the largest clinical trial to investigate the safety 20 21 22 and efficacy of a Chinese compound formula in patients with HICH. 23 24 Three other influential RCT trials of medical treatment with drugs that 25 26 exhibit very different mechanisms than RBS, including FAST, 27 28 29 INTERACT2, and CHANT, used similar methods to evaluate the safety 30 31 and efficacy and found no significant benefit.[28 30] 32 33 34 35 Data from the clinical study suggested that administration of RBS 36 37 herbal medicine should be avoided in HICH patients during the initial 6 h 38 39 time window from stroke onset to avoid the increased risk of bleeding. 40 41 42 Further clinical studies should be performed to confirm the safety and 43 44 efficacy of these agents beyond the 6 h of ICH onset. This research 45 46 47 suggests that early administration of RBS herbal medicine in ICH patients 48 49 increases the risk of bleeding, such as gastrointestinal bleeding and 50 51 52 hematoma growth. Some Chinese patent drugs (Naoxuekang capsule 53 54 (Z10960009), Naoxuekang pill (Z20050312) or Naoxuekang drop pills 55 56 57 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 24 of 55
1 2 3 4 (Z10980039)), which primarily consist of hirudo, should be reevaluated 5 6 and used under supervision. The relevant manufacturers should revise the 7 8 9 drug instruction and add a warning of “Do not use for superacute cerebral 10 11 hemorrhage within 6 h from onset”, if necessary. 12 13 14 This study had some limitations. First, there were no available data 15 16 For peer review only 17 to elucidate the mechanism of AEs or serious AEs. Second, there was a 18 19 significant difference in the number of patients between research centers. 20 21 22 Third, the investigators would rather study on the patients with minor 23 24 hematoma’ volume, because they were afraid of the rebleeding risk of the 25 26 herbal medicine. 27 28 29 30 Summary 31 32 33 This study demonstrates that ultra early administration of RBS 34 35 herbal medicine, within 6 h of ICH onset, for AICH patients increased the 36 37 38 risk of bleeding, such as gastrointestinal bleeding, and hematoma growth. 39 40 It also shows that RBS herbal medicine did not exert significantly 41 42 43 beneficial effects on clinical outcomes in hypertensive ICH patients in the 44 45 ultra early stage. These results support that ultra early administration of 46 47 48 RBS herbal medicine is unsafe and less effective. Future high quality 49 50 research should further assess the effectiveness and safety of herbal 51 52 medicine for the intracerebral hemorrhage beyond 6 hrs time window. 53 54 55 56 57 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 25 of 55 BMJ Open
1 2 3 Supplementary Material A complete list of supplementary Material in the CCRICH 4 trial is provided in the Supplementary Appendix. 5 6 Data Sharing Statement No additional unpublished data are available. 7 8 Acknowledgments We thank the patients and families who volunteered for this study, 9 Zehuai.Wen, Ouyang Wen for their assistance with data summarization, and Yubo Lv 10 11 for his guidance. CRRICH trial was supported by SATCM Grant No:ZDJX2012074 12 awarded to Dr. Jianwen Guo from the State Administration of Traditional Chinese 13 Medicine of the P.R.C. (SATCM). 14 15 Contributions JG, LZ, and JW organized the trial hypotheses, designed the trial, 16 For peer review only 17 and provided guidance about the data analysis and interpretation/presentation of the 18 data. JG is the subject primarily responsible of the Clinical trial (CRRICH Trial) and 19 provided critical review of the manuscript. LZ drafted most of the sections of the 20 21 manuscript. JL,GS,YZ,SL,GH,QZ and YW were involved in the design of the study 22 and provided contributions to the writing and revising of the manuscript. JW, GT and 23 24 JB organized and managed the trial including trial start up, data collection, quality 25 assurance, and trial close out. XL provided the region of interest calculations for all 26 volumetric measurement results. JW and TH provided independent review and 27 28 adjudication of all safety events. QZ,HL,BG,XC,YZ and ZW were involved in the 29 statistical analysis, data interpretation, and contributed to the development and 30 31 revisions to the manuscript. The CRRICH investigators contributed equally to the 32 identification and, when eligible, randomization of trial participants. 33 34 Funding State Administration of Traditional Chinese Medicine of the P.R.C. 35 (SATCM) has allocated to Guangdong Provincial Hospital of TCM (GPHTCM): 36 37 SATCM Grant No: ZDJX2012074,JDZX2015048, and Project of Department of 38 Science and Technology of Guangdong Province, Grant No. 2014A020221074. JG is 39 the subject primarily responsible. This report is an independent study supported by the 40 SATCM and conducted by the GPHTCM in the name of the SATCM–GPHTCM 41 partnership. The viewpoints stated in this essay are those of the authors and may not 42 43 be those of the SATCM, GPHTH or the Public Health Bureau. 44 45 Competing interests None declared. 46 47 Ethics approval B2013 085 01; CRRICH trial were approved by institutional review 48 boards at all participating centres (specified in the text). 49 50 51 52 53 References 54 55 56 57 24 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 55
1 2 3 [1] Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009. 373(9675): 1632 44. 4 5 [2] Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity 6 7 in children and adults during 1980 2013: a systematic analysis for the Global Burden of Disease Study 8 2013. Lancet. 2014. 384(9945): 766 81. 9 10 [3] Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the Global Burden of Ischemic and Hemorrhagic 11
12 Stroke in 1990 2013: The GBD 2013 Study. Neuroepidemiology. 2015. 45(3): 161 76. 13 14 [4] Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, 15 and a national priority. Stroke. 2011. 42(12): 3651 4. 16 For peer review only 17 [5] van Asch CJ, Luitse MJ, Rinkel GJ. Incidence, case fatality, and functional outcome of intracerebral 18 19 haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta analysis. 20 Lancet Neurol. 2010. 9(2): 167 76. 21 22 [6] Tsai CF, Thomas B, Sudlow CL. Epidemiology of stroke and its subtypes in Chinese vs white populations: 23 24 a systematic review. Neurology. 2013. 81(3): 264 72. 25 26 [7] Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous 27 Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart 28 29 Association/American Stroke Association. Stroke. 2015. 46(7): 2032 60. 30 31 [8] Rabinstein AA. Intracerebral haemorrhage: no good treatment but treatment helps. Lancet. 2017. 32 389(10069): 575 576. 33 34 35 [9] Li HQ, Wei JJ, Xia W, et al. Promoting blood circulation for removing blood stasis therapy for acute 36 intracerebral hemorrhage: a systematic review and meta analysis. Acta Pharmacol Sin. 2015. 36(6): 37 659 75. 38 39 40 [10] Wang YQ, Shi Q, Wang WP. Clinical study of xuefuzhuyu decoction on hypertensive intracerebral 41 hemorrhage. J Emerg Tradit Chin Med 2013; 22: 1686 7, 1689. Chinese . 42 43 [11] Zhang ZZ, Zhang BH, Chen M. The study of Danshen Injection for prevention and treatment of brain 44 45 edema in acute intracerebral hemorrhage. Zhejiang J Integr Tradit Chin West Med 2003; 13: 355 7. 46 Chinese . 47 48 [12] Monreal M, Costa J, Salva P. Pharmacological properties of hirudin and its derivatives. Potential clinical 49
50 advantages over heparin. Drugs Aging. 1996. 8(3): 171 82. 51 52 [13] Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. 53 Stroke. 1997. 28(1): 1 5. 54 55 [14] Xu Y, Guo J, Liu X. Can Herbal Medicine Cause Hematoma Enlargement of Hypertensive Intracerebral 56 57 25 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 55 BMJ Open
1 2 3 Hemorrhage within 24 hrs Time Window? A Retrospective Study of 256 Cases from a Single Center in 4 China. Evid Based Complement Alternat Med. 2015. 2015: 868731. 5 6 7 [15] Zeng L, Guo J, Wang J. Clinical re evaluation of removing blood stasis therapy in treating acute 8 intracerebral hemorrhage safety and efficacy: a protocol for a randomized, controlled, multicenter study 9 (CRRICH Trial). Springerplus. 2016. 5(1): 1466. 10 11 12 [16] Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 13 1996. 27(8): 1304 5. 14 15 [17] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 16 intracerebralFor hemorrhage. peer N Engl J Med. review2008. 358(20): 2127 37 . only 17 18 19 [18] Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor 20 outcome after intracerebral hemorrhage. Neurology. 2006. 66(8): 1175 81. 21 22 [19] Mayer SA. Ultra early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003. 34(1): 224 9. 23 24 25 [20] Wartenberg KE, Mayer SA. Ultra Early Hemostatic Therapy for Intracerebral Hemorrhage: Future 26 Directions. Front Neurol Neurosci. 2015. 37: 107 29. 27 28 [21] Chinese Pharmacopoeia Committee. Chinese Pharmacopoeia. Beijing:China Medical Science and 29
30 Technology Press. 2010: 111 113 . 31 32 [22] Si GZ. preliminary clinical study of herbal medicine on hemorrhagic stroke: Removing Blood Stasis 33 Therapy. Tianjin Medical Journal.1982;08: 473 476.Chinese . 34 35 [23] The Professional Board of Neurology Department of Chinese Association of Integrative Medicine in 36 37 Beijing，GAO L． Expert consensus on hypertensive intracerebral hemorrhage in acute stage in diagnosis 38 and treatment combining traditional Chinese medicine and Western medicine［J］. Chinese General 39 ， ， － 40 Practice 2016 19 (30): 3641 3648. Chinese . 41 42 [24] Zou YH, Ma Bin. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for 43 healthcare professionals from the China Association of Chinese Medicine.Chinese traditional Chinese 44
45 medicine modern remote education.2011.9(23): 110 112.Chinese . 46 47 [25] Brouwers HB, Falcone GJ, McNamara KA, et al. CTA spot sign predicts hematoma expansion in patients 48 with delayed presentation after intracerebral hemorrhage. Neurocrit Care. 2012. 17(3): 421 8. 49 50 [26] L.Bin, L Jian. Clinical observation of early use promoting blood circulation and removing blood stasis 51 52 herbal injection to treat acute intracerebral hemorrhage. Shandong Journal of Traditional Chinese Medicine. 53 2000; 19(8):461 462.Chinese . 54 55 [27] Demchuk AM, Dowlatshahi D, Rodriguez Luna D, et al. Prediction of haematoma growth and outcome in 56 57 26 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 55
1 2 3 patients with intracerebral haemorrhage using the CT angiography spot sign (PREDICT): a prospective 4 observational study. Lancet Neurol. 2012. 11(4): 307 14. 5 6 7 [28] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 8 intracerebral hemorrhage. N Engl J Med. 2008. 358(20): 2127 37. 9 10 [29] Anderson CS, Heeley E, Huang Y, et al. Rapid blood pressure lowering in patients with acute intracerebral 11
12 hemorrhage. N Engl J Med. 2013. 368(25): 2355 65. 13 14 [30] Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY 059 for acute intracerebral 15 hemorrhage: the CHANT Trial. Stroke. 2007. 38(8): 2262 9. 16 For peer review only 17 18 19 20 21 22 23 Figure 2 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin scale 24 evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). There were 25 26 no significant differences between the three groups. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 27 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 55 BMJ Open
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1. Enrollment and Follow-up. AEs, adverse events; FAS, full analysis set; PPS, per-protocol population 33 set; RBS, removing blood stasis;ICH denotes intracerebral hemorrhage; ICH-1 denotes herbal medicine with 34 RBS herbals hirudo and tabanus (8 herbals); ICH-2 denotes herbal medicine without RBS herbals hirudo or 35 tabanus (6 herbals) 36 172x136mm (96 x 96 DPI) 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 55
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 2 Kaplan-Meier Survival Curves. Group placebo with 4 cases dead, respectively at day 4,5,8,9; Group 33 ICH 1 with 3 cases dead, respectively at day 4,5,9; Group ICH 2 with 1 case dead at day 3.A possible small 34 benefit of treatment with ICH 1,ICH 2 was evident from 10 to 90 days after treatment. 35 36 220x176mm (72 x 72 DPI) 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 55 BMJ Open
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 Figure 3 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin scale evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). 28 There were no significant differences between the three groups. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 55
1 2 3 4 supplemental material 5 6 S1 Table : Full list of Principle investigators and study centers 7 8 Number of 9 Centre Centre address, zip code 10 Principle Investigator patients NO. 11 randomized 12 Zhangyong Xia, Rui Liaocheng People's Hospital, Liaocheng, 13 1 39 14 Zhang, Guangzeng Li Shandong Province, China, 252000 15 Guangsheng Chen, Boluo County People's Hospital, 16 2 Bochang Lin, Weiming Huizhou, Guangdong, China, 514610 32 17 18 Zhu For peer review only 19 Qianshan Zhao, Richao Jiangmen Wuyi Traditional Chinese Medicine 20 3 Chen, Yongtong He Hospital, Jiangmen, Guangdong, China, 9 21 22 529000 23 Jiexia Li, Xiaomei Huang, The hospital of Chinese Medicine of Conghua 24 4 27 Mengxin Huang City, Conghua, Guangdong, China, 5109000 25 26 Chaojun Chen, Jianfang Guangzhou Hospital of Integrated traditional 27 5 Hu, Peiqun Yang and west medicine, Guangzhou, Guangdong, 2 28 China, 510800 29 30 Yongbo Zhang, Quanliang Shouguang City People's Hospital, 6 21 31 Wang, Xiulan Huang Shouguang, Shandong, China, 262700 32 33 Gan Huang, Lianying Li, Yangjiang Hospital of Traditional Chinese 34 7 Yanchun Li Medicine, Yangjiang, Guangdong, China, 13 35 529500 36 Kaiyun Zhu, Ningping Liu, Panyu Hospital of Chinese Medicine 37 8 1 38 Yinghong Zhang Guangzhou, Guangdong, China, 511400 39 Saihua Luo ,Zai Liang, Lianjiang People's hospital, Lianjiang, 40 9 19 Bing Qiu Guangdong, China, 524400 41 42 Guanghai Tang, Kai Zhao, Shenyang No.2 traditional Chinese medical 10 54 43 Guang Yang hospital, Shenyang, Liaoning, China, 110000 44 Jianbin Zhong, Simin Boji-affiliated Hospital of Sun Yat-sen 45 46 11 Zhong, Sijun Zhang University, zengcheng, Guangdong, China, 42 47 511300 48 Jianwen Guo, Liling Zeng, Guangdong Provincial Hospital of Chinese 49 50 12 Jing Wang Medicine, Guangzhou, Guangdong, China, 42 51 510120 52 Yue Wang, Wenjun Liu, Zhongshan Hospital of Hubei Province, 53 13 9 54 Jing Zuo Wuhan, Hubei, China,430032 55 Tao Huang, Ronming Lin, Guangzhou Charity Hospital, Guangzhou, 14 14 56 Qixin Zhang Guangdong, China,510000 57 58 59 60
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1 2 3 S1 Fig: Study design 4 5 6 7 Stroke onset 0-6h 8 9 10 Screening 11 and Arriving at treating hospital 12 13 Randomization 14 15 Perform CT, Baseline NIHSS,GCS 16 ≤ 6 hours post stroke 17 18 For peer review only 19 No 20 Subject not consider Hemorrhage? 21 for study 22 23 yes 24 No 25 Does subject meet all 26 Subject not consider for 27 entry criteria study 28 29 Yes 30 31 Randomize 32 33 34 35 36 Group Placebo Group ICH-2 Group ICH-1 37 38 39 40 41 Perform CT ,NIHSS,GCS after 24h of onset 42 43 44 Treatment period 45 Yes 46 10 days Reccurence of hemorrhage between 24h and 10-14 Perform 47 CT,NIHSS,GCS,BI,mRS 48 days of onset? 49 50 No 51 52 Perform CT ,NIHSS,GC,BI,mRS after 10-14 days of onset 53 54 55 follow-up period 56 3 months 57 90 days follow-up , Perform NIHSS,GCS,BI,mRS 58 59 60 S1 Fig. Study design diagram. Subjects who had suffered hypertensive intracerebral
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1 2 3 hemorrhage were randomized to receive placebo, ICH-1, ICH-2in a 1:1 :1ratio within 4 5 6 hours following the stroke onset. The trial consisted of a screening period (up to 6 6 hours), followed by a randomized treatment period (up to2 weeks treatment period), 7 ending with a 3-month efficacy follow-up period (where subjects were allowed to 8 9 undergo treatment in accordance with standard clinical practice).CT, computed 10 tomography; CTA, computed tomography angiography; NIHSS, National Institutes of 11 Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index; GCS, Glasgow 12 13 coma scale. 14 15 S2 Tables: study inclusion and exclusion criteria 16 17 18 Table 2 study inclusionFor and exclusionpeer criteria review only 19 20 Inclusion Criteria: 21 22 ages eligible for Study: 18 years or older 23 24 genders eligible for Study: Both 25 AICH confirmed by craniocerebral CT scan 26 27 within 6 hours after the onset of symptom 28 GCS≥6 29 30 sign the informed consent form 31 Exclusion Criteria: 32 33 34 secondary intracerebral hemorrhage resulting from trauma, brain tumor, blood 35 diseases, arteriovenous malformation or aneurysm, etc; 36 37 patients with severe heart, liver or kidney disease. 38 Intolerance to herbal medicine, 39 40 patients with allergies 41 patients planning a surgical evacuation of hematoma with severe cerebral hernia 42 43 at super-early stage 44 patients with poor compliance 45 46 TCM,Chinese Medicine. AICH, acute intracerebral hemorrhage.CT, computed tomography; GCS, 47 Glasgow coma scale. 48 S3 Table : Groups and Interventions 49 50 51 Groups Interventions Signa 52 8 herbals(with 2 herbals of one dose, bid, by oral or nasogastric 53 RBS,(Hirudo and Tabanus),as well as tube for 10 days 54 ICH-1 55 herbals of PBC and other combined 56 herbals) 57 6 herbals(remove 2 herbals of RBS, one dose, bid, by oral or nasogastric 58 59 ICH-2 left with PBC and other combined tube for 10 days 60 herbals )
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1 2 3 Placebo placebo herbal medicine(with one dose, bid, by oral or nasogastric 4 5 Comparator dextrin, farina and so on) tube for 10 days 6 *RBS, removing blood stasis; PBC, promoting blood circulation. 7 8 9 S4 Table : All primary, secondary and safety endpoints 10 Primary 11 hematoma enlargement:the percent change in the volume of hematoma at 24 hours,on 10-14th day 12 13 Secondary 14 Between-group differences in the NIHSS at 3 months 15 mortality on the 10th-14th day, 3 months 16 17 poor prognosis popularly as defined by mRS score≥5 at 3 months 18 Adverse events For peer review only 19 NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 Reporting checklist for qualitative study. 4 5 6 Based on the SRQR guidelines. 7 8 Instructions to authors 9 10 11 Complete this checklist by entering the page numbers from your manuscript where readers will find 12 each of the items listed below. 13 14 15 Your article may not currently address all the items on the checklist. Please modify your text to 16 include the missing information.For Ifpeer you are certain review that an item onlydoes not apply, please write "n/a" and 17 18 provide a short explanation. 19 20 Upload your completed checklist as an extra file when you submit to a journal. 21 22 In your methods section, say that you used the SRQR reporting guidelines, and cite them as: 23 24 O'Brien BC, Harris IB, Beckman TJ, Reed DA, Cook DA. Standards for reporting qualitative research: 25 26 a synthesis of recommendations. Acad Med. 2014;89(9):1245-1251. 27 28 29 Page 30 31 Reporting Item Number 32 33 34 # Concise description of the nature and topic of the P1-2 35 1 study identifying the study as qualitative or indicating 36 37 the approach (e.g. ethnography, grounded theory) or 38 data collection methods (e.g. interview, focus group) 39 40 is recommended 41 42 43 # Summary of the key elements of the study using the P1-3 44 2 abstract format of the intended publication; typically 45 46 includes background, purpose, methods, results and 47 conclusions 48 49 50 51 P # Description and signifcance of the problem / P3-5 52 r 3 phenomenon studied: review of relevant theory and 53 54 o empirical work; problem statement 55 b 56 57 l 58 e 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 55 BMJ Open
m 1 2 3 f 4 5 o 6 r 7 8 m 9 u 10 11 l 12 a 13 14 t 15 i 16 For peer review only 17 o 18 n 19 20 21 P # Purpose of the study and specific objectives or P1 22 23 u 4 questions 24 r 25 26 p 27 o 28 29 s 30 e 31 32 33 o 34 35 r 36 r 37 38 e 39 s 40 41 e 42 a 43 44 r 45 c 46 47 h 48 49 50 q 51 u 52 53 e 54 s 55 56 t 57 i 58 59 o 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 55
n 1 2 3 Q # Qualitative approach (e.g. ethnography, grounded P5-7 4 5 u 5 theory, case study, phenomenolgy, narrative 6 a research) and guiding theory if appropriate; 7 8 li identifying the research paradigm (e.g. postpositivist, 9 t constructivist / interpretivist) is also recommended; 10 11 a rationale. The rationale should briefly discuss the 12 t justification for choosing that theory, approach, 13 14 i method or technique rather than other options 15 v available; the assumptions and limitations implicit in 16 For peer review only 17 e those choices and how those choices influence study 18 conclusions and transferability. As appropriate the 19 20 a rationale for several items might be discussed 21 p together. 22 23 p 24 r 25 26 o 27 a 28 29 c 30 h 31 32 33 a 34 35 n 36 d 37 38 39 r 40 41 e 42 s 43 44 e 45 a 46 47 r 48 c 49 50 h 51 52 53 p 54 a 55 56 r 57 a 58 59 d 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 55 BMJ Open
i 1 2 g 3 m 4 5 6 R # Researchers' characteristics that may influence the P5,P22 7 8 e 6 research, including personal attributes, qualifications / 9 s experience, relationship with participants, 10 11 e assumptions and / or presuppositions; potential or 12 a actual interaction between researchers' 13 14 r characteristics and the research questions, approach, 15 c methods, results and / or transferability 16 For peer review only 17 h 18 e 19 20 r 21 c 22 23 h 24 a 25 26 r 27 a 28 29 c 30 t 31 32 e 33 r 34 35 i 36 s 37 38 t 39 i 40 41 c 42 s 43 44 45 a 46 47 n 48 d 49 50 51 r 52 53 e 54 f 55 56 l 57 e 58 59 x 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 55
i 1 2 v 3 i 4 5 t 6 y 7 8 9 C # Setting / site and salient contextual factors; rationale 10 11 o 7 12 n 13 14 t 15 e 16 For peer review only 17 x 18 t 19 20 21 22 S # How and why research participants, documents, or P5 23 a 8 events were selected; criteria for deciding when no 24 25 m further sampling was necessary (e.g. sampling 26 p saturation); rationale 27 28 li 29 n 30 31 g 32 33 34 s 35 t 36 37 r 38 a 39 t 40 41 e 42 g 43 44 y 45 46 47 E # Documentation of approval by an appropriate ethics P10,P24 48 49 t 9 review board and participant consent, or explanation 50 h for lack thereof; other confidentiality and data security 51 52 i issues 53 c 54 55 a 56 l 57 58 i 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 55 BMJ Open
s 1 2 s 3 u 4 5 e 6 s 7 8 9 p 10 11 e 12 r 13 14 t 15 a 16 For peer review only 17 i 18 n 19 20 i 21 n 22 23 g 24 25 26 t 27 o 28 29 30 h 31 32 u 33 m 34 35 a 36 n 37 38 39 s 40 41 u 42 b 43 44 j 45 e 46 47 c 48 t 49 50 s 51 52 53 D # Types of data collected; details of data collection P6-9 54 a 1 procedures including (as appropriate) start and stop 55 56 t 0 dates of data collection and analysis, iterative 57 a process, triangulation of sources / methods, and 58 59 modification of procedures in response to evolving 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 55
c study findings; rationale 1 2 o 3 ll 4 5 e 6 c 7 8 t 9 i 10 11 o 12 n 13 14 15 m 16 For peer review only 17 e 18 t 19 20 h 21 o 22 23 d 24 s 25 26 27 D # Description of instruments (e.g. interview guides, P5-6,P9- 28 29 a 1 questionnaires) and devices (e.g. audio recorders) 10 30 t 1 used for data collection; if / how the instruments(s) 31 32 a changed over the course of the study 33 34 35 c 36 o 37 38 ll 39 e 40 41 c 42 t 43 44 i 45 o 46 47 n 48 49 50 i 51 n 52 53 s 54 t 55 56 r 57 u 58 59 m 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 55 BMJ Open
e 1 2 n 3 t 4 5 s 6 7 8 a 9 n 10 11 d 12 13 14 t 15 e 16 For peer review only 17 c 18 h 19 20 n 21 o 22 23 l 24 o 25 26 g 27 i 28 29 e 30 s 31 32 33 U # Number and relevant characteristics of participants, P11-12 34 35 n 1 documents, or events included in the study; level of 36 i 2 participation (could be reported in results) 37 38 t 39 s 40 41 42 o 43 44 f 45 s 46 47 t 48 u 49 50 d 51 y 52 53 54 D # Methods for processing data prior to and during P11-12 55 56 a 1 analysis, including transcription, data entry, data 57 t 3 management and security, verification of data 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 55
a integrity, data coding, and anonymisation / 1 2 deidentification of excerpts 3 p 4 5 r 6 o 7 8 c 9 e 10 11 s 12 s 13 14 i 15 n 16 For peer review only 17 g 18 19 20 D # Process by which inferences, themes, etc. were P12-13 21 a 1 identified and developed, including the researchers 22 23 t 4 involved in data analysis; usually references a 24 a specific paradigm or approach; rationale 25 26 27 a 28 29 n 30 a 31 32 l 33 y 34 35 s 36 i 37 38 s 39 40 41 T # Techniques to enhance trustworthiness and credibility P11-14 42 e 1 of data analysis (e.g. member checking, audit trail, 43 44 c 5 triangulation); rationale 45 h 46 47 n 48 i 49 50 q 51 u 52 53 e 54 s 55 56 57 t 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 55 BMJ Open
o 1 2 3 e 4 5 n 6 h 7 8 a 9 n 10 11 c 12 e 13 14 15 t 16 For peer review only 17 r 18 u 19 20 s 21 t 22 23 w 24 o 25 26 r 27 t 28 29 h 30 i 31 32 n 33 e 34 35 s 36 s 37 38 39 S # Main findings (e.g. interpretations, inferences, and P14-17 40 41 y 1 themes); might include development of a theory or 42 n 6 model, or integration with prior research or theory 43 44 t 45 h 46 47 e 48 s 49 50 e 51 s 52 53 54 a 55 56 n 57 d 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 55
i 1 2 n 3 t 4 5 e 6 r 7 8 p 9 r 10 11 e 12 t 13 14 a 15 t 16 For peer review only 17 i 18 o 19 20 n 21 22 23 L # Evidence (e.g. quotes, field notes, text excerpts, P18-21 24 i 1 photographs) to substantiate analytic findings 25 26 n 7 27 k 28 29 s 30 31 32 t 33 o 34 35 36 e 37 38 m 39 p 40 41 i 42 r 43 44 i 45 c 46 47 a 48 l 49 50 d 51 a 52 53 t 54 a 55 56 57 I # Short summary of main findings; explanation of how P22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 55 BMJ Open
n 1 findings and conclusions connect to, support, 1 2 t 8 elaborate on, or challenge conclusions of earlier 3 e scholarship; discussion of scope of application / 4 5 r generalizability; identification of unique 6 g contributions(s) to scholarship in a discipline or field 7 8 r 9 a 10 11 t 12 i 13 14 o 15 n 16 For peer review only 17 18 w 19 20 i 21 t 22 23 h 24 25 26 p 27 r 28 29 i 30 o 31 32 r 33 w 34 35 o 36 r 37 38 k 39 , 40 41 i 42 m 43 44 p 45 li 46 47 c 48 a 49 50 t 51 i 52 53 o 54 n 55 56 s 57 , 58 59 t 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 55
r 1 2 a 3 n 4 5 s 6 f 7 8 e 9 r 10 11 a 12 b 13 14 il 15 i 16 For peer review only 17 t 18 y 19 20 21 a 22 23 n 24 d 25 26 27 c 28 29 o 30 n 31 32 t 33 r 34 35 i 36 b 37 38 u 39 t 40 41 i 42 o 43 44 n 45 ( 46 47 s 48 ) 49 50 t 51 o 52 53 54 t 55 56 h 57 e 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 55 BMJ Open
f 1 2 i 3 e 4 5 l 6 d 7 8 9 L # Trustworthiness and limitations of findings 10 11 i 1 12 m 9 13 14 i 15 t 16 For peer review only 17 a 18 t 19 20 i 21 o 22 23 n 24 s 25 26 27 28 C # Potential sources of influence of perceived influence P3, P20- 29 o 2 on study conduct and conclusions; how these were 21 30 31 n 0 managed 32 f 33 34 li 35 c 36 37 t 38 s 39 40 41 o 42 f 43 44 i 45 n 46 47 t 48 e 49 50 r 51 e 52 53 s 54 t 55 56 57 58 F # Sources of funding and other support; role of funders P10.P23- 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 55
u 2 in data collection, interpretation and reporting 24 1 2 n 1 3 d 4 5 i 6 n 7 8 g 9 10 11 The SRQR checklist is distributed with permission of Wolters Kluwer © 2014 by the Association of 12 American Medical Colleges. This checklist can be completed online using 13 14 https://www.goodreports.org/, a tool made by the EQUATOR Network in collaboration with 15 Penelope.ai 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 55 BMJ Open
Checklist of Items for Reporting Trials of Chinese Herbal Medicine Formulas* 1 2 Section/Topic Item Standard CONSORT Checklist Item Extension for CHM Formulas 珈ਤ⊀ʤ㦠珈⁀ 3 4 Number ⊀R Page 5 Number 6 7 8 Title, abstract, and 1a I⁀珈R㦠ifica㦠i⊀R as a ʤaR⁀⊀miz珈⁀ 㦠ʤial iR 㦠h珈 㦠i㦠l珈 Statement of whether the trial targets a TCM Pa㦠㦠珈ʤR, a Western P1 9 keywords medicine–defined disease, or a Western medicine–defined disease with a 10 11 specific TCM Pa㦠㦠珈ʤR, if applicable 12 For peer review only 13 1b S㦠ʤuc㦠uʤ珈⁀ summaʤy ⊀f 㦠ʤial ⁀珈sigR, m珈㦠h⊀⁀s, ʤ珈sul㦠s, aR⁀ c⊀Rclusi⊀Rs Illustration of the name and form of the formula used, and the TCM P1-3 14 (f⊀ʤ sਤ珈cific gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ abs㦠ʤac㦠s [26, 27]) Pa㦠㦠珈ʤR applied, if applicable 15 16 17 1c Determination of appropriate keywords, including “Chinese herbal P3 18 medicine formula” and “randomized controlled trial” 19 20 Introduction 21 22 23 Backgʤ⊀uR⁀ aR⁀ 2a Sci珈R㦠ific backgʤ⊀uR⁀ aR⁀ 珈xਤlaRa㦠i⊀R ⊀f ʤa㦠i⊀Ral珈 Statement with biomedical science approaches and/or TCM approaches P4 24 ⊀bj珈c㦠iv珈s 25 2b Sਤ珈cific ⊀bj珈c㦠iv珈s ⊀ʤ hyਤ⊀㦠h珈s珈s Statement of whether the formula targets a Western medicine–defined P5 26 disease, a TCM Pa㦠㦠珈ʤR, or a Western medicine–defined disease with a 27 28 specific TCM Pa㦠㦠珈ʤR 29 30 Methods 31 32 Tʤial ⁀珈sigR 3a D珈scʤiਤ㦠i⊀R ⊀f 㦠ʤial ⁀珈sigR (such as ਤaʤall珈l, fac㦠⊀ʤial), iRclu⁀iRg P5 33 34 all⊀ca㦠i⊀R ʤa㦠i⊀ 35 36 3b Imਤ⊀ʤ㦠aR㦠 chaRg珈s 㦠⊀ m珈㦠h⊀⁀s af㦠珈ʤ 㦠ʤial c⊀mm珈Rc珈m珈R㦠 (such as P5 37 38 珈ligibili㦠y cʤi㦠珈ʤia), wi㦠h ʤ珈as⊀Rs 39 40 Paʤ㦠iciਤaR㦠s 4a Eligibili㦠y cʤi㦠珈ʤia f⊀ʤ ਤaʤ㦠iciਤaR㦠s Statement of whether participants with a specific TCM Pa㦠㦠珈ʤR were P5-6 41 recruited, in terms of 1) diagnostic criteria and 2) inclusion and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 52 of 55
1 exclusion criteria. All criteria used should be universally recognized, or 2 reference given to where detailed explanation can be found. 3 4 5 4b S珈㦠㦠iRgs aR⁀ l⊀ca㦠i⊀Rs wh珈ʤ珈 㦠h珈 ⁀a㦠a w珈ʤ珈 c⊀ll珈c㦠珈⁀ P6 6 7 IR㦠珈ʤv珈R㦠i⊀Rs 5 Th珈 iR㦠珈ʤv珈R㦠i⊀Rs f⊀ʤ 珈ach gʤ⊀uਤ wi㦠h suffici珈R㦠 ⁀珈㦠ails 㦠⊀ all⊀w Description(s) for different types of formulas should include the P6-8 8 ʤ珈ਤlica㦠i⊀R, iRclu⁀iRg h⊀w aR⁀ wh珈R 㦠h珈y w珈ʤ珈 ac㦠ually a⁀miRis㦠珈ʤ珈⁀ following: 9 10 5a. For fixed CHM formulas 11 1. Name, source, and dosage form (e.g., decoctions, granules, 12 For peer review only 13 powders) 14 2. Name, source, processing method, and dosage of each medical 15 16 substance. Names of substances should be presented in at least 2 17 languages: Chinese (PiRyiR), Latin, or English. Names of the parts of 18 19 the substances used should be specified. 20 3. Authentication method of each ingredient and how, when, where, 21 22 and by whom it was conducted; statement of whether any voucher 23 specimen was retained, and if so, where they were kept and whether 24 25 they are accessible 26 4. Principles, rationale, and interpretation of forming the formula 27 28 5. Reference(s) as to the efficacy of the formula, if any 29 6. Pharmacologic study results of the formula, if any 30 31 7. Production method of the formula, if any 32 8. Quality control of each ingredient and of the product of the 33 34 formula, if any. This would include any quantitative and/or 35 qualitative testing method(s); when, where, how, and by whom these 36 37 tests were conducted; whether the original data and samples were 38 kept, and, if so, whether they are accessible. 39 40 9. Safety assessment of the formula, including tests for heavy metals 41 and toxic elements, pesticide residues, microbial limit, and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 53 of 55 BMJ Open
1 acute/chronic toxicity, if any. If yes, it should be stated when, where, 2 how, and by whom these tests were conducted; if the original data 3 4 and samples were kept; and, if so, whether they are accessible. 5 10. Dosage of the formula, and how the dosage was determined 6 7 11. Administration route (e.g., oral, external) 8 5b. For individualized CHM formulas 9 10 1. See recommendations 5a 1–11 11 2. Additional information: how, when, and by whom the formula was 12 For peer review only 13 modified 14 5c. For patent proprietary CHM formulas 15 16 1. Reference to publicly available materials, such as pharmacopeia, 17 for the details about the composition, dosage, efficacy, safety, and 18 19 quality control of the formula 20 2. Illustration of the details of the formula, namely 1) the proprietary 21 22 product name (i.e., brand name), 2) name of manufacturer, 3) lot 23 number, 4) production date and expiry date, 5) name and percentage 24 25 of added materials, and 6) whether any additional quality control 26 measures were conducted 27 28 3. Statement of whether the patent proprietary formula used in the 29 trial is for a condition that is identical to the publicly available 30 31 reference 32 5d. Control groups 33 34 Placebo control 35 1. Name and amount of each ingredient 36 37 2. Description of the similarity of placebo with the intervention 38 (e.g., color, smell, taste, appearance, packaging) 39 40 3. Quality control and safety assessment, if any 41 4. Administration route, regimen, and dosage 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 54 of 55
1 5. Production information: where, when, how, and by whom the 2 placebo was produced 3 4 Active control 5 1. If a CHM formula was used, see recommendations 5a–5c 6 7 2. If a chemical drug was used, see item 5 of the CONSORT 8 Statement (24) 9 10 11 Ou㦠c⊀m珈s 6a C⊀mਤl珈㦠珈ly ⁀珈fiR珈⁀, ਤʤ珈sਤ珈cifi珈⁀ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈 Illustration of outcome measures with Pa㦠㦠珈ʤR in detail P8-9 12 m珈asuʤ珈s, iRclu⁀iRgFor h⊀w aR⁀ wh珈R peer 㦠h珈y w珈ʤ珈 ass珈ss珈⁀ review only 13 14 6b ARy chaRg珈s 㦠⊀ 㦠ʤial ⊀u㦠c⊀m珈s af㦠珈ʤ 㦠h珈 㦠ʤial c⊀mm珈Rc珈⁀, wi㦠h ʤ珈as⊀Rs P8-9 15 16 17 Samਤl珈 siz珈 7a H⊀w samਤl珈 siz珈 was ⁀珈㦠珈ʤmiR珈⁀ P10 18 19 7b Wh珈R aਤਤlicabl珈, 珈xਤlaRa㦠i⊀R ⊀f aRy iR㦠珈ʤim aRalys珈s aR⁀ s㦠⊀ਤਤiRg 20 gui⁀珈liR珈s 21 22 23 aR⁀⊀miza㦠i⊀R 24 25 S珈qu珈Rc珈 8a M珈㦠h⊀⁀ us珈⁀ 㦠⊀ g珈R珈ʤa㦠珈 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 P6 26 g珈R珈ʤa㦠i⊀R 27 8b Tyਤ珈 ⊀f ʤaR⁀⊀miza㦠i⊀R; ⁀珈㦠ails ⊀f aRy ʤ珈s㦠ʤic㦠i⊀R (such as bl⊀ckiRg aR⁀ P6 28 29 bl⊀ck siz珈) 30 31 All⊀ca㦠i⊀R 9 M珈chaRism us珈⁀ 㦠⊀ imਤl珈m珈R㦠 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 (such P6 32 c⊀Rc珈alm珈R㦠 as s珈qu珈R㦠ially Rumb珈ʤ珈⁀ c⊀R㦠aiR珈ʤs), ⁀珈scʤibiRg aRy s㦠珈ਤs 㦠ak珈R 㦠⊀ 33 34 m珈chaRism c⊀Rc珈al 㦠h珈 s珈qu珈Rc珈 uR㦠il iR㦠珈ʤv珈R㦠i⊀Rs w珈ʤ珈 assigR珈⁀ 35 36 Imਤl珈m珈R㦠a㦠i⊀R 10 Wh⊀ g珈R珈ʤa㦠珈⁀ 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈, wh⊀ 珈Rʤ⊀ll珈⁀ P6-8 37 38 ਤaʤ㦠iciਤaR㦠s, aR⁀ wh⊀ assigR珈⁀ ਤaʤ㦠iciਤaR㦠s 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs 39 40 BliR⁀iRg 11a If ⁀⊀R珈, wh⊀ was bliR⁀珈⁀ af㦠珈ʤ assigRm珈R㦠 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs (f⊀ʤ P6 41 珈xamਤl珈, ਤaʤ㦠iciਤaR㦠s, caʤ珈 ਤʤ⊀vi⁀珈ʤs, 㦠h⊀s珈 ass珈ssiRg ⊀u㦠c⊀m珈s) aR⁀ 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 55 of 55 BMJ Open
1 h⊀w 2 3 11b If ʤ珈l珈vaR㦠, ⁀珈scʤiਤ㦠i⊀R ⊀f 㦠h珈 similaʤi㦠y ⊀f iR㦠珈ʤv珈R㦠i⊀Rs P6-7 4 5 S㦠a㦠is㦠ical 12a S㦠a㦠is㦠ical m珈㦠h⊀⁀s us珈⁀ 㦠⊀ c⊀mਤaʤ珈 gʤ⊀uਤs f⊀ʤ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy P9-10 6 7 m珈㦠h⊀⁀s ⊀u㦠c⊀m珈s 8 9 12b M珈㦠h⊀⁀s f⊀ʤ a⁀⁀i㦠i⊀Ral aRalys珈s, such as subgʤ⊀uਤ aRalys珈s aR⁀ P9-10 10 11 a⁀jus㦠珈⁀ aRalys珈s 12 For peer review only 13 Results 14 15 Paʤ㦠iciਤaR㦠 fl⊀w 13a F⊀ʤ 珈ach gʤ⊀uਤ, 㦠h珈 Rumb珈ʤs ⊀f ਤaʤ㦠iciਤaR㦠s wh⊀ w珈ʤ珈 ʤaR⁀⊀mly P11-13 16 17 (a ⁀iagʤam is assigR珈⁀, ʤ珈c珈iv珈⁀ iR㦠珈R⁀珈⁀ 㦠ʤ珈a㦠m珈R㦠, aR⁀ w珈ʤ珈 aRalyz珈⁀ f⊀ʤ 㦠h珈 18 s㦠ʤ⊀Rgly ਤʤimaʤy ⊀u㦠c⊀m珈 19 20 ʤ珈c⊀mm珈R⁀珈⁀) 13b F⊀ʤ 珈ach gʤ⊀uਤ, l⊀ss珈s aR⁀ 珈xclusi⊀Rs af㦠珈ʤ ʤaR⁀⊀miza㦠i⊀R, 㦠⊀g珈㦠h珈ʤ P11-13 21 22 wi㦠h ʤ珈as⊀Rs 23 24 珈cʤui㦠m珈R㦠 14a Da㦠珈s ⁀珈fiRiRg 㦠h珈 ਤ珈ʤi⊀⁀s ⊀f ʤ珈cʤui㦠m珈R㦠 aR⁀ f⊀ll⊀w-uਤ P7 25 26 14b Why 㦠h珈 㦠ʤial 珈R⁀珈⁀ ⊀ʤ was s㦠⊀ਤਤ珈⁀ P22 27 28 29 Bas珈liR珈 ⁀a㦠a 15 A 㦠abl珈 sh⊀wiRg bas珈liR珈 ⁀珈m⊀gʤaਤhic aR⁀ cliRical chaʤac㦠珈ʤis㦠ics f⊀ʤ P13-14 30 珈ach gʤ⊀uਤ 31 32 Numb珈ʤs 16 F⊀ʤ 珈ach gʤ⊀uਤ, Rumb珈ʤ ⊀f ਤaʤ㦠iciਤaR㦠s (⁀珈R⊀miRa㦠⊀ʤ) iRclu⁀珈⁀ iR 珈ach P14-17 33 34 aRalyz珈⁀ aRalysis aR⁀ wh珈㦠h珈ʤ 㦠h珈 aRalysis was by ⊀ʤigiRal assigR珈⁀ gʤ⊀uਤs 35 36 Ou㦠c⊀m珈s aR⁀ 17a F⊀ʤ 珈ach ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈, ʤ珈sul㦠s f⊀ʤ 珈ach gʤ⊀uਤ, aR⁀ P14-17 37 38 珈s㦠ima㦠i⊀R 㦠h珈 珈s㦠ima㦠珈⁀ 珈ff珈c㦠 siz珈 aR⁀ i㦠s ਤʤ珈cisi⊀R (such as 95% c⊀Rfi⁀珈Rc珈 39 iR㦠珈ʤval) 40 41 17b F⊀ʤ biRaʤy ⊀u㦠c⊀m珈s, ਤʤ珈s珈R㦠a㦠i⊀R ⊀f b⊀㦠h abs⊀lu㦠珈 aR⁀ ʤ珈la㦠iv珈 珈ff珈c㦠 P14-17 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 56 of 55
1 siz珈s is ʤ珈c⊀mm珈R⁀珈⁀ 2 3 ARcillaʤy 18 珈sul㦠s ⊀f aRy ⊀㦠h珈ʤ aRalys珈s ਤ珈ʤf⊀ʤm珈⁀, iRclu⁀iRg subgʤ⊀uਤ aRalys珈s P17 4 5 aRalys珈s aR⁀ a⁀jus㦠珈⁀ aRalys珈s, ⁀is㦠iRguishiRg ਤʤ珈sਤ珈cifi珈⁀ fʤ⊀m 珈xਤl⊀ʤa㦠⊀ʤy 6 7 Haʤms 19 All imਤ⊀ʤ㦠aR㦠 haʤms ⊀ʤ uRiR㦠珈R⁀珈⁀ 珈ff珈c㦠s iR 珈ach gʤ⊀uਤ (f⊀ʤ sਤ珈cific (There is no extension for this item) P15-17 8 gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ haʤms [28]) 9 10 11 Discussion 12 For peer review only 13 Limi㦠a㦠i⊀Rs 20 Tʤial limi㦠a㦠i⊀Rs; a⁀⁀ʤ珈ssiRg s⊀uʤc珈s ⊀f ਤ⊀㦠珈R㦠ial bias; imਤʤ珈cisi⊀R; aR⁀, P22 14 if ʤ珈l珈vaR㦠, mul㦠iਤlici㦠y ⊀f aRalys珈s 15 16 17 G珈R珈ʤalizabili㦠y 21 G珈R珈ʤalizabili㦠y (珈x㦠珈ʤRal vali⁀i㦠y, aਤਤlicabili㦠y) ⊀f 㦠h珈 㦠ʤial fiR⁀iRgs Discussion of how the formula works on different TCM Pa㦠㦠珈ʤRs or P20-21 18 diseases 19 20 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R 22 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R c⊀Rsis㦠珈R㦠 wi㦠h ʤ珈sul㦠s, balaRciRg b珈R珈fi㦠s aR⁀ haʤms, Interpretation with TCM theory P17-21 21 22 aR⁀ c⊀Rsi⁀珈ʤiRg ⊀㦠h珈ʤ ʤ珈l珈vaR㦠 珈vi⁀珈Rc珈 23 24 Other information 25 26 珈gis㦠ʤa㦠i⊀R 23 珈gis㦠ʤa㦠i⊀R Rumb珈ʤ aR⁀ Ram珈 ⊀f 㦠ʤial ʤ珈gis㦠ʤy P2 27 28 29 Pʤ⊀㦠⊀c⊀l 24 Wh珈ʤ珈 㦠h珈 full 㦠ʤial ਤʤ⊀㦠⊀c⊀l caR b珈 acc珈ss珈⁀, if availabl珈 P5 30 31 FuR⁀iRg 25 S⊀uʤc珈s ⊀f fuR⁀iRg aR⁀ ⊀㦠h珈ʤ suਤਤ⊀ʤ㦠 (such as suਤਤly ⊀f ⁀ʤugs), ʤ⊀l珈 ⊀f P10 32 33 fuR⁀珈ʤs 34 35 CHM = ChiR珈s珈 h珈ʤbal m珈⁀iciR珈; CONSO T = C⊀Rs⊀li⁀a㦠珈⁀ S㦠aR⁀aʤ⁀s ⊀f 珈ਤ⊀ʤ㦠iRg Tʤials; TCM = 㦠ʤa⁀i㦠i⊀Ral ChiR珈s珈 m珈⁀iciR珈. 36 * Th珈 ⊀ʤigiRal CONSO T i㦠珈ms aʤ珈 ਤʤ⊀vi⁀珈⁀; 珈lab⊀ʤa㦠i⊀Rs f⊀ʤ CHM f⊀ʤmulas aʤ珈 iR i㦠aliciz珈⁀ 㦠珈x㦠. W珈 s㦠ʤ⊀Rgly ʤ珈c⊀mm珈R⁀ ʤ珈a⁀iRg 㦠his ch珈cklis㦠 iR c⊀RjuRc㦠i⊀R wi㦠h 㦠h珈 CONSO T 2010 37 38 ExਤlaRa㦠i⊀R aR⁀ Elab⊀ʤa㦠i⊀R (29) f⊀ʤ imਤ⊀ʤ㦠aR㦠 claʤifica㦠i⊀Rs ⊀R all ⊀ʤigiRal i㦠珈ms ⊀f CONSO T S㦠a㦠珈m珈R㦠. 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open
Safety and Efficacy of Herbal Medicine for Acute Intracerebral Hemorrhage (CRRICH): A Multicenter Randomized Controlled Trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024932.R1
Article Type: Research
Date Submitted by the 18-Jan-2019 Author:
Complete List of Authors: Zeng, Liling; The Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine Wang, Jing; Neurology Department, Shenzhen Longhua New District Center Hospita, Shenzhen Tang, Guanghai; Shenyang No.2 traditional Chinese medical hospital, Shenyang, Liaoning Zhong, Jianbin ; Boji-affiliated Hospital of Sun Yat-sen University Xia , Zhangyong ; Liaocheng People's Hospital, Liaocheng clinical school of Taishan Medical University Li, Jiexia; Conghua City’s hospital of Chinese Medicine Chen, Guangsheng ; Boluo County People's Hospital Zhang, Yongbo ; Shouguang City People's Hospital Luo, Saihua; Lianjiang People's hospital Huang , Gan ; Yangjiang Hospital of Chinese Medicine Zhao, Qianshan; Jiangmen Wuyi Hospital of Chinese Medicine Wan, Yue ; Zhongshan Hospital of Hubei Province Chen , Chaojun; Guangzhou Hospital of Integrated traditional and west medicine Zhu, Kaiyun ; Panyu Hospital of Chinese Medicine Qiao , Hanzi; Guangdong Provincial hospital of Chinese medicine, Neurology Wang, Jian ; First Affiliated Hospital to Changchun University of Chinese Medicine Huang, Tao ; Guangdong Provincial hospital of Chinese medicine, Neurology Liu, Xian; Guangdong Provincial hospital of Chinese medicine, Neurology Zhang, Qixin ; Guangdong Provincial hospital of Chinese medicine, Neurology Lin, Rongming ; Guangdong Second Hospital of traditional Chinese Medicine Li, Haijun ; Guangdong Provincial hospital of Chinese medicine, Neurology Gong, Baoying ; Guangdong Provincial hospital of Chinese medicine, Neurology Chen, Xiuyan ; Guangdong Provincial hospital of Chinese medicine, Neurology Zhou, Yuexiang; Guangdong Provincial hospital of Chinese medicine, Neurology Wen, Zehuai; Guangdong Provincial Hospital of Chinese Medicine, Key
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1 2 3 Unit of Methodology in Clinical Research 4 Guo, Jianwen; Guangdong Provincial hospital of Chinese medicine, 5 Neurology 6 Primary Subject 7 Neurology 8 Heading: 9 Secondary Subject Heading: Complementary medicine, Neurology 10 intracerebral hemorrhage, Herbal medicine < THERAPEUTICS, 11 Keywords: 12 randomized controlled trials, hematoma enlargement, CRRICH 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 40
1 2 3 4 Safety and Efficacy of Herbal Medicine for Acute Intracerebral 5 6 7 Hemorrhage (CRRICH): A Multicenter Randomized Controlled 8 9 Trial 10 11 12 Liling Zeng, Jing Wang, Guanghai Tang, Jianbin Zhong, Zhangyong Xia, Jiexia Li, 13 14 Guangsheng Chen, Yongbo Zhang, Saihua Luo, Gan Huang, Qianshan Zhao, Yue Wan, 15 16 Chaojun Chen, Kaiyun Zhu, Hanzi Qiao, Jian Wang, Tao Huang, Xian Liu, Qixin Zhang, 17 18 Rongming Lin, HaijunFor Li, Baoyingpeer Gong, review Xiuyan Chen, Yuexiang only Zhou, Zehuai Wen, 19 20 Jianwen Guo* 21 22 23 Jianwen Guo, MD, Neurologist. 24 25 Guangdong Provincial Hospital of Chinese Medicine, Guangdong University of Chinese 26 Medicine 27 28 29 111 Da De Rd., Yuexiu District, Guangzhou, Guangdong Province, 30 31 PRC, 510120 32 33 Email: [email protected] 34 35 36 Telephone 86-20-81867705 37 38 FAX 86-20-81867705 39 40 41 Author affiliations (Liling Zeng, Jianwen Guo, Haijun Li, Qixin Zhang, Tao Huang, 42 43 Xian Liu, Baoying Gong, Xiuyan Chen, Yuexiang Zhou, Zehuai Wen, Hanzi Qiao) The 44 45 Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, 46 Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; (Jing Wang) 47 48 Shenzhen Longhua New District Center Hospital, Shenzhen, China; (Jian Wang) 49 Changchun Chinese Medicine University Affiliated Hospital, Changchun, China; 50 51 (Zhangyong Xia) Liaocheng People's Hospital, Liaocheng Clinical School of Taishan 52 Medical University, Liaocheng, China; (Jiexia Li) Conghua City’s Hospital of Chinese 53 54 Medicine, Conghua, China; (Guangsheng Chen) Boluo County People's Hospital, 55 Huizhou, China; (Qianshan Zhao) Jiangmen Wuyi Hospital of Chinese Medicine, 56 57 Jiangmen, China; (Chaojun Chen) Guangzhou Hospital of Integrated Traditional and 58 Western Medicine, Guangzhou, China; (Yongbo Zhang) Shouguang City People's 59 60 Hospital, Shouguang, China; (Gan Huang) Yangjiang Hospital of Chinese Medicine, 1
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1 2 3 Yangjiang, Guangdong, China; (Kaiyun Zhu) Panyu Hospital of Chinese Medicine， 4 5 Guangzhou, China; (Saihua Luo) Lianjiang People's Hospital, Lianjiang, China; 6 (Guanghai Tang) Shenyang No.2 Traditional Chinese Medical Hospital, Shenyang, 7 8 China; (Jianbin Zhong) Boji-affiliated Hospital of Sun Yat-sen University, Zengcheng, 9 China; (Yue Wan) Zhongshan Hospital of Hubei Province, Wuhan, Hubei, China; 10 11 Guangdong Second Hospital of traditional Chinese Medicine (Rongming Lin) 12 13 14 ABSTRACT 15 16 17 Objective: To evaluate the safety and efficacy of herbal medicine for 18 For peer review only 19 20 the treatment of acute intracerebral hemorrhage (AICH) within a 6-h time 21 22 23 window. 24 25 26 Study design: A randomized, multicenter, double-blind, 27 28 29 placebo-controlled study performed in 14 hospitals in China. 30 31 32 Participants and Interventions: Patients with AICH were randomly 33 34 35 assigned to receive a placebo, the ICH-1 formula (8 herbs, including the 36 37 removing blood stasis (RBS) herbs hirudo and tabanus) or the ICH-2 38 39 40 formula (6 herbs without the RBS herbs hirudo and tabanus) within 6 h 41 42 of ICH onset. 43 44 45 46 Outcomes: The primary safety outcome was the incidence of hematoma 47 48 enlargement at 24 h and at 10 days after treatment. The secondary 49 50 51 outcome was the incidence of poor prognosis (mortality or modified 52 53 54 Rankin Scale (mRS) score ≥5) assessed at 90 days after symptom onset. 55 56 57 Results: A total of 324 subjects were randomized between October 2013 58 59 60 and May 2016: 105 patients received placebo; 108 patients received the 2
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1 2 3 4 ICH-1 formula; and 111 patients received the ICH-2 formula. The 5 6 7 incidence of hematoma enlargement at 24 h were 7.8% in the placebo 8 9 group, 12.3% in the ICH-1 group, and 7.5% in the ICH-2 group; the 10 11 12 incidence of hematoma enlargement on day 10 were 1.1% in the placebo 13 14 15 group, 1.1% in the ICH-1 group, and 3.1% in the ICH-2 group, with no 16 17 significant differences among the groups (P>0.05). The mortality rates 18 For peer review only 19 20 were 3.8% in the placebo group, 2.8% in the ICH-1 group, and 0.9% in 21 22 the ICH-2 group; the incidences of poor prognosis were 7.1% in the 23 24 25 placebo group, 6.0% in the ICH-1 group, and 4.8% in the ICH-2 group at 26 27 28 3 months, with no significant differences among the groups (P>0.05). 29 30 However, the overall frequency of treatment-emergent adverse events in 31 32 33 the ICH-1 group (12.1%) was higher among the three groups (5.8% and 34 35 2.8%, respectively, P<0.05). All 3 cases of serious adverse events were 36 37 38 in the ICH-1 group. 39 40 41 Conclusions: Ultra-early administration, namely, within 6 h of ICH 42 43 44 onset, of RBS herbal medicine for AICH patients did not exert significant 45 46 47 beneficial effects on clinical outcomes but increased the risk of bleeding, 48 49 such as gastrointestinal bleeding, and hematoma growth. 50 51 52 53 Clinical Trial Registration: URL:http//www.ClinicalTrials.gov. 54 55 Unique identifier: NCT01918722. 56 57 58 59 Keywords: intracerebral hemorrhage; herbal medicine; randomized 60 3
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1 2 3 4 controlled trials; hematoma enlargement; CRRICH 5 6 7 8 Word count: 4646 9 10 11 Strengths and limitations of this study 12 13 14 ▪ The CRRICH trial is the largest multicenter clinical trial to examine the 15 16 17 safety and efficacy of a Chinese compound formula in patients with 18 For peer review only 19 20 AICH. 21 22 23 ▪ This study highlights the possibility that the early use of RBS herbal 24 25 26 medicine in AICH could increase the risk of bleeding, which spurs further 27 28 research on the safety of Chinese medicines. 29 30 31 32 ▪ There were no available data to elucidate the mechanisms of TEAEs or 33 34 serious TEAEs. 35 36 37 38 39 40 41 Introduction 42 43 44 [1] 45 Acute intracerebral hemorrhage accounts for approximately 15% of 46 47 all acute strokes; stroke is the third most common cause of death in most 48 49 [2, 3] 50 Western countries, following coronary heart disease and cancer. 51 52 AICH has been the leading cause of death in China in recent years[4] and 53 54 55 is responsible for approximately one-third of the total number of deaths 56 57 [5] 58 from stroke worldwide. 59 60 4
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1 2 3 4 Available specific medical and surgical treatments do not improve 5 6 [6, 7] 7 prognosis substantially, and AICH still accounts for a higher 8 9 proportion of stroke in Chinese people than in white populations.[8] 10 11 12 Therefore, traditional Chinese medicine (TCM) physicians in China 13 14 15 widely use removing blood stasis (RBS) herbs for the treatment of AICH. 16 17 Meta-analysis showed that RBS herbal therapy for AICH could improve 18 For peer review only 19 20 the neurological function deficit, reduce the volume of hematoma and 21 22 perihematomal edema, and lower the mortality rate and dependency.[9] It 23 24 25 is possible that RBS herbal medicine promotes hematoma absorption and 26 27 [10, 11] 28 improves the recovery of neurological impairment ; RBS herbal 29 30 medicine has already been included by guidelines for the management of 31 32 33 spontaneous ICH. However, sufficient evidence of long-term benefits and 34 35 risks of superacute stage is lacking. RBS herbals, such as Hirudo 36 37 38 nipponica Whitman, which acts as a thrombin inhibitor with anticoagulant 39 40 [12] 41 pharmacological effects, may cause rebleeding risk in clinical practice. 42 43 A total of 90% of hematoma growth, which plays an important role in 44 45 [13] 46 prognosis, occurs within a 6-h time window. Therefore, a confirmation 47 48 of the safety and efficacy of RBS herbal medicines in the treatment of 49 50 51 early-stage AICH is urgently needed. 52 53 54 We performed a retrospective study that demonstrated that RBS 55 56 57 herbal medicine for AICH patients was safe and effective.[14] However, 58 59 60 little additional evidence of the safety and efficacy of this treatment 5
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1 2 3 4 exists. We designed a multicenter, three-group, prospective, randomized, 5 6 7 double-blinded and placebo-controlled clinical trial on hematoma 8 9 enlargement in AICH patients treated with RBS herbal medicine within a 10 11 12 6-h time window from symptom onset (CRRICH) to evaluate its safety 13 14 15 and efficacy in AICH patients and to provide a high level of evidence for 16 17 clinical practice. 18 For peer review only 19 20 21 Methods 22 23 24 Study Design 25 26 27 The CRRICH trial was a multicenter, randomized, double-blinded, 28 29 30 placebo-controlled, parallel-group study to assess the safety and efficacy 31 32 33 of RBS herbal medicine in AICH patients. This trial is registered at 34 35 clinicaltrials.gov (NCT01918722), and the research design proposal has 36 37 [15] 38 been published. 39 40 41 Participants 42 43 44 45 Patients with a Glasgow Coma Scale [GCS] score ≥6 were enrolled 46 47 if they were ≥18 years of age and had a clinical diagnosis of ICH 48 49 50 confirmed with computed tomography within 6 h of onset. All 51 52 participants signed an informed consent form. If the participants don’t 53 54 55 have the capacity to sign the informed consent for serious condition or 56 57 58 illiteracy, the researcher will explain the informed consent to the patients 59 60 or their authorized immediate family. Weighing the pros and cons of both 6
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1 2 3 4 sides, their immediate family will decide whether to sign the informed 5 6 7 consent on behalf of the patient. Patients who suffered secondary ICH 8 9 resulting from trauma, brain tumor, blood diseases, arteriovenous 10 11 12 malformation or aneurysm were excluded. A detailed patient history was 13 14 15 recorded. S1 Table in the online-only Data Supplement provides a full list 16 17 of study inclusion and exclusion criteria during the screening period. 18 For peer review only 19 20 21 Randomization and Blinding 22 23 24 Patients were randomized to receive placebo, ICH-1, or ICH-2 in 25 26 27 a 1:1:1 ratio with a stratification and block size of 6 using the PROC 28 29 PLAN process in SAS software version 9.13. Stratified block and 30 31 32 randomization were concealed using sequentially numbered opaque 33 34 envelopes. Persons involved in the study, including the investigators, 35 36 37 patients and data analysts, were blinded to treatment assignment during 38 39 40 double-blinded treatment until the end of follow-up. Only the data 41 42 administrators were permitted access to unblinded data. 43 44 45 46 Procedures 47 48 Enrollment, Intervention and Follow-up 49 50 51 Patients were recruited from October 2013 through May 2016 at 14 52 53 54 hospitals in China (S2 Table in the online-only Data Supplement). The 55 56 57 study consisted of a screening and randomization period (≤6 h poststroke), 58 59 a 10-day double-blinded treatment period and a 3-month follow-up period 60 7
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1 2 3 4 (S1 Figure in the online-only Data Supplement). Participants were 5 6 7 randomly assigned to one of three treatment groups at a ratio of 1:1:1 8 9 during the double-blinded treatment (shown in the S3 and S4 Table in the 10 11 12 online-only Data Supplement): (1) The ICH-1 group received the ICH-1 13 14 15 formula, which consisted of 8 herbs including RBS medicines; (2) The 16 17 ICH-2 group received the ICH-2 formula, which consisted of 6 herbal 18 For peer review only 19 20 medicines without RBS herbs(Hirudo nipponica Whitman and Tabanus 21 22 bivittatus Matsumura) in the same doses as those in the ICH-1 group, 23 24 25 with the remaining dose filled with a placebo; and (3) The placebo group 26 27 28 received a placebo that included dextrin and farina. Each unit of TCM 29 30 medicine or placebo was dissolved in 200 ml of boiling water. Each 31 32 33 patient received 200 ml orally or through a nasogastric tube two times 34 35 daily for 10 days (S3 Table in the online-only Data Supplement). 36 37 38 39 Patients were followed up for 3 months after the 10-day 40 41 double-blinded treatment period. Patients were hospitalized in stroke 42 43 44 units and received standard stroke care in accordance with local 45 46 47 guidelines, which included general supportive care, treatment of acute 48 49 complications, and rehabilitation. Astringents and other RBS drugs were 50 51 52 prohibited. Visits were scheduled at baseline, 24 h poststroke, and at the 53 54 end of the treatment period, with a single visit scheduled 3 months 55 56 57 poststroke (S1 Figure in the online-only Data Supplement). Adverse 58 59 60 events (AEs), treatment compliance, and concomitant medication use 8
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1 2 3 4 were reported during each visit. Participants were randomly assigned to 5 6 7 one of three treatment groups at a ratio of 1:1:1 during double-blinded 8 9 treatment. 10 11 12 13 Primary and Secondary Outcomes 14 15 16 The incidence of hematoma enlargement, which was defined as the 17 18 For peer review only 19 percentage of participants experienced hematoma enlargement, was the 20 21 primary outcome of the study. Hematoma enlargement was operationally 22 23 24 defined as an increase in hematoma volume of >33% or 12.5 ml, as 25 26 27 measured on image analysis on the 24-h CT compared with the baseline 28 29 CT scan. Hematoma volume was measured using the ABC/2 Coniglobus 30 31 [16] 32 formula at 24 h after onset. The same measurement was performed on 33 34 days 10-14 as a primary outcome measure. The following secondary end 35 36 37 points were assessed: change in NIHSS score at 3 months; mortality at 3 38 39 40 months; and poor prognosis rate, which was defined as the proportion of 41 42 patients who died or were severely disabled based on an mRS score ≥5 at 43 44 [17] 45 3 months. Safety data focused on treatment-emergent AEs (TEAEs). 46 47 TEAEs were defined as AEs that first occurred or worsened (increased in 48 49 50 severity) after the first dose of study drug. The patient spontaneously 51 52 53 reported TEAEs in response to an open-ended question from the contact 54 55 person at each visit. A worsened patient condition, prolonged patient 56 57 58 hospitalization, and life-threatening TEAEs in patients were reported as 59 60 9
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1 2 3 4 serious adverse events (TEsAEs). Abnormal laboratory values that 5 6 7 constituted a serious AE or led to the discontinuation of experimental 8 9 drugs were also reported as TEsAEs. S5 Table in the online-only Data 10 11 12 Supplement provides a full list of all primary, secondary and safety end 13 14 15 points. 16 17 18 Statistical AnalysesFor peer review only 19 20 21 All reported efficacy analyses were predefined and based on the full 22 23 24 analysis set (FAS) (patients who were randomized and received any study 25 26 27 medication) according to the intent-to-treat (ITT) principle. Supportive 28 29 analyses were performed in a predefined per-protocol population set 30 31 32 (PPS), which included FAS patients who did not have one or more key 33 34 protocol deviations, including violations of inclusion and exclusion 35 36 37 criteria. The last observation for surviving patients with missing outcome 38 39 40 data was carried forward. Patients who had died by the 90-day follow-up 41 42 were assigned a Barthel index score of 0 and an mRS score of 6, and the 43 44 45 last recorded NIHSS score was carried forward. The incidence of 46 47 hematoma enlargement at 24 h (primary end point), the rate of poor 48 49 50 prognosis and the incidence of total TEAEs among the three groups were 51 52 2 53 analyzed using the χ test. The incidence of hematoma enlargement on 54 55 days 10-14 (primary end point) and mortality among the three groups 56 57 58 were compared using Fisher’s exact test. The mean differences in NIHSS 59 60 10
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1 2 3 4 score among groups were analyzed using one-way ANOVA. 5 6 7 Demographic characteristics and serious TEAEs were summarized using 8 9 descriptive statistics. 10 11 12 13 Power and sample size were determined using relative hematoma 14 15 volume at 24 h as the primary outcome variable. A total of 285 16 17 18 participants wereFor required peer at the review final follow-up only to provide 90% power 19 20 21 with a two-sided alpha level at 0.05 to test the primary efficacy, which 22 23 was calculated using the PASS (Power Analysis and Sample Size) 24 25 26 software program (licensed by NCSS, LLC). A total of 360 participants 27 28 were needed for primary outcome randomization assuming a dropout rate 29 30 31 of 20%, with 120 patients per treatment arm. The statistical package 32 33 34 STATA (version 13.1) was used for all statistical analyses. 35 36 37 Patient and Public Involvement Statement 38 39 40 While we put forward the research question and outcome measures, 41 42 43 the patients’ priorities, experience, and preferences were fully considered 44 45 46 by a survey. Patients were involved in the recruitment to and conduct of 47 48 the study. The results would be disseminated to study participants by 49 50 51 posting a letter. The CRRICH trial was a randomized controlled trial, and 52 53 the patients themselves had fully assessed the burden of the intervention. 54 55 56 Patient advisors should also be thanked in the contributorship 57 58 59 statement/acknowledgments. 60 11
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1 2 3 4 Funding and Ethical Statements 5 6 7 8 The State Administration of Traditional Chinese Medicine of the 9 10 P.R.C. (SATCM) awarded Guangdong Provincial Hospital of TCM 11 12 13 (GPHTCM) SATCM Grant No: ZDJX2012074 and provided input 14 15 during the study period. This report was an independent study supported 16 17 18 by SATCM andFor performed peer by the review GPHTCM in only a SATCM–GPHTCM 19 20 21 partnership. The viewpoints stated in this manuscript are those of the 22 23 authors and may not represent the opinions of SATCM, GPHTH or the 24 25 26 Public Health Bureau. The SATCM and GPHTCM approved the decision 27 28 to submit this paper for publication. Dr. Jianwen Guo had full access to 29 30 31 all study data and had final responsibility for the decision to submit for 32 33 34 publication. 35 36 37 Each respective institutional review board or ethics committee 38 39 40 approved the study protocol, which followed the established Good 41 42 Clinical Practice guidelines. All patients provided written informed 43 44 45 consent to participate in the study. An independent contract research 46 47 organization, S&R (Department of Science and Research of Guangdong 48 49 50 Provincial Hospital of Chinese medicine), managed the administration, 51 52 53 coordination, and monitoring of the study, including researcher training, 54 55 study inspection, data management and statistical analyses, with oversight 56 57 58 by the State Administration of Traditional Chinese Medicine of the 59 60 12
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1 2 3 4 P.R.C. 5 6 7 8 Results 9 10 Study Population 11 12 13 Patient recruitment began in October 2013, and the study ended in 14 15 16 May 2016. A total of 5589 individuals with ICH were screened (Figure 1). 17 18 For peer review only 19 The most frequent reasons for exclusion in descending order were time 20 21 window >6 h, refusal to participate, secondary ICH (i.e., not AICH) and 22 23 24 other reasons. A total of 319 of the 324 randomized patients (105 placebo, 25 26 108 ICH-1, 111 ICH-2) received the assigned treatment following the 27 28 29 elimination of five patients (one patient for missing the time window, one 30 31 32 patient for kidney failure, one patient for secondary ICH, one patient for 33 34 surgery within 24 h and one patient withdrew consent). Therefore, only 35 36 37 the 319 participants who underwent randomization and received study 38 39 medication were included in the FAS and safety analysis set based on ITT. 40 41 42 Twenty-three patients in the FAS did not completely adhere to the 43 44 45 protocol and dropped out during the treatment period. A total of 296 46 47 patients were included in the PPS (see Figure 1 for patient flow diagram). 48 49 50 The mean dropout rate was <8%. Table 1 presents the demographics and 51 52 baseline characteristics of the FAS, which were well balanced with no 53 54 55 significant between-group differences. The mean age was 62.5±12.7 56 57 58 years (mean±SD, n=319); 65.5% of the patients were male, and 98.7% 59 60 were ethnic Han. The median GCS score was 15 (range, 3 to 15), and the 13
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1 2 3 4 mean NIHSS score was 8 (range, 0 to 47). The deep gray matter was 5 6 7 involved in 93.4% of cases, and the lobar regions were involved in 6.6% 8 9 of cases. The baseline characteristics of the three treatment groups were 10 11 12 similar. The mean volume of the ICH at baseline for all patients was 11.0 13 14 15 ml (range, 0.3 to 86.7 ml), which was similar in the three groups (Table 16 17 1). The mean time from onset of symptoms to admission was 3.36±1.49 h, 18 For peer review only 19 20 and the mean time from onset of symptoms to treatment was 4.10±1.38 h. 21 22 Fourteen percent of patients were treated within 3 h after symptom onset. 23 24 25 Two patients were treated outside of the 6-h time window. The timing of 26 27 28 the treatment was similar in the three groups (Table 1). 29 30 31 32 33 34 Figure 1. Enrollment and Follow-up. AEs, adverse events; FAS, full analysis set; PPS, per-protocol population set; 35 RBS, removing blood stasis; ICH denotes intracerebral hemorrhage; ICH-1 denotes herbal medicine with RBS 36 37 herbals hirudo and tabanus (8 herbals); ICH-2 denotes herbal medicine without RBS herbals hirudo or tabanus (6 38 herbals). 39 40 41 42 43 Table 1. Baseline Characteristics and Treatment Timing. 44 45 Variable Placebo (N=104) ICH-2 (N=108) ICH-1 (N=107) 46 47 48 Age (yr) 61.95±13.38 62.56±12.64 62.84±12.23 49 50 Sex n (%) Male 69(66.3) 69(63.9) 71(66.4) 51 52 53 Female 35(33.7) 39(36.1) 36(33.6) 54 55 Ethnic group n (%) 56 57 58 Ethnic Han 103(99.0) 105(97.2) 107(100.0) 59 60 14
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1 2 3 Not ethnic Han 1(1.0) 3(2.8) 0(0) 4 5 6 Hemisphere hematoma n (%) 7 8 Left hemisphere 44(42.3) 53(49.1) 56(52.3) 9 10 11 Right hemisphere 59(56.7) 54(50.0) 51(47.7) 12 13 Supratentorial hematoma n (%) 14 15 16 Putamen or globus 69(66.3) 72(66.7) 64(59.8) 17 pallidus 18 For peer review only 19 20 Thalamus 19(18.3) 24(22.2) 28(26.2) 21 22 Lobar hemisphere 10(9.6) 7(6.5) 4(3.7) 23 24 25 None 6(5.8) 5(4.6) 11(10.3) 26 27 Subtentorial hematoma n (%) 28 29 Cerebellum 4(3.8) 2(1.9) 7(6.5) 30 31 32 Pons or midbrain 2(2.0) 4(3.7) 5(5.0) 33 34 None 98(94.2) 102(94.4) 95(88.8) 35 36 37 Intraventricular hemorrhage n (%) 38 39 Yes 17(16.3) 19(17.6) 25(23.4) 40 41 42 No 87(83.7) 89(82.4) 82(76.6) 43 44 GCS score‡ 14.18±1.86 13.77±2.34 13.76±2.06 45 46 47 NIHSS score 7.88±5.24 9.00±7.24 9.13±6.16 48 49 Volume of the 50 intracerebral 51 9.82±7.45 11.56±9.67 11.57±11.55 52 hemorrhage at 53 54 baseline 55 56 Systolic BP at time 57 58 of admission 171.34±28.04 174.14±23.72 172.04±22.53 59 (mmHg) 60 15
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1 2 3 Time from onset to 4.31±1.38 4.02±1.35 3.97±1.39 4 5 treatment (h) 6 7 Time from onset to 8 3.61±1.54 3.08±1.47 3.05±1.63 9 admission (h) 10 11 * The values are expressed as counts and % within group, and plus–minus values are the means±SD. Percentages 12 may not total 100 because of rounding. GCS, Glasgow Coma Scale (Scores range from 15 (normal) to 3 (deep 13 coma)); NIHSS, National Institutes of Health Stroke Scale (Scores range from 0 (normal) to 42 (coma with 14 quadriplegia)); BP, blood pressure. 15 16 Primary Outcome (Radiographic Outcomes) 17 18 For peer review only 19 20 At 24 h, a total of 319 baseline CT scans and 315 CT scans were 21 22 available for analysis. The incidence of hematoma enlargement were 23 24 25 7.8% in the placebo group, 12.3% in the ICH-1 group and 7.5% in the 26 27 28 ICH-2 group. There was no significant difference in the incidence of 29 30 hematoma enlargement at 24 h among the three groups (P=0.409). The 31 32 33 incidence of hematoma enlargement on days 10-14 were 1.1% in the 34 35 placebo group, 3.1% in the ICH-2 group and 1.1% in the ICH-1 group. 36 37 38 There was also no significant difference among the three groups in the 39 40 41 incidence of hematoma enlargement on days 10-14 (P=0.625) (Table 2). 42 43 44 Secondary Outcomes (Clinical Outcomes) 45 46 47 48 Mortality at 3 months was approximately 2.6% in the three groups 49 50 (Table 2). Poor prognosis (i.e., the proportion of patients who died or 51 52 53 were severely disabled, mRS ≥5) did not differ significantly among the 54 55 three groups. It is the least patients of poor prognosis occurred in the 56 57 58 ICH-2 treatment, but no statistical difference compared with placebo 59 60 16
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1 2 3 4 treatment (Table 2). The distributions of outcomes on the modified 5 6 7 Rankin Scale (Figure 2) were similar among the three groups. The 8 9 differences in the NIHSS scores at 3 months among the three groups were 10 11 12 not significant (Table 2). 13 14 15 16 17 18 Figure2 Clinical OutcomeFor at 90peer Days According review to the Modified Rankin only Scale. The modified Rankin Scale 19 20 evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). There were 21 no significant differences among the three groups. 22 23 24 25 26 Adverse Events 27 28 29 30 There were altogether 35 AEs reported by investigators, of which 22 31 32 AEs may have been TEAEs. All the TEAEs occurred during the 33 34 35 double-blinded treatment period (within 2 weeks). TEAEs occurred in 13 36 37 38 (12.1%) ICH-1-treated patients, 3 (2.8%) ICH-2-treated patients and 6 39 40 (5.8%) placebo-treated patients. The patterns of TEAEs were similar in 41 42 43 the 3 groups, but the overall frequencies of TEAEs among the three 44 45 groups were significantly different (P=0.022), as shown in Table 2. And 46 47 48 the paired comparisons showed that the test for difference in the overall 49 50 51 TEAEs rate between group ICH-1 and group ICH-2 yields a p-value of 52 53 0.029. Table 3 shows the TEAEs that occurred during the study. The most 54 55 56 frequent event was diarrhea, and its incidence was similar in the 3 57 58 treatment groups . Treatment was discontinued because of TEsAEs in 3 59 60 17
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1 2 3 4 (1.9%) ICH-1-treated patients. The 3 cases with TEsAEs (2 cases of 5 6 7 gastrointestinal bleeding, 1 case of cerebral hernia) reported by 8 9 investigators occurred in ICH-1-treated patients. There was no consistent 10 11 12 pattern to this difference, and all serious TEAEs occurred within the 13 14 15 10-day drug treatment period. There were no statistically significant 16 17 differences in the incidence or type of serious TEAEs leading to death 18 For peer review only 19 20 among groups (data not shown). There was no relationship between 21 22 TEAEs, serious TEAEs, or mortality and poor outcome (data not shown). 23 24 25 Table 2 Primary outcome and secondary outcomes 26 27 28 Differences 29 Among Groups 30 Placebo ICH-2 ICH-1 31 32 P Value 33 34 Primary outcome: the incidence of hematoma enlargement at 24 h and at day 14 35 36 At 24 h 8/104(7.8) 8/108(7.5) 13/107(12.3) 0.409 37 38 39 On days 10-14 1/92(1.1) 3/97(3.1) 1/91(1.1) 0.625 40 41 Hemorrhage Volumes（ml）at Baseline and Follow-up 42 43 44 At baseline 9.82±7.45 11.56±9.67 11.57±11.55 0.284 45 46 At 24 h 9.71±6.94 11.97±10.02 14.44±19.33 0.313 47 48 49 percent increase from 50 baseline- means% (95% -14.1(4.5-32.7) 3.4(0.2-6.5) 41(9.4-91.4) 0.22 51 52 CI) 53 54 milliliters of increase 55 -0.13±1.41 0.22±2.24 3.13±16.10 0.168 56 from baseline 57 58 Secondary outcomes: 59 60 18
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1 2 3 NIHSS# at 3 months 3.58±5.32 3.58±5.32 3.58±5.32 0.475 4 5 6 Mortality at 3 months 4/104(3.8) 1/108(0.9) 3/107(2.8) 0.328 7 8 Poor prognosis (mRS 0.783 9 7/99(7.1) 5/105(4.8) 6/100(6.0) 10 ≥5) 11 12 Total TEAEs 6/104(5.8) 3/108(2.8) 13/107(12.1) 0.022 13 14 The values are expressed as n/N(%) within group or the means±SD; # denotes the number of patients at 15 16 3 months: 104 in the placebo group, 107 in the ICH-2 group, and 105 in the ICH-1 group. 17 18 For peer review only 19 20 21 22 Table 3 Treatment-emergent adverse events 23 24 Placebo ICH-2 ICH-1 25 26 Vomiting 1/104(1.0) 0/108(0.0) 2/107(1.9) 27 28 29 Gastrointestinal 0/104(0.0) 0/108(0.0) 2/107(1.9) 30 bleeding* 31 32 33 Stomachache 0/104(0.0) 0/108(0.0) 1/107(0.9) 34 35 Chest congestion 1/104(1.0) 0/108(0.0) 0/107(0.0) 36 37 Cerebral hernia* 0/104(0.0) 0/108(0.0) 1/107(0.9) 38 39 The values are expressed as n/N (%) within group. All adverse events are listed in order of frequency from the 40 overall study period (90 days); adverse events were collected from investigator reports. The principal investigator 41 at each site determined whether an adverse event or serious adverse event was related to the intervention. TEAEs, 42 treatment-emergent adverse events. *indicates TEAEs. 43 44 45 46 47 48 Discussion 49 50 51 52 RBS administration within 6 h after the symptom onset of ICH did 53 54 not significantly reduce hematoma growth and failed to improve survival 55 56 57 or functional outcome at 90 days. Conversely, compared to the ICH-2, the 58 59 incidence of TEAEs showed an increasing trend in the ICH-1 group (P= 60 19
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1 2 3 4 0.029, ICH-1vs. ICH-2). Significant increases were also demonstrated in 5 6 7 total TEAE frequency and in serious TEAEs in the ICH-1 group. Three 8 9 serious bleeding events occurred in the RBS group (ICH-1, with 2 RBS 10 11 12 herbals), including two cases of gastrointestinal bleeding and one case of 13 14 15 intracerebral rebleeding. All three cases were fatal serious TEAEs (Table 16 17 2). These data suggest that RBS treatment for ICH patients within 6 h of 18 For peer review only 19 20 symptom onset is a safety concern. However, no data were available to 21 22 suggest a mechanism for this effect. 23 24 25 26 As can be seen from the table 2, ICH-2 treatment 27 28 was least vulnerable to poor prognosis and TEAEs. Therefore, ICH-2 29 30 31 formula would have the potential to be an effective herbal drug for ICH 32 33 34 patients of superacute stage. 35 36 37 This result contrasts with the clinical benefit demonstrated in a 38 39 [9] 40 previous meta-analysis , which included 9 randomized controlled 41 42 clinical trials with 798 individuals, demonstrating that RBS therapy for 43 44 45 acute ICH reduced brain hematoma and cerebral edema volumes, 46 47 improved the neural function and reduced the mortality and disability 48 49 50 rates with fewer TEAEs. The present trial revealed significant 51 52 53 heterogeneity compared with the studies included in the meta-analysis, 54 55 possibly because of differences in the intervention time window. This 56 57 58 research is the first prospective, multicenter, randomized, double-blind, 59 60 20
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1 2 3 4 placebo-controlled study to assess the efficacy and safety of RBS in 5 6 7 AICH patients within a 6-h time window from symptom onset, unlike 8 9 prior studies that examined these effects within a 24-h or later 10 11 12 intervention time window. Earlier RBS administration increased the risk 13 14 15 of bleeding events (e.g., gastrointestinal bleeding or intracerebral 16 17 rebleeding), which counteracted the benefit to some extent. 18 For peer review only 19 20 21 The primary outcome of the incidence of hematoma enlargement, 22 23 which is an independent prognostic determinant of mortality and poor 24 25 [18] 26 prognosis, was also used to assess safety. The incidence of hematoma 27 28 enlargement at 24 h in the three groups in the CRRICH trial (placebo, 29 30 31 ICH-2, and ICH-1) were 7.8%, 7.5%, and 12.3%, respectively, and they 32 33 34 were not significantly different (Table 2). The mean incidence of 35 36 hematoma enlargement was only 9.2%, which was far lower than the 37 38 [18] 39 mean level of 18-30%. The main reasons for lower hematoma 40 41 expansion incidence may include the following: (1) the investigators’ 42 43 44 inclination toward surgery in AICH patients with large hemorrhage 45 46 47 volumes within 24 h of onset, which resulted in the exclusion of patients 48 49 susceptible to rebleed in the study; and (2) patients with terrible and 50 51 52 unstable conditions who were prone to hematoma expansion were 53 54 excluded by investigators privately for fear that deterioration risk would 55 56 57 increase during study. 58 59 60 21
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1 2 3 4 Hematoma growth is an independent determinant of death and 5 6 [19] 7 disability. Therefore, hematoma expansion may be an attractive 8 9 therapeutic target.[20, 21] However, no proven specific therapies or 10 11 12 treatments exist to prevent hematoma expansion or improve outcomes 13 14 15 after ICH. Sufficient evidence-based medical research to prove that 16 17 mini-traumatic surgeries and the present available medicines provide 18 For peer review only 19 [6, 7] 20 ideal treatment is lacking. 21 22 23 Herbal medicine in China has been used to treat ICH for at least 2,000 24 25 26 years, and RBS herbal medicines are listed in the 2010 Chinese 27 28 Pharmacopeia.[22] Dr. Si reported the earliest available literature on AICH 29 30 31 with RBS herbal medicine therapy in 1981.[23] Another RBS medicine, 32 33 34 Naoxuekang capsule, was approved as routine treatment for AICH 35 36 patients by the Chinese State Food and Drug Administration [22] 37 38 39 (Naoxuekang capsule, register No. Z10960009). RBS herbal medicines 40 41 have been studied in AICH patients in more than 200 clinical studies over 42 43 44 the past 30 years, and they have gradually come to be considered a 45 46 [24] 47 regular therapy. AICH management guideline in China cited this 48 49 treatment.[25] However, safety evidence in the early stage of AICH is 50 51 52 lacking. Some studies demonstrated that 30% of ICH patients suffered 53 54 continued bleeding within 6 h of onset[26]. Some research has provided 55 56 57 low-level evidence of the safety of RBS herbal medicine for superacute 58 59 60 cerebral hemorrhage, but whether RBS herbal medicine administration in 22
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1 2 3 4 an early-stage induced hematoma growth was not known because RBS 5 6 [27] 7 herbal medicine exhibits an anticoagulation effect. Marketed RBS 8 9 drugs that are clinically recognized and widely used did not illustrate a 10 11 12 specific application time window. Early administration of RBS drugs may 13 14 15 cause hematoma expansion and increase the risk of death and serious 16 17 disability. The CRRICH trial was a prospective, double-blinded, 18 For peer review only 19 20 multicenter clinical trial that demonstrated that early administration of 21 22 RBS drugs did not increase hematoma growth but significantly increased 23 24 25 TEAEs. 26 27 28 The CRRICH trial is the largest clinical trial to investigate the safety 29 30 31 and efficacy of a Chinese compound formula in patients with AICH. 32 33 34 Three other influential RCT trials of medical treatments with drugs, 35 36 including FAST, INTERACT2, and CHANT, that exhibit mechanisms 37 38 39 very different from those of RBS used similar methods to evaluate the 40 41 safety and efficacy and found no significant benefit.[28-30] 42 43 44 45 Data from the clinical study suggested that the administration of 46 47 RBS herbal medicine should be avoided in AICH patients during the 48 49 50 initial 6-h time window from stroke onset to avoid the increased risk of 51 52 53 bleeding. Further clinical studies should be performed to confirm the 54 55 safety and efficacy of these agents beyond the 6 h of ICH onset. This 56 57 58 research suggests that the early administration of RBS herbal medicine in 59 60 23
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1 2 3 4 ICH patients increases the risk of bleeding, such as gastrointestinal 5 6 7 bleeding, and hematoma growth. Some Chinese patent drugs 8 9 (Naoxuekang capsule (Z10960009), Naoxuekang pill (Z20050312) or 10 11 12 Naoxuekang drop pills (Z10980039)), which primarily consist of Hirudo 13 14 15 nipponica Whitman, should be reevaluated and used under supervision. 16 17 The relevant manufacturers should revise the drug instructions and add a 18 For peer review only 19 20 warning, “Do not use for superacute cerebral hemorrhage within 6 h from 21 22 onset”, if necessary. 23 24 25 26 This study had some limitations. First, there were no available data 27 28 to elucidate the mechanism of TEAEs or serious TEAEs. Second, there 29 30 31 was a significant difference in the number of patients among research 32 33 34 centers. Third, the investigators preferred to study patients with minor 35 36 hematoma volume because they were afraid of the rebleed risk from the 37 38 39 herbal medicine. 40 41 42 Summary 43 44 45 46 This study demonstrates that ultra-early administration, namely, 47 48 within 6 h of ICH onset, of RBS herbal medicine for AICH patients 49 50 51 increased the risk of bleeding, such as gastrointestinal bleeding, and 52 53 hematoma growth. This study also shows that RBS herbal medicine did 54 55 56 not exert significantly beneficial effects on clinical outcomes in 57 58 59 hypertensive ICH patients in the ultra-early stage. These results support 60 24
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1 2 3 4 the idea that the ultra-early administration of RBS herbal medicine is 5 6 7 unsafe and has a low efficacy. Future high-quality research should further 8 9 assess the efficacy and safety of herbal medicine for intracerebral 10 11 12 hemorrhage beyond the 6- h time window. 13 14 15 16 17 18 SupplementaryFor Material peer A complete review list of supplementary only material in the CCRICH 19 20 trial is provided in the Supplementary Appendix. 21 22 Data Sharing Statement No additional unpublished data are available. 23 24 Acknowledgments We thank the patients and families who volunteered for this study; 25 26 Zehuai Wen and Ouyang Wen for their assistance with data summarization; and Yubo 27 Lv for his guidance. The CRRICH trial was supported by an SATCM Grant (No: 28 29 ZDJX2012074) awarded to Dr. Jianwen Guo from the State Administration of 30 Traditional Chinese Medicine of the P.R.C. (SATCM). 31 32 33 Contributions JG, LZ, and JW organized the trial hypotheses, designed the trial, and 34 provided guidance about the data analysis and interpretation/presentation of the data. 35 36 JG is the subject primarily responsible of the clinical trial (CRRICH trial) and 37 provided a critical review of the manuscript. LZ drafted most sections of the 38 39 manuscript. JL, GC, YZ, SL, GH, QZ and YW were involved in the design of the 40 study and contributed to writing and revising the manuscript. GT, JZ, ZX, RL, CC, 41 42 KZ, and HQ organized and managed the trial including trial start-up, data collection, 43 quality assurance, and trial close-out. XL provided the region of interest calculations 44 45 for all volumetric measurement results. JW and TH provided an independent review 46 and adjudication of all safety events. QZ, HL, BG, XC, YZ and ZW were involved in 47 48 the statistical analysis and data interpretation and contributed to the development of 49 and revisions to the manuscript. The CRRICH investigators contributed equally to the 50 51 identification and, when eligible, randomization of trial participants. 52 53 Funding The State Administration of Traditional Chinese Medicine of the P.R.C. 54 (SATCM) has allocated to Guangdong Provincial Hospital of TCM (GPHTCM): 55 56 SATCM Grant No: ZDJX2012074, JDZX2015048, and a Project of the Department 57 of Science and Technology of Guangdong Province, Grant No. 2014A020221074. JG 58 59 is the subject primarily responsible. This report is an independent study supported by 60 25
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1 2 3 the SATCM and conducted by the GPHTCM in the name of the SATCM–GPHTCM 4 5 partnership. The viewpoints stated in this manuscript are those of the authors and may 6 not be those of the SATCM, GPHTH or the Public Health Bureau. 7 8 9 Competing Interests None declared. 10 11 Ethics approval B2013-085-01; the CRRICH trial was approved by the institutional 12 13 review boards at all participating centers (specified in the text). 14 15 16 17 18 For peerReferences review only 19 20 21 22 23 [1] Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009. 373(9675): 1632-44. 24 25 26 [2] Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity 27 in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 28 29 2013. Lancet. 2014. 384(9945): 766-81. 30 31 [3] Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the Global Burden of Ischemic and Hemorrhagic 32 33 Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015. 45(3): 161-76. 34 35 [4] Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, 36 and a national priority. Stroke. 2011. 42(12): 3651-4. 37 38 39 [5] van Asch CJ, Luitse MJ, Rinkel GJ. Incidence, case fatality, and functional outcome of intracerebral 40 haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. 41 42 Lancet Neurol. 2010. 9(2): 167-76. 43 44 [6] Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous 45 Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart 46 47 Association/American Stroke Association. Stroke. 2015. 46(7): 2032-60. 48 49 [7] Rabinstein AA. Intracerebral haemorrhage: no good treatment but treatment helps. Lancet. 2017. 50 51 389(10069): 575-576. 52 53 [8] Tsai CF, Thomas B, Sudlow CL. Epidemiology of stroke and its subtypes in Chinese vs white populations: 54 55 a systematic review. Neurology. 2013. 81(3): 264-72. 56 57 [9] Li HQ, Wei JJ, Xia W, et al. Promoting blood circulation for removing blood stasis therapy for acute 58 intracerebral hemorrhage: a systematic review and meta-analysis. Acta Pharmacol Sin. 2015. 36(6): 59 60 659-75. 26
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1 2 3 [10] Wang YQ, Shi Q, Wang WP. Clinical study of xuefuzhuyu decoction on hypertensive intracerebral 4 5 hemorrhage. J Emerg Tradit Chin Med 2013; 22: 1686-7, 1689. Chinese . 6 7 [11] Zhang ZZ, Zhang BH, Chen M. The study of Danshen Injection for prevention and treatment of brain 8 9 edema in acute intracerebral hemorrhage. Zhejiang J Integr Tradit Chin West Med 2003; 13: 355-7. 10 Chinese . 11 12 13 [12] Monreal M, Costa J, Salva P. Pharmacological properties of hirudin and its derivatives. Potential clinical 14 advantages over heparin. Drugs Aging. 1996. 8(3): 171-82. 15 16 [13] Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. 17 18 Stroke. 1997.For 28(1): 1-5. peer review only 19 20 [14] Xu Y, Guo J, Liu X. Can Herbal Medicine Cause Hematoma Enlargement of Hypertensive Intracerebral 21 22 Hemorrhage within 24 hrs Time Window? A Retrospective Study of 256 Cases from a Single Center in 23 China. Evid Based Complement Alternat Med. 2015. 2015: 868731. 24 25 [15] Zeng L, Guo J, Wang J. Clinical re-evaluation of removing blood stasis therapy in treating acute 26 27 intracerebral hemorrhage safety and efficacy: a protocol for a randomized, controlled, multicenter study 28 (CRRICH Trial). Springerplus. 2016. 5(1): 1466. 29 30 31 [16] Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. 32 Stroke. 1996. 27(8): 1304-5. 33 34 35 [17] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 36 intracerebral hemorrhage. N Engl J Med. 2008. 358(20): 2127-37 . 37 38 [18] Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, et al. Prediction of haematoma growth and outcome in 39 40 patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective 41 observational study. Lancet Neurol. 2012. 11(4): 307-14. 42 43 44 [19] Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor 45 outcome after intracerebral hemorrhage. Neurology. 2006. 66(8): 1175-81. 46 47 48 [20] Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003. 34(1): 224-9. 49 50 [21] Wartenberg KE, Mayer SA. Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage: Future 51 Directions. Front Neurol Neurosci. 2015. 37: 107-29. 52 53 54 [22] Chinese Pharmacopoeia Committee. Chinese Pharmacopoeia. Beijing:China Medical Science and 55 Technology Press. 2010: 111-113 . 56 57 58 [23] Si GZ. preliminary clinical study of herbal medicine on hemorrhagic stroke: Removing Blood Stasis 59 Therapy. Tianjin Medical Journal.1982;08: 473-476.Chinese . 60 27
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1 2 3 [24] The Professional Board of Neurology Department of Chinese Association of Integrative Medicine in 4 5 Beijing，GAO L． Expert consensus on hypertensive intracerebral hemorrhage in acute stage in diagnosis 6 and treatment combining traditional Chinese medicine and Western medicine ［ J ］ . Chinese General 7 8 Practice，2016，19 (30): 3641 －3648. Chinese . 9 10 [25] Zou YH, Ma Bin. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for 11 12 healthcare professionals from the China Association of Chinese Medicine.Chinese traditional Chinese 13 medicine modern remote education.2011.9(23): 110-112.Chinese . 14 15 [26] Brouwers HB, Falcone GJ, McNamara KA, et al. CTA spot sign predicts hematoma expansion in patients 16 17 with delayed presentation after intracerebral hemorrhage. Neurocrit Care. 2012. 17(3): 421-8. 18 For peer review only 19 [27] L.Bin, L Jian. Clinical observation of early use promoting blood circulation and removing blood stasis 20 21 herbal injection to treat acute intracerebral hemorrhage. Shandong Journal of Traditional Chinese 22 Medicine. 2000; 19(8):461-462.Chinese . 23 24 25 [28] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 26 intracerebral hemorrhage. N Engl J Med. 2008. 358(20): 2127-37. 27 28 [29] Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral 29 30 hemorrhage. N Engl J Med. 2013. 368(25): 2355-65. 31 32 [30] Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral 33 34 hemorrhage: the CHANT Trial. Stroke. 2007. 38(8): 2262-9. 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 28
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1. Enrollment and Follow-up. AEs, adverse events; FAS, full analysis set; PPS, per-protocol population 33 set; RBS, removing blood stasis; ICH denotes intracerebral hemorrhage; ICH-1 denotes herbal medicine 34 with RBS herbals hirudo and tabanus (8 herbals); ICH-2 denotes herbal medicine without RBS herbals 35 hirudo or tabanus (6 herbals). 36 172x136mm (300 x 300 DPI) 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 40 BMJ Open
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 Figure2 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin Scale evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). 28 There were no significant differences among the three groups. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 40
1 2 3 4 Supplemental Material 5 6 S1 Table: study inclusion and exclusion criteria 7 8 Study inclusion and exclusion criteria 9 10 Inclusion Criteria: 11 12 13 ages eligible for Study: 18 years or older 14 genders eligible for Study: Both 15 16 AICH confirmed by craniocerebral CT scan 17 within 6 hours after the onset of symptom 18 For peer review only 19 GCS≥6 20 sign the informed consent form 21 22 Exclusion Criteria: 23 24 secondary intracerebral hemorrhage resulting from trauma, brain tumor, blood 25 diseases, arteriovenous malformation or aneurysm, etc; 26 27 patients with severe heart, liver or kidney disease. 28 Intolerance to herbal medicine, 29 30 patients with allergies 31 patients planning a surgical evacuation of hematoma with severe cerebral hernia 32 33 at super-early stage 34 patients with poor compliance 35 36 TCM,Chinese Medicine. AICH, acute intracerebral hemorrhage.CT, computed tomography; GCS, 37 Glasgow coma scale. 38 39 40 S2 Table : Full list of Principle investigators and study centers 41 Number of 42 Centre Centre address, zip code 43 Principle Investigator patients NO. 44 randomized 45 Zhangyong Xia, Rui Liaocheng People's Hospital, Liaocheng, 46 1 39 47 Zhang, Guangzeng Li Shandong Province, China, 252000 48 Guangsheng Chen, Boluo County People's Hospital, 49 2 Bochang Lin, Weiming Huizhou, Guangdong, China, 514610 32 50 51 Zhu 52 Qianshan Zhao, Richao Jiangmen Wuyi Traditional Chinese Medicine 53 3 Chen, Yongtong He Hospital, Jiangmen, Guangdong, China, 9 54 55 529000 56 Jiexia Li, Xiaomei Huang, The hospital of Chinese Medicine of Conghua 4 27 57 Mengxin Huang City, Conghua, Guangdong, China, 5109000 58 59 60
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1 2 3 Chaojun Chen, Jianfang Guangzhou Hospital of Integrated traditional 4 5 5 Hu, Peiqun Yang and west medicine, Guangzhou, Guangdong, 2 6 China, 510800 7 Yongbo Zhang, Quanliang Shouguang City People's Hospital, 8 6 21 9 Wang, Xiulan Huang Shouguang, Shandong, China, 262700 10 Gan Huang, Lianying Li, Yangjiang Hospital of Traditional Chinese 11 12 7 Yanchun Li Medicine, Yangjiang, Guangdong, China, 13 13 529500 14 Kaiyun Zhu, Ningping Liu, Panyu Hospital of Chinese Medicine 15 8 1 16 Yinghong Zhang Guangzhou, Guangdong, China, 511400 17 Saihua Luo ,Zai Liang, Lianjiang People's hospital, Lianjiang, 9 19 18 Bing QiuFor peer Guangdong,review China, 524400only 19 Guanghai Tang, Kai Zhao, Shenyang No.2 traditional Chinese medical 20 10 54 21 Guang Yang hospital, Shenyang, Liaoning, China, 110000 22 Jianbin Zhong, Simin Boji-affiliated Hospital of Sun Yat-sen 23 11 Zhong, Sijun Zhang University, zengcheng, Guangdong, China, 42 24 25 511300 26 Jianwen Guo, Liling Zeng, Guangdong Provincial Hospital of Chinese 27 12 Jing Wang Medicine, Guangzhou, Guangdong, China, 42 28 29 510120 30 Yue Wang, Wenjun Liu, Zhongshan Hospital of Hubei Province, 13 9 31 Jing Zuo Wuhan, Hubei, China,430032 32 Tao Huang, Ronming Lin, Guangzhou Charity Hospital, Guangzhou, 33 14 14 34 Qixin Zhang Guangdong, China,510000 35 36 37 S1 Fig: Study design 38 39 40 Stroke onset 0-6h 41 42 43 Screening 44 and Arriving at treating hospital 45 46 Randomization 47 48 Perform CT, Baseline NIHSS,GCS 49 ≤ 50 6 hours post stroke 51 52 No 53 Subject not consider 54 Hemorrhage? for study 55 56 Yes 57 No 58 59 Does subject meet all Subject not consider for 60 entry criteria study
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1 2 3 4 Yes 5 6 7 Randomize 8 9 10 11 Group Placebo 12 Group ICH-2 Group ICH-1 13 14 15 16 17 Perform CT ,NIHSS,GCS after 24h of onset 18 For peer review only 19 Treatment period 20 Yes 21 Perform CT, NIHSS, 22 10 days Reccurence of hemorrhage between 24h and 10-14 days 23 of onset? GCS, BI, mRS 24 25 No 26 27 Perform CT ,NIHSS,GC,BI,mRS after 10-14 days of 28 29 onset 30 Follow-up period 31 3 months 32 90 days follow-up , Perform NIHSS,GCS,BI,mRS 33 34 35 36 S1 Fig. Study design diagram. Subjects who had suffered hypertensive intracerebral hemorrhage 37 were randomized to receive placebo, ICH-1, ICH-2in a 1:1 :1ratio within 6 hours following the 38 stroke onset. The trial consisted of a screening period (up to 6 hours), followed by a randomized 39 treatment period (up to2 weeks treatment period), ending with a 3-month efficacy follow-up 40 41 period (where subjects were allowed to undergo treatment in accordance with standard clinical 42 practice).CT, computed tomography; CTA, computed tomography angiography; NIHSS, National 43 Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index; GCS, Glasgow 44 45 coma scale. 46 47 S3 Table : Groups and Interventions 48 49 Groups Interventions Direction 50 51 8 herbal, including 2 herbals of RBS (Hirudo one dose, bid, by oral or 52 ICH-1 nipponica Whitman and Tabanus bivittatus nasogastric tube for 10 days 53 Matsumura) 54 6 herbals(removed the 2 herbals of RBS from the one dose, bid, by oral or 55 ICH-2 56 ICH-1 formula) nasogastric tube for 10 days 57 Placebo placebo herbal medicine (with dextrin, farina and one dose, bid, by oral or 58 Comparator so on) nasogastric tube for 10 days 59 60
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1 2 3 *RBS, removing blood stasis. 4 5 6 S4 Table: Composition of the ICH-1formula 7 8 Plant/animal TCM ID Condition dosage(gram) dosage form 9 parts included 10 11 Hirudo nipponica entire body dry 1.0 granules 12 Whitman 13 Tabanus bivittatus 14 entire body dry 1.0 granules 15 Matsumura 16 17 Rheum officinale Baill rhizome dry 1.5 granules 18 For peer review only 19 Typha angustifolia L pollen dry 1.5 granules 20 21 Trichosanthes seed dry 1.5 granules 22 kirilowii Maxim. 23 Panax notoginseng 24 rhizome dry 1.0 granules 25 （Burk.）F. H. Chen 26 Acorus tatarinowii 27 rhizome dry 1.0 granules 28 Schott 29 Chinemys reevesii 30 shell dry 1.5 granules 31 (Gray) 32 33 34 35 S5 Table : All primary, secondary and safety endpoints 36 37 Primary 38 Hematoma enlargement:the percent change in the volume of hematoma at 24 hours,on 10-14th day 39 40 Secondary 41 Between-group differences in the NIHSS at 3 months 42 Mortality on the 10th-14th day, 3 months 43 44 Poor prognosis popularly as defined by mRS score≥5 at 3 months 45 Adverse events 46 NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale. 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Checklist of Items for Reporting Trials of Chinese Herbal Medicine Formulas* 1 2 Section/Topic Item Standard CONSORT Checklist Item Extension for CHM Formulas 珈ਤ⊀ʤ㦠珈⁀ 3 4 Number ⊀R Page 5 Number 6 7 8 Title, abstract, and 1a I⁀珈R㦠ifica㦠i⊀R as a ʤaR⁀⊀miz珈⁀ 㦠ʤial iR 㦠h珈 㦠i㦠l珈 Statement of whether the trial targets a TCM Pa㦠㦠珈ʤR, a Western P1 9 keywords medicine–defined disease, or a Western medicine–defined disease with a 10 11 specific TCM Pa㦠㦠珈ʤR, if applicable 12 For peer review only 13 1b S㦠ʤuc㦠uʤ珈⁀ summaʤy ⊀f 㦠ʤial ⁀珈sigR, m珈㦠h⊀⁀s, ʤ珈sul㦠s, aR⁀ c⊀Rclusi⊀Rs Illustration of the name and form of the formula used, and the TCM P1-3 14 (f⊀ʤ sਤ珈cific gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ abs㦠ʤac㦠s [26, 27]) Pa㦠㦠珈ʤR applied, if applicable 15 16 17 1c Determination of appropriate keywords, including “Chinese herbal P3 18 medicine formula” and “randomized controlled trial” 19 20 Introduction 21 22 23 Backgʤ⊀uR⁀ aR⁀ 2a Sci珈R㦠ific backgʤ⊀uR⁀ aR⁀ 珈xਤlaRa㦠i⊀R ⊀f ʤa㦠i⊀Ral珈 Statement with biomedical science approaches and/or TCM approaches P4 24 ⊀bj珈c㦠iv珈s 25 2b Sਤ珈cific ⊀bj珈c㦠iv珈s ⊀ʤ hyਤ⊀㦠h珈s珈s Statement of whether the formula targets a Western medicine–defined P5 26 disease, a TCM Pa㦠㦠珈ʤR, or a Western medicine–defined disease with a 27 28 specific TCM Pa㦠㦠珈ʤR 29 30 Methods 31 32 Tʤial ⁀珈sigR 3a D珈scʤiਤ㦠i⊀R ⊀f 㦠ʤial ⁀珈sigR (such as ਤaʤall珈l, fac㦠⊀ʤial), iRclu⁀iRg P5 33 34 all⊀ca㦠i⊀R ʤa㦠i⊀ 35 36 3b Imਤ⊀ʤ㦠aR㦠 chaRg珈s 㦠⊀ m珈㦠h⊀⁀s af㦠珈ʤ 㦠ʤial c⊀mm珈Rc珈m珈R㦠 (such as P5 37 38 珈ligibili㦠y cʤi㦠珈ʤia), wi㦠h ʤ珈as⊀Rs 39 40 Paʤ㦠iciਤaR㦠s 4a Eligibili㦠y cʤi㦠珈ʤia f⊀ʤ ਤaʤ㦠iciਤaR㦠s Statement of whether participants with a specific TCM Pa㦠㦠珈ʤR were P5-6 41 recruited, in terms of 1) diagnostic criteria and 2) inclusion and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 37 of 40 BMJ Open
1 exclusion criteria. All criteria used should be universally recognized, or 2 reference given to where detailed explanation can be found. 3 4 5 4b S珈㦠㦠iRgs aR⁀ l⊀ca㦠i⊀Rs wh珈ʤ珈 㦠h珈 ⁀a㦠a w珈ʤ珈 c⊀ll珈c㦠珈⁀ P6 6 7 IR㦠珈ʤv珈R㦠i⊀Rs 5 Th珈 iR㦠珈ʤv珈R㦠i⊀Rs f⊀ʤ 珈ach gʤ⊀uਤ wi㦠h suffici珈R㦠 ⁀珈㦠ails 㦠⊀ all⊀w Description(s) for different types of formulas should include the P6-8 8 ʤ珈ਤlica㦠i⊀R, iRclu⁀iRg h⊀w aR⁀ wh珈R 㦠h珈y w珈ʤ珈 ac㦠ually a⁀miRis㦠珈ʤ珈⁀ following: 9 10 5a. For fixed CHM formulas 11 1. Name, source, and dosage form (e.g., decoctions, granules, 12 For peer review only 13 powders) 14 2. Name, source, processing method, and dosage of each medical 15 16 substance. Names of substances should be presented in at least 2 17 languages: Chinese (PiRyiR), Latin, or English. Names of the parts of 18 19 the substances used should be specified. 20 3. Authentication method of each ingredient and how, when, where, 21 22 and by whom it was conducted; statement of whether any voucher 23 specimen was retained, and if so, where they were kept and whether 24 25 they are accessible 26 4. Principles, rationale, and interpretation of forming the formula 27 28 5. Reference(s) as to the efficacy of the formula, if any 29 6. Pharmacologic study results of the formula, if any 30 31 7. Production method of the formula, if any 32 8. Quality control of each ingredient and of the product of the 33 34 formula, if any. This would include any quantitative and/or 35 qualitative testing method(s); when, where, how, and by whom these 36 37 tests were conducted; whether the original data and samples were 38 kept, and, if so, whether they are accessible. 39 40 9. Safety assessment of the formula, including tests for heavy metals 41 and toxic elements, pesticide residues, microbial limit, and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 38 of 40
1 acute/chronic toxicity, if any. If yes, it should be stated when, where, 2 how, and by whom these tests were conducted; if the original data 3 4 and samples were kept; and, if so, whether they are accessible. 5 10. Dosage of the formula, and how the dosage was determined 6 7 11. Administration route (e.g., oral, external) 8 5b. For individualized CHM formulas 9 10 1. See recommendations 5a 1–11 11 2. Additional information: how, when, and by whom the formula was 12 For peer review only 13 modified 14 5c. For patent proprietary CHM formulas 15 16 1. Reference to publicly available materials, such as pharmacopeia, 17 for the details about the composition, dosage, efficacy, safety, and 18 19 quality control of the formula 20 2. Illustration of the details of the formula, namely 1) the proprietary 21 22 product name (i.e., brand name), 2) name of manufacturer, 3) lot 23 number, 4) production date and expiry date, 5) name and percentage 24 25 of added materials, and 6) whether any additional quality control 26 measures were conducted 27 28 3. Statement of whether the patent proprietary formula used in the 29 trial is for a condition that is identical to the publicly available 30 31 reference 32 5d. Control groups 33 34 Placebo control 35 1. Name and amount of each ingredient 36 37 2. Description of the similarity of placebo with the intervention 38 (e.g., color, smell, taste, appearance, packaging) 39 40 3. Quality control and safety assessment, if any 41 4. Administration route, regimen, and dosage 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 39 of 40 BMJ Open
1 5. Production information: where, when, how, and by whom the 2 placebo was produced 3 4 Active control 5 1. If a CHM formula was used, see recommendations 5a–5c 6 7 2. If a chemical drug was used, see item 5 of the CONSORT 8 Statement (24) 9 10 11 Ou㦠c⊀m珈s 6a C⊀mਤl珈㦠珈ly ⁀珈fiR珈⁀, ਤʤ珈sਤ珈cifi珈⁀ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈 Illustration of outcome measures with Pa㦠㦠珈ʤR in detail P8-9 12 m珈asuʤ珈s, iRclu⁀iRgFor h⊀w aR⁀ wh珈R peer 㦠h珈y w珈ʤ珈 ass珈ss珈⁀ review only 13 14 6b ARy chaRg珈s 㦠⊀ 㦠ʤial ⊀u㦠c⊀m珈s af㦠珈ʤ 㦠h珈 㦠ʤial c⊀mm珈Rc珈⁀, wi㦠h ʤ珈as⊀Rs P8-9 15 16 17 Samਤl珈 siz珈 7a H⊀w samਤl珈 siz珈 was ⁀珈㦠珈ʤmiR珈⁀ P10 18 19 7b Wh珈R aਤਤlicabl珈, 珈xਤlaRa㦠i⊀R ⊀f aRy iR㦠珈ʤim aRalys珈s aR⁀ s㦠⊀ਤਤiRg 20 gui⁀珈liR珈s 21 22 23 aR⁀⊀miza㦠i⊀R 24 25 S珈qu珈Rc珈 8a M珈㦠h⊀⁀ us珈⁀ 㦠⊀ g珈R珈ʤa㦠珈 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 P6 26 g珈R珈ʤa㦠i⊀R 27 8b Tyਤ珈 ⊀f ʤaR⁀⊀miza㦠i⊀R; ⁀珈㦠ails ⊀f aRy ʤ珈s㦠ʤic㦠i⊀R (such as bl⊀ckiRg aR⁀ P6 28 29 bl⊀ck siz珈) 30 31 All⊀ca㦠i⊀R 9 M珈chaRism us珈⁀ 㦠⊀ imਤl珈m珈R㦠 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 (such P6 32 c⊀Rc珈alm珈R㦠 as s珈qu珈R㦠ially Rumb珈ʤ珈⁀ c⊀R㦠aiR珈ʤs), ⁀珈scʤibiRg aRy s㦠珈ਤs 㦠ak珈R 㦠⊀ 33 34 m珈chaRism c⊀Rc珈al 㦠h珈 s珈qu珈Rc珈 uR㦠il iR㦠珈ʤv珈R㦠i⊀Rs w珈ʤ珈 assigR珈⁀ 35 36 Imਤl珈m珈R㦠a㦠i⊀R 10 Wh⊀ g珈R珈ʤa㦠珈⁀ 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈, wh⊀ 珈Rʤ⊀ll珈⁀ P6-8 37 38 ਤaʤ㦠iciਤaR㦠s, aR⁀ wh⊀ assigR珈⁀ ਤaʤ㦠iciਤaR㦠s 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs 39 40 BliR⁀iRg 11a If ⁀⊀R珈, wh⊀ was bliR⁀珈⁀ af㦠珈ʤ assigRm珈R㦠 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs (f⊀ʤ P6 41 珈xamਤl珈, ਤaʤ㦠iciਤaR㦠s, caʤ珈 ਤʤ⊀vi⁀珈ʤs, 㦠h⊀s珈 ass珈ssiRg ⊀u㦠c⊀m珈s) aR⁀ 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 40 of 40
1 h⊀w 2 3 11b If ʤ珈l珈vaR㦠, ⁀珈scʤiਤ㦠i⊀R ⊀f 㦠h珈 similaʤi㦠y ⊀f iR㦠珈ʤv珈R㦠i⊀Rs P6-7 4 5 S㦠a㦠is㦠ical 12a S㦠a㦠is㦠ical m珈㦠h⊀⁀s us珈⁀ 㦠⊀ c⊀mਤaʤ珈 gʤ⊀uਤs f⊀ʤ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy P9-10 6 7 m珈㦠h⊀⁀s ⊀u㦠c⊀m珈s 8 9 12b M珈㦠h⊀⁀s f⊀ʤ a⁀⁀i㦠i⊀Ral aRalys珈s, such as subgʤ⊀uਤ aRalys珈s aR⁀ P9-10 10 11 a⁀jus㦠珈⁀ aRalys珈s 12 For peer review only 13 Results 14 15 Paʤ㦠iciਤaR㦠 fl⊀w 13a F⊀ʤ 珈ach gʤ⊀uਤ, 㦠h珈 Rumb珈ʤs ⊀f ਤaʤ㦠iciਤaR㦠s wh⊀ w珈ʤ珈 ʤaR⁀⊀mly P11-13 16 17 (a ⁀iagʤam is assigR珈⁀, ʤ珈c珈iv珈⁀ iR㦠珈R⁀珈⁀ 㦠ʤ珈a㦠m珈R㦠, aR⁀ w珈ʤ珈 aRalyz珈⁀ f⊀ʤ 㦠h珈 18 s㦠ʤ⊀Rgly ਤʤimaʤy ⊀u㦠c⊀m珈 19 20 ʤ珈c⊀mm珈R⁀珈⁀) 13b F⊀ʤ 珈ach gʤ⊀uਤ, l⊀ss珈s aR⁀ 珈xclusi⊀Rs af㦠珈ʤ ʤaR⁀⊀miza㦠i⊀R, 㦠⊀g珈㦠h珈ʤ P11-13 21 22 wi㦠h ʤ珈as⊀Rs 23 24 珈cʤui㦠m珈R㦠 14a Da㦠珈s ⁀珈fiRiRg 㦠h珈 ਤ珈ʤi⊀⁀s ⊀f ʤ珈cʤui㦠m珈R㦠 aR⁀ f⊀ll⊀w-uਤ P7 25 26 14b Why 㦠h珈 㦠ʤial 珈R⁀珈⁀ ⊀ʤ was s㦠⊀ਤਤ珈⁀ P22 27 28 29 Bas珈liR珈 ⁀a㦠a 15 A 㦠abl珈 sh⊀wiRg bas珈liR珈 ⁀珈m⊀gʤaਤhic aR⁀ cliRical chaʤac㦠珈ʤis㦠ics f⊀ʤ P13-14 30 珈ach gʤ⊀uਤ 31 32 Numb珈ʤs 16 F⊀ʤ 珈ach gʤ⊀uਤ, Rumb珈ʤ ⊀f ਤaʤ㦠iciਤaR㦠s (⁀珈R⊀miRa㦠⊀ʤ) iRclu⁀珈⁀ iR 珈ach P14-17 33 34 aRalyz珈⁀ aRalysis aR⁀ wh珈㦠h珈ʤ 㦠h珈 aRalysis was by ⊀ʤigiRal assigR珈⁀ gʤ⊀uਤs 35 36 Ou㦠c⊀m珈s aR⁀ 17a F⊀ʤ 珈ach ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈, ʤ珈sul㦠s f⊀ʤ 珈ach gʤ⊀uਤ, aR⁀ P14-17 37 38 珈s㦠ima㦠i⊀R 㦠h珈 珈s㦠ima㦠珈⁀ 珈ff珈c㦠 siz珈 aR⁀ i㦠s ਤʤ珈cisi⊀R (such as 95% c⊀Rfi⁀珈Rc珈 39 iR㦠珈ʤval) 40 41 17b F⊀ʤ biRaʤy ⊀u㦠c⊀m珈s, ਤʤ珈s珈R㦠a㦠i⊀R ⊀f b⊀㦠h abs⊀lu㦠珈 aR⁀ ʤ珈la㦠iv珈 珈ff珈c㦠 P14-17 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 41 of 40 BMJ Open
1 siz珈s is ʤ珈c⊀mm珈R⁀珈⁀ 2 3 ARcillaʤy 18 珈sul㦠s ⊀f aRy ⊀㦠h珈ʤ aRalys珈s ਤ珈ʤf⊀ʤm珈⁀, iRclu⁀iRg subgʤ⊀uਤ aRalys珈s P17 4 5 aRalys珈s aR⁀ a⁀jus㦠珈⁀ aRalys珈s, ⁀is㦠iRguishiRg ਤʤ珈sਤ珈cifi珈⁀ fʤ⊀m 珈xਤl⊀ʤa㦠⊀ʤy 6 7 Haʤms 19 All imਤ⊀ʤ㦠aR㦠 haʤms ⊀ʤ uRiR㦠珈R⁀珈⁀ 珈ff珈c㦠s iR 珈ach gʤ⊀uਤ (f⊀ʤ sਤ珈cific (There is no extension for this item) P15-17 8 gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ haʤms [28]) 9 10 11 Discussion 12 For peer review only 13 Limi㦠a㦠i⊀Rs 20 Tʤial limi㦠a㦠i⊀Rs; a⁀⁀ʤ珈ssiRg s⊀uʤc珈s ⊀f ਤ⊀㦠珈R㦠ial bias; imਤʤ珈cisi⊀R; aR⁀, P22 14 if ʤ珈l珈vaR㦠, mul㦠iਤlici㦠y ⊀f aRalys珈s 15 16 17 G珈R珈ʤalizabili㦠y 21 G珈R珈ʤalizabili㦠y (珈x㦠珈ʤRal vali⁀i㦠y, aਤਤlicabili㦠y) ⊀f 㦠h珈 㦠ʤial fiR⁀iRgs Discussion of how the formula works on different TCM Pa㦠㦠珈ʤRs or P20-21 18 diseases 19 20 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R 22 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R c⊀Rsis㦠珈R㦠 wi㦠h ʤ珈sul㦠s, balaRciRg b珈R珈fi㦠s aR⁀ haʤms, Interpretation with TCM theory P17-21 21 22 aR⁀ c⊀Rsi⁀珈ʤiRg ⊀㦠h珈ʤ ʤ珈l珈vaR㦠 珈vi⁀珈Rc珈 23 24 Other information 25 26 珈gis㦠ʤa㦠i⊀R 23 珈gis㦠ʤa㦠i⊀R Rumb珈ʤ aR⁀ Ram珈 ⊀f 㦠ʤial ʤ珈gis㦠ʤy P2 27 28 29 Pʤ⊀㦠⊀c⊀l 24 Wh珈ʤ珈 㦠h珈 full 㦠ʤial ਤʤ⊀㦠⊀c⊀l caR b珈 acc珈ss珈⁀, if availabl珈 P5 30 31 FuR⁀iRg 25 S⊀uʤc珈s ⊀f fuR⁀iRg aR⁀ ⊀㦠h珈ʤ suਤਤ⊀ʤ㦠 (such as suਤਤly ⊀f ⁀ʤugs), ʤ⊀l珈 ⊀f P10 32 33 fuR⁀珈ʤs 34 35 CHM = ChiR珈s珈 h珈ʤbal m珈⁀iciR珈; CONSO T = C⊀Rs⊀li⁀a㦠珈⁀ S㦠aR⁀aʤ⁀s ⊀f 珈ਤ⊀ʤ㦠iRg Tʤials; TCM = 㦠ʤa⁀i㦠i⊀Ral ChiR珈s珈 m珈⁀iciR珈. 36 * Th珈 ⊀ʤigiRal CONSO T i㦠珈ms aʤ珈 ਤʤ⊀vi⁀珈⁀; 珈lab⊀ʤa㦠i⊀Rs f⊀ʤ CHM f⊀ʤmulas aʤ珈 iR i㦠aliciz珈⁀ 㦠珈x㦠. W珈 s㦠ʤ⊀Rgly ʤ珈c⊀mm珈R⁀ ʤ珈a⁀iRg 㦠his ch珈cklis㦠 iR c⊀RjuRc㦠i⊀R wi㦠h 㦠h珈 CONSO T 2010 37 38 ExਤlaRa㦠i⊀R aR⁀ Elab⊀ʤa㦠i⊀R (29) f⊀ʤ imਤ⊀ʤ㦠aR㦠 claʤifica㦠i⊀Rs ⊀R all ⊀ʤigiRal i㦠珈ms ⊀f CONSO T S㦠a㦠珈m珈R㦠. 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open
Safety and Efficacy of Herbal Medicine for Acute Intracerebral Hemorrhage (CRRICH): A Multicenter Randomized Controlled Trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-024932.R2
Article Type: Research
Date Submitted by the 20-Mar-2019 Author:
Complete List of Authors: Zeng, Liling; The Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine Tang, Guanghai; Shenyang No.2 traditional Chinese medical hospital, Shenyang, Liaoning Wang, Jing; Neurology Department, Shenzhen Longhua New District Center Hospita, Shenzhen Zhong, Jianbin ; Boji-affiliated Hospital of Sun Yat-sen University Xia , Zhangyong ; Liaocheng People's Hospital, Liaocheng clinical school of Taishan Medical University Li, Jiexia; Conghua City’s hospital of Chinese Medicine Chen, Guangsheng ; Boluo County People's Hospital Zhang, Yongbo ; Shouguang City People's Hospital Luo, Saihua; Lianjiang People's hospital Huang , Gan ; Yangjiang Hospital of Chinese Medicine Zhao, Qianshan; Jiangmen Wuyi Hospital of Chinese Medicine Wan, Yue ; Zhongshan Hospital of Hubei Province Chen , Chaojun; Guangzhou Hospital of Integrated traditional and west medicine Zhu, Kaiyun ; Panyu Hospital of Chinese Medicine Qiao , Hanzi; Guangdong Provincial hospital of Chinese medicine, Neurology Wang, Jian ; First Affiliated Hospital to Changchun University of Chinese Medicine Huang, Tao ; Guangdong Provincial hospital of Chinese medicine, Neurology Liu, Xian; Guangdong Provincial hospital of Chinese medicine, Neurology Zhang, Qixin ; Guangdong Provincial hospital of Chinese medicine, Neurology Lin, Rongming ; Guangdong Second Hospital of traditional Chinese Medicine Li, Haijun ; Guangdong Provincial hospital of Chinese medicine, Neurology Gong, Baoying ; Guangdong Provincial hospital of Chinese medicine, Neurology Chen, Xiuyan ; Guangdong Provincial hospital of Chinese medicine, Neurology Zhou, Yuexiang; Guangdong Provincial hospital of Chinese medicine, Neurology Wen, Zehuai; Guangdong Provincial Hospital of Chinese Medicine, Key
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1 2 3 Unit of Methodology in Clinical Research 4 Guo, Jianwen; Guangdong Provincial hospital of Chinese medicine, 5 Neurology 6 Primary Subject 7 Neurology 8 Heading: 9 Secondary Subject Heading: Complementary medicine, Neurology 10 intracerebral hemorrhage, Herbal medicine < THERAPEUTICS, 11 Keywords: 12 randomized controlled trials, hematoma enlargement, CRRICH 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 29
1 2 3 4 Safety and Efficacy of Herbal Medicine for Acute Intracerebral 5 6 Hemorrhage (CRRICH): A Multicenter Randomized Controlled 7 8 Trial 9 10 Liling Zeng, Guanghai Tang, Jing Wang,, Jianbin Zhong, Zhangyong Xia, Jiexia Li, 11 Guangsheng Chen, Yongbo Zhang, Saihua Luo, Gan Huang, Qianshan Zhao, Yue Wan, 12 13 Chaojun Chen, Kaiyun Zhu, Hanzi Qiao, Jian Wang, Tao Huang, Xian Liu, Qixin Zhang, 14 Rongming Lin, Haijun Li, Baoying Gong, Xiuyan Chen, Yuexiang Zhou, Zehuai Wen, 15 16 Jianwen Guo* 17 18 *Corresponding authorFor peer review only 19 Jianwen Guo, MD, Neurologist. 20 Guangdong Provincial Hospital of Chinese Medicine, Guangdong University of Chinese 21 Medicine 22 111 Da De Rd., Yuexiu District, Guangzhou, Guangdong Province, 23 PRC, 510120 24 Email: [email protected] 25 Telephone 86-20-81867705 26 FAX 86-20-81867705 27 Author affiliations (Liling Zeng, Jianwen Guo, Haijun Li, Qixin Zhang, Tao Huang, 28 Xian Liu, Baoying Gong, Xiuyan Chen, Yuexiang Zhou, Zehuai Wen, Hanzi Qiao) The 29 30 Second Clinical Medical Collage, Guangzhou University of Chinese Medicine, 31 Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China; (Jing Wang) 32 Shenzhen Longhua New District Center Hospital, Shenzhen, China; (Jian Wang) 33 Changchun Chinese Medicine University Affiliated Hospital, Changchun, China; 34 (Zhangyong Xia) Liaocheng People's Hospital, Liaocheng Clinical School of Taishan 35 Medical University, Liaocheng, China; (Jiexia Li) Conghua City’s Hospital of Chinese 36 37 Medicine, Conghua, China; (Guangsheng Chen) Boluo County People's Hospital, 38 Huizhou, China; (Qianshan Zhao) Jiangmen Wuyi Hospital of Chinese Medicine, 39 Jiangmen, China; (Chaojun Chen) Guangzhou Hospital of Integrated Traditional and 40 Western Medicine, Guangzhou, China; (Yongbo Zhang) Shouguang City People's 41 Hospital, Shouguang, China; (Gan Huang) Yangjiang Hospital of Chinese Medicine, 42 Yangjiang, Guangdong, China; (Kaiyun Zhu) Panyu Hospital of Chinese Medicine， 43 44 Guangzhou, China; (Saihua Luo) Lianjiang People's Hospital, Lianjiang, China; 45 (Guanghai Tang) Shenyang No.2 Traditional Chinese Medical Hospital, Shenyang, 46 China; (Jianbin Zhong) Boji-affiliated Hospital of Sun Yat-sen University, Zengcheng, 47 China; (Yue Wan) Zhongshan Hospital of Hubei Province, Wuhan, Hubei, China; 48 Guangdong Second Hospital of traditional Chinese Medicine (Rongming Lin) 49 50 ABSTRACT 51 Objective: To evaluate the safety and efficacy of removing blood stasis 52 (RBS) herbal medicine for the treatment of acute intracerebral 53 54 hemorrhage (AICH) within a 6-h time window. 55 Study design: A randomized, multicenter, double-blind, placebo- 56 57 controlled study performed in 14 hospitals in China. 58 Participants and Interventions: Patients with AICH were randomly 59 assigned to receive a placebo, the ICH-1 formula (8 herbs, including the 60
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1 2 3 removing blood stasis (RBS) herbs hirudo and tabanus) or the ICH-2 4 5 formula (6 herbs without the RBS herbs hirudo and tabanus) within 6 h 6 of ICH onset. 7 8 Outcomes: The primary safety outcome was the incidence of hematoma 9 enlargement at 24 h and at 10 days after treatment. The secondary 10 outcome was the incidence of poor prognosis (mortality or modified 11 12 Rankin Scale (mRS) score ≥5) assessed at 90 days after symptom onset. 13 Results: A total of 324 subjects were randomized between October 2013 14 and May 2016: 105 patients received placebo; 108 patients received the 15 16 ICH-1 formula; and 111 patients received the ICH-2 formula. The 17 incidence of hematoma enlargement at 24 h was 7.8% in the placebo group, 18 12.3% in the ForICH-1 group,peer and 7.5%review in the ICH-2 only group; the incidence of 19 20 hematoma enlargement on day 10 was 1.1% in the placebo group, 1.1% in 21 the ICH-1 group, and 3.1% in the ICH-2 group, with no significant 22 differences among the groups (P>0.05). The mortality rates were 3.8% in 23 24 the placebo group, 2.8% in the ICH-1 group, and 0.9% in the ICH-2 group; 25 the incidences of poor prognosis were 7.1% in the placebo group, 6.0% in 26 the ICH-1 group, and 4.8% in the ICH-2 group at 3 months, with no 27 28 significant differences among the groups (P>0.05). However, the overall 29 frequency of treatment-emergent adverse events(TEAEs) in the ICH-1 30 group (12.1%) was higher among the three groups (5.8% and 2.8%, 31 32 respectively, P<0.05). All 3 cases of serious adverse events were in the 33 ICH-1 group. 34 35 Conclusions: Ultra-early administration of ICH-1formula for AICH 36 patients did not exert significant beneficial effects on clinical outcomes 37 but increased the risk of bleeding, which probably resulted from the 38 39 inclusion of RBS herbal medicines in ICH-1. 40 Clinical Trial Registration: URL:http//www.ClinicalTrials.gov. 41 Unique identifier: NCT01918722. 42 43 Keywords: intracerebral hemorrhage; herbal medicine; randomized 44 controlled trials; hematoma enlargement; CRRICH 45 46 Word count: 4646 47 Strengths and limitations of this study 48 ▪ The CRRICH trial is the largest multicenter clinical trial to examine the 49 50 safety and efficacy of two Chinese compound formulas in patients with 51 AICH. 52 ▪ This study highlights the possibility that the early use of RBS herbal 53 54 medicine in AICH could increase the risk of bleeding, which spurs further 55 research on the safety of Chinese medicines. 56 ▪ There were no available data to elucidate the mechanisms of TEAEs or 57 58 serious TEAEs. 59 60
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1 2 3 4 Introduction 5 Acute intracerebral hemorrhage(AICH) accounts for approximately 6 15%[1] of all acute strokes; stroke is the third most common cause of 7 8 death in most Western countries, following coronary heart disease and 9 cancer.[2, 3] AICH has been the leading cause of death in China in recent 10 years[4] and is responsible for approximately one-third of the total number 11 [5] 12 of deaths from stroke worldwide. 13 Available specific medical and surgical treatments do not improve 14 prognosis substantially,[6, 7] and AICH still accounts for a higher 15 [8] 16 proportion of stroke in Chinese people than in white populations. 17 Therefore, traditional Chinese medicine (TCM) physicians in China 18 widely use removingFor peerblood stasis review (RBS) herbs onlyfor the treatment of AICH. 19 20 Meta-analysis showed that RBS herbal therapy for AICH could improve 21 the neurological function deficit, reduce the volume of hematoma and 22 perihematomal edema, and lower the mortality rate and dependency.[9] It 23 24 is possible that RBS herbal medicine promotes hematoma absorption and 25 improves the recovery of neurological impairment[10, 11]; RBS herbal 26 medicine has already been included by guidelines for the management of 27 28 spontaneous ICH. However, sufficient evidence of long-term benefits and 29 risks of superacute stage is lacking. RBS herbals, such as Hirudo 30 nipponica Whitman, which acts as a thrombin inhibitor with 31 32 anticoagulant pharmacological effects, may cause rebleeding risk in 33 clinical practice.[12] A total of 90% of hematoma growth, which plays an 34 important role in prognosis, occurs within a 6-h time window.[13] 35 36 Therefore, a confirmation of the safety and efficacy of RBS herbal 37 medicines in the treatment of early-stage AICH is urgently needed. 38 We performed a retrospective study that demonstrated that RBS 39 [14] 40 herbal medicine for AICH patients was safe and effective. However, 41 little additional evidence of the safety and efficacy of this treatment 42 exists. We designed a multicenter, three-group, prospective, randomized, 43 44 double-blinded and placebo-controlled clinical trial on hematoma 45 enlargement in AICH patients treated with RBS herbal medicine within a 46 47 6-h time window from symptom onset (CRRICH) to evaluate its safety 48 and efficacy in AICH patients and to provide a high level of evidence for 49 clinical practice. 50 51 Methods 52 Study Design 53 The CRRICH trial was a multicenter, randomized, double-blinded, 54 55 placebo-controlled, parallel-group study to assess the safety and efficacy 56 of RBS herbal medicine in AICH patients. This trial is registered at 57 clinicaltrials.gov (NCT01918722), and the research design proposal has 58 [15] 59 been published. 60 Participants
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1 2 3 Patients with a Glasgow Coma Scale [GCS] score ≥6 were enrolled 4 5 if they were ≥18 years of age and had a clinical diagnosis of ICH 6 confirmed with computed tomography within 6 h of onset. All 7 8 participants signed an informed consent form. If the participants did not 9 have the capacity to sign the informed consent for serious condition or 10 illiteracy, the researcher will explain the informed consent to the patients 11 12 or their authorized immediate family. Weighing the pros and cons of both 13 sides, their immediate family will decide whether to sign the informed 14 consent on behalf of the patient. Patients who suffered secondary ICH 15 16 resulting from trauma, brain tumor, blood diseases, arteriovenous 17 malformation or aneurysm were excluded. A detailed patient history was 18 recorded. S1 TableFor in peer the online-only review Data Supplement only provides a full list 19 20 of study inclusion and exclusion criteria during the screening period. 21 Randomization and Blinding 22 Patients were randomized to receive placebo, ICH-1, or ICH-2 in 23 24 a 1:1:1 ratio with a stratification and block size of 6 using the PROC 25 PLAN process in SAS software version 9.13. Stratified block and 26 randomization were concealed using sequentially numbered opaque 27 28 envelopes. Persons involved in the study, including the investigators, 29 patients and data analysts, were blinded to treatment assignment during 30 double-blinded treatment until the end of follow-up. Only the data 31 32 administrators were permitted access to unblinded data. 33 Procedures 34 Enrollment, Intervention and Follow-up 35 Patients were recruited from October 2013 through May 2016 at 14 36 37 hospitals in China (S2 Table in the online-only Data Supplement). The 38 study consisted of a screening and randomization period (≤6 h 39 40 poststroke), a 10-day double-blinded treatment period and a 3-month 41 follow-up period (S1 Figure in the online-only Data Supplement). 42 Participants were randomly assigned to one of three treatment groups at a 43 44 ratio of 1:1:1 during the double-blinded treatment (shown in the S3 and 45 S4 Table in the online-only Data Supplement): (1) The ICH-1 group 46 received the ICH-1 formula, which consisted of 8 herbs including RBS 47 48 medicines; (2) The ICH-2 group received the ICH-2 formula, which 49 consisted of 6 herbal medicines without RBS herbs(Hirudo nipponica 50 Whitman and Tabanus bivittatus Matsumura) in the same doses as those 51 52 in the ICH-1 group, with the remaining dose filled with a placebo; and (3) 53 The placebo group received a placebo that included dextrin and farina. 54 Each unit of TCM medicine or placebo was dissolved in 200 ml of 55 56 boiling water. Each patient received 200 ml orally or through a 57 nasogastric tube two times daily for 10 days (S3 Table in the online-only 58 Data Supplement). 59 60 Patients were followed up for 3 months after the 10-day double-
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1 2 3 blinded treatment period. Patients were hospitalized in stroke units and 4 5 received standard stroke care in accordance with local guidelines, which 6 included general supportive care, treatment of acute complications, and 7 8 rehabilitation. Astringents and other RBS drugs were prohibited. Visits 9 were scheduled at baseline, 24 h poststroke, and at the end of the 10 treatment period, with a single visit scheduled 3 months poststroke (S1 11 12 Figure in the online-only Data Supplement). Adverse events (AEs), 13 treatment compliance, and concomitant medication use were reported 14 during each visit. Participants were randomly assigned to one of three 15 16 treatment groups at a ratio of 1:1:1 during double-blinded treatment. 17 Primary and Secondary Outcomes 18 The incidenceFor of peer hematoma review enlargement, onlywhich was defined as the 19 20 percentage of participants who experienced hematoma enlargement, was 21 the primary outcome of the study. Hematoma enlargement was 22 operationally defined as an increase in hematoma volume of >33% or 23 24 12.5 ml, as measured on image analysis on the 24-h CT compared with 25 the baseline CT scan. Hematoma volume was measured using the ABC/2 26 Coniglobus formula[16] at 24 h after onset. The same measurement was 27 28 performed on days 10-14 as a primary outcome measure. 29 NIHSS(National Institutes of Health Stroke Scale) scores range from 0 30 (normal) to 42 (coma with quadriplegia); and mRS(modified Rankin 31 32 Scale) scores range from 0 (no symptoms or disability) to 6 (death). Both 33 of them can be used to evaluate the clinical outcomes.The following 34 secondary end points were assessed: change in NIHSS score at 3 months; 35 36 mortality at 3 months; and poor prognosis rate, which was defined as the 37 proportion of patients who died or were severely disabled based on an 38 mRS score ≥5 at 3 months.[17] Safety data focused on treatment-emergent 39 40 AEs (TEAEs). TEAEs were defined as AEs that first occurred or 41 worsened (increased in severity) after the first dose of study drug. The 42 patient spontaneously reported TEAEs in response to an open-ended 43 44 question from the contact person at each visit. A worsened patient 45 condition, prolonged patient hospitalization, and life-threatening TEAEs 46 in patients were reported as serious adverse events (TEsAEs). Abnormal 47 48 laboratory values that constituted a serious AE or led to the 49 discontinuation of experimental drugs were also reported as TEsAEs. S5 50 Table in the online-only Data Supplement provides a full list of all 51 52 primary, secondary and safety end points. 53 Statistical Analyses 54 All reported efficacy analyses were predefined and based on the full 55 56 analysis set (FAS) (patients who were randomized and received any study 57 medication) according to the intent-to-treat (ITT) principle. Supportive 58 analyses were performed in a predefined per-protocol population set 59 60 (PPS), which included FAS patients who did not have one or more key
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1 2 3 protocol deviations, including violations of inclusion and exclusion 4 5 criteria. The last observation for surviving patients with missing outcome 6 data was carried forward. Patients who had died by the 90-day follow-up 7 8 were assigned a Barthel index score of 0 and an mRS score of 6, and the 9 last recorded NIHSS score was carried forward. The incidence of 10 hematoma enlargement at 24 h (primary end point), the rate of poor 11 12 prognosis and the incidence of total TEAEs among the three groups were 2 13 analyzed using the χ test. The incidence of hematoma enlargement on 14 days 10-14 (primary end point) and mortality among the three groups 15 16 were compared using Fisher’s exact test. The mean differences in NIHSS 17 score among groups were analyzed using one-way ANOVA. 18 DemographicFor characteristics peer and review serious TEAEs only were summarized using 19 20 descriptive statistics. 21 Power and sample size were determined using relative hematoma 22 volume at 24 h as the primary outcome variable. A total of 285 23 24 participants were required at the final follow-up to provide 90% power 25 with a two-sided alpha level at 0.05 to test the primary efficacy, which 26 was calculated using the PASS (Power Analysis and Sample Size) 27 28 software program (licensed by NCSS, LLC). A total of 360 participants 29 were needed for primary outcome randomization assuming a dropout rate 30 of 20%, with 120 patients per treatment arm. The statistical package 31 32 STATA (version 13.1) was used for all statistical analyses. 33 Patient and Public Involvement Statement 34 While we put forward the research question and outcome measures, 35 36 the patients’ priorities, experience, and preferences were fully considered 37 by a survey. Patients were involved in the recruitment to and conduct of 38 the study. The results would be disseminated to study participants by 39 40 posting a letter. The CRRICH trial was a randomized controlled trial, and 41 the patients themselves had fully assessed the burden of the intervention. 42 Patient advisors should also be thanked in the contributorship 43 44 statement/acknowledgments. 45 Funding and Ethical Statements 46 The State Administration of Traditional Chinese Medicine of the 47 48 P.R.C. (SATCM) awarded Guangdong Provincial Hospital of TCM 49 (GPHTCM) SATCM Grant No: ZDJX2012074 and provided input 50 during the study period. This report was an independent study supported 51 52 by SATCM and performed by the GPHTCM in a SATCM–GPHTCM 53 partnership. The viewpoints stated in this manuscript are those of the 54 authors and may not represent the opinions of SATCM, GPHTH or the 55 56 Public Health Bureau. The SATCM and GPHTCM approved the decision 57 to submit this paper for publication. Dr. Jianwen Guo had full access to 58 all study data and had final responsibility for the decision to submit for 59 60 publication.
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1 2 3 Each respective institutional review board or ethics committee 4 5 approved the study protocol, which followed the established Good 6 Clinical Practice guidelines. All patients provided written informed 7 8 consent to participate in the study. An independent contract research 9 organization, S&R (Department of Science and Research of Guangdong 10 Provincial Hospital of Chinese medicine), managed the administration, 11 12 coordination, and monitoring of the study, including researcher training, 13 study inspection, data management and statistical analyses, with 14 oversight by the State Administration of Traditional Chinese Medicine of 15 16 the P.R.C. 17 Results 18 Study PopulationFor peer review only 19 20 Patient recruitment began in October 2013, and the study ended in 21 May 2016. A total of 5589 individuals with ICH were screened (Figure 22 1). The most frequent reasons for exclusion in descending order were 23 24 time window >6 h, refusal to participate, secondary ICH (i.e., not AICH) 25 and other reasons. A total of 319 of the 324 randomized patients (105 26 placebo, 108 ICH-1, 111 ICH-2) received the assigned treatment 27 28 following the elimination of five patients (one patient for missing the 29 time window, one patient for kidney failure, one patient for secondary 30 ICH, one patient for surgery within 24 h and one patient withdrew 31 32 consent). Therefore, only the 319 participants who underwent 33 randomization and received study medication were included in the FAS 34 and safety analysis set based on ITT. Twenty-three patients in the FAS 35 36 did not completely adhere to the protocol and dropped out during the 37 treatment period. A total of 296 patients were included in the PPS (see 38 Figure 1 for patient flow diagram). The mean dropout rate was <8%. 39 40 Table 1 presents the demographics and baseline characteristics of the 41 FAS, which were well balanced with no significant between-group 42 differences. The mean age was 62.5±12.7 years (mean±SD, n=319); 43 44 65.5% of the patients were male, and 98.7% were ethnic Han. The 45 median GCS score was 15 (range, 3 to 15), and the mean NIHSS score 46 was 8 (range, 0 to 47). The deep gray matter was involved in 93.4% of 47 48 cases, and the lobar regions were involved in 6.6% of cases. The baseline 49 characteristics of the three treatment groups were similar. The mean 50 volume of the ICH at baseline for all patients was 11.0 ml (range, 0.3 to 51 52 86.7 ml), which was similar in the three groups (Table 1). The mean time 53 from onset of symptoms to admission was 3.36±1.49 h, and the mean 54 time from onset of symptoms to treatment was 4.10±1.38 h. Fourteen 55 56 percent of patients were treated within 3 h after symptom onset. Two 57 patients were treated outside of the 6-h time window. The timing of the 58 59 treatment was similar in the three groups (Table 1). 60
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1 2 3 Figure 1. Enrollment and Follow-up. AEs, adverse events; FAS, full analysis set; PPS, per-protocol population 4 set; RBS, removing blood stasis; ICH denotes intracerebral hemorrhage; ICH-1 denotes herbal medicine with RBS 5 herbals hirudo and tabanus (8 herbals); ICH-2 denotes herbal medicine without RBS herbals hirudo or tabanus (6 6 herbals). 7 8 Table 1. Baseline Characteristics and Treatment Timing. 9 10 Variable Placebo (N=104) ICH-2 (N=108) ICH-1 (N=107) 11 Age (yr) 61.95±13.38 62.56±12.64 62.84±12.23 12 13 Sex n (%) Male 69(66.3) 69(63.9) 71(66.4) 14 15 Female 35(33.7) 39(36.1) 36(33.6) 16 17 Ethnic group n (%) 18 Ethnic Han For peer103(99.0) review105(97.2) only 107(100.0) 19 20 Not ethnic Han 1(1.0) 3(2.8) 0(0) 21 22 Hemisphere hematoma n (%) 23 Left hemisphere 44(42.3) 53(49.1) 56(52.3) 24 25 Right hemisphere 59(56.7) 54(50.0) 51(47.7) 26 27 Supratentorial hematoma n (%) 28 Putamen or globus 69(66.3) 72(66.7) 64(59.8) 29 pallidus 30 31 Thalamus 19(18.3) 24(22.2) 28(26.2) 32 33 Lobar hemisphere 10(9.6) 7(6.5) 4(3.7) 34 None 6(5.8) 5(4.6) 11(10.3) 35 36 Subtentorial hematoma n (%) 37 38 Cerebellum 4(3.8) 2(1.9) 7(6.5) 39 40 Pons or midbrain 2(2.0) 4(3.7) 5(5.0) 41 None 98(94.2) 102(94.4) 95(88.8) 42 43 Intraventricular hemorrhage n (%) 44 45 Yes 17(16.3) 19(17.6) 25(23.4) 46 47 No 87(83.7) 89(82.4) 82(76.6) 48 GCS score‡ 14.18±1.86 13.77±2.34 13.76±2.06 49 50 NIHSS score 7.88±5.24 9.00±7.24 9.13±6.16 51 52 Volume of the intracerebral 53 9.82±7.45 11.56±9.67 11.57±11.55 54 hemorrhage at 55 baseline 56 Systolic BP at time 57 of admission 171.34±28.04 174.14±23.72 172.04±22.53 58 (mmHg) 59 60
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1 2 3 Time from onset to 4 4.31±1.38 4.02±1.35 3.97±1.39 5 treatment (h) 6 Time from onset to 7 3.61±1.54 3.08±1.47 3.05±1.63 admission (h) 8 9 10 11 12 13 * The values are expressed as counts and % within group, and plus–minus values are the means±SD. Percentages 14 may not total 100 because of rounding. GCS, Glasgow Coma Scale (Scores range from 15 (normal) to 3 (deep 15 coma)); NIHSS, National Institutes of Health Stroke Scale (Scores range from 0 (normal) to 42 (coma with 16 quadriplegia)); BP, blood pressure. 17 Primary Outcome (Radiographic Outcomes) 18 At 24 h,For a total peerof 319 baseline review CT scans only and 315 CT scans were 19 20 available for analysis. The incidence of hematoma enlargement were 7.8% 21 in the placebo group, 12.3% in the ICH-1 group and 7.5% in the ICH-2 22 group. There was no significant difference in the incidence of hematoma 23 24 enlargement at 24 h among the three groups (P=0.409). The incidence of 25 hematoma enlargement on days 10-14 was 1.1% in the placebo group, 26 3.1% in the ICH-2 group and 1.1% in the ICH-1 group. There was also no 27 28 significant difference among the three groups in the incidence of hematoma 29 enlargement on days 10-14 (P=0.625) (Table 2). 30 Secondary Outcomes (Clinical Outcomes) 31 32 Mortality at 3 months was approximately 2.6% in the three groups 33 (Table 2). Poor prognosis (i.e., the proportion of patients who died or 34 were severely disabled, mRS ≥5) did not differ significantly among the 35 36 three groups. It is the least patients of poor prognosis occurred in the 37 ICH-2 treatment, but no statistical difference compared with placebo 38 treatment (Table 2). The distributions of outcomes on the modified 39 40 Rankin Scale (Figure 2) were similar among the three groups. The 41 differences in the NIHSS scores at 3 months among the three groups were 42 not significant (Table 2). 43 44 45 Figure2 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin Scale 46 evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). There were no significant differences among the three groups. 47 48 49 Adverse Events 50 There were altogether 35 AEs reported by investigators, of which 22 51 AEs may have been TEAEs. All the TEAEs occurred during the double- 52 53 blinded treatment period (within 2 weeks). TEAEs occurred in 13 54 (12.1%) ICH-1-treated patients, 3 (2.8%) ICH-2-treated patients and 6 55 (5.8%) placebo-treated patients. The patterns of TEAEs were similar in 56 57 the 3 groups, but the overall frequencies of TEAEs among the three 58 groups were significantly different (P=0.022), as shown in Table 2. And 59 the paired comparisons showed that the test for difference in the overall 60
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1 2 3 TEAEs rate between group ICH-1 and group ICH-2 yields a p-value of 4 5 0.029. Table 3 shows the TEAEs that occurred during the study. The most 6 frequent event was diarrhea, and its incidence was similar in the 3 7 8 treatment groups . Treatment was discontinued because of TEsAEs in 3 9 (1.9%) ICH-1-treated patients. The 3 cases with TEsAEs (2 cases of 10 gastrointestinal bleeding, 1 case of cerebral hernia) reported by 11 12 investigators occurred in ICH-1-treated patients. There was no consistent 13 pattern to this difference, and all serious TEAEs occurred within the 10- 14 day drug treatment period. There were no statistically significant 15 16 differences in the incidence or type of serious TEAEs leading to death 17 among groups (data not shown). There was no relationship between 18 TEAEs, seriousFor TEAEs, peer or mortality review and poor outcomeonly (data not shown). 19 20 Table 2 Primary outcome and secondary outcomes 21 22 Differences 23 Placebo ICH-2 ICH-1 Among Groups 24 P Value 25 26 Primary outcome: the incidence of hematoma enlargement at 24 h and at day 14 27 28 At 24 h 8/104(7.8) 8/108(7.5) 13/107(12.3) 0.409 29 30 On days 10-14 1/92(1.1) 3/97(3.1) 1/91(1.1) 0.625 31 Hemorrhage Volumes（ml）at Baseline and Follow-up 32 33 At baseline 9.82±7.45 11.56±9.67 11.57±11.55 0.284 34 35 At 24 h 9.71±6.94 11.97±10.02 14.44±19.33 0.313 36 37 percent increase from 38 baseline- means% (95% -14.1(4.5-32.7) 3.4(0.2-6.5) 41(9.4-91.4) 0.22 39 CI) 40 milliliters of increase -0.13±1.41 0.22±2.24 3.13±16.10 0.168 41 from baseline 42 43 Secondary outcomes: 44 # 45 NIHSS at 3 months 3.58±5.32 3.58±5.32 3.58±5.32 0.475 46 Mortality at 3 months 4/104(3.8) 1/108(0.9) 3/107(2.8) 0.328 47 48 Poor prognosis (mRS 0.783 7/99(7.1) 5/105(4.8) 6/100(6.0) 49 ≥5) 50 51 Total TEAEs 6/104(5.8) 3/108(2.8) 13/107(12.1) 0.022 52 The values are expressed as n/N(%) within group or the means±SD; # denotes the number of patients at 3 months: 53 104 in the placebo group, 107 in the ICH-2 group, and 105 in the ICH-1 group. 54 55 56 57 58 59 60
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1 2 3 4 Table 3 Treatment-emergent adverse events 5 6 Placebo ICH-2 ICH-1 7 Vomiting 1/104(1.0) 0/108(0.0) 2/107(1.9) 8 9 Gastrointestinal 0/104(0.0) 0/108(0.0) 2/107(1.9) 10 bleeding* 11 12 Stomachache 0/104(0.0) 0/108(0.0) 1/107(0.9) 13 14 Chest congestion 1/104(1.0) 0/108(0.0) 0/107(0.0) 15 Cerebral hernia* 0/104(0.0) 0/108(0.0) 1/107(0.9) 16 17 The values are expressed as n/N (%) within group. All adverse events are listed in order of frequency from the 18 overall study Forperiod (90 days);peer adverse events review were collected from only investigator reports. The principal investigator at 19 each site determined whether an adverse event or serious adverse event was related to the intervention. TEAEs, 20 treatment-emergent adverse events. *indicates TEAEs. 21 22 23 24 25 26 27 28 Discussion 29 ICH-1 administration within 6 h after the symptom onset of ICH did 30 31 not significantly reduce hematoma growth and failed to improve survival 32 33 34 or functional outcome at 90 days. Conversely, compared to the ICH-2, 35 36 the incidence of TEAEs showed an increasing trend in the ICH-1 group 37 38 (P= 0.029, ICH-1vs. ICH-2). Significant increases were also 39 40 demonstrated in total TEAE frequency and in serious TEAEs in the ICH- 41 42 1 group. Three serious bleeding events occurred in the ICH-1 group 43 44 (ICH-1, with 2 RBS herbals), including two cases of gastrointestinal 45 46 bleeding and one case of intracerebral rebleeding. All three cases were 47 48 fatal serious TEAEs (Table 2). These data suggest that RBS treatment for 49 50 ICH patients within 6 h of symptom onset is a safety concern. However, 51 52 no data were available to suggest a mechanism for this effect. The 53 54 possible rebreeding mechanism is that RBS medicine, such as Hirudo 55 56 nipponica Whitman, which has anticoagulant pharmacological effects, 57 [12] 58 could increase bleeding risk according to the previous literature. 59 60 As can be seen from the table 2, ICH-2 treatment
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1 2 3 was least vulnerable to poor prognosis and TEAEs. Therefore, ICH-2 4 5 6 formula would have the potential to be an effective herbal drug for ICH 7 8 patients of superacute stage. 9 10 This result contrasts with the clinical benefit demonstrated in a 11 [9] 12 previous meta-analysis , which included 9 randomized controlled 13 14 clinical trials with 798 individuals, demonstrating that RBS therapy for 15 16 acute ICH reduced brain hematoma and cerebral edema volumes, 17 18 improved the Forneural functionpeer and review reduced the mortalityonly and disability 19 20 rates with fewer TEAEs. The present trial revealed significant 21 22 heterogeneity compared with the studies included in the meta-analysis, 23 24 possibly because of differences in the intervention time window. This 25 26 research is the first prospective, multicenter, randomized, double-blind, 27 28 placebo-controlled study to assess the efficacy and safety of ICH-1 in 29 30 AICH patients within a 6-h time window from symptom onset, unlike 31 32 prior studies that examined these effects within a 24-h or later 33 34 intervention time window. Earlier RBS administration increased the risk 35 36 of bleeding events (e.g., gastrointestinal bleeding or intracerebral 37 38 rebleeding), which counteracted the benefit to some extent. 39 40 The primary outcome of the incidence of hematoma enlargement, 41 42 which is an independent prognostic determinant of mortality and poor 43 [18] 44 prognosis, was also used to assess safety. The incidence of hematoma 45 46 enlargement at 24 h in the three groups in the CRRICH trial (placebo, 47 48 ICH-2, and ICH-1) were 7.8%, 7.5%, and 12.3%, respectively, and they 49 50 were not significantly different (Table 2). The mean incidence of 51 52 hematoma enlargement was only 9.2%, which was far lower than the 53 [18] 54 mean level of 18-30%. The main reasons for lower hematoma 55 56 expansion incidence may include the following: (1) the investigators’ 57 58 inclination toward surgery in AICH patients with large hemorrhage 59 60 volumes within 24 h of onset, which resulted in the exclusion of patients
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1 2 3 susceptible to rebleed in the study; and (2) patients with terrible and 4 5 6 unstable conditions who were prone to hematoma expansion were 7 8 excluded by investigators privately for fear that deterioration risk would 9 10 increase during study. 11 12 Hematoma growth is an independent determinant of death and 13 [19] 14 disability. Therefore, hematoma expansion may be an attractive 15 [20, 21] 16 therapeutic target. However, no proven specific therapies or 17 18 treatments existFor to prevent peer hematoma review expansion only or improve outcomes 19 20 after ICH. Sufficient evidence-based medical research to prove that mini- 21 22 traumatic surgeries and the present available medicines provide ideal 23 [6, 7] 24 treatment is lacking. 25 26 Herbal medicine in China has been used to treat ICH for at least 2,000 27 28 years, and RBS herbal medicines are listed in the 2010 Chinese 29 [22] 30 Pharmacopeia. Dr. Si reported the earliest available literature on AICH 31 [23] 32 with RBS herbal medicine therapy in 1981. Another RBS medicine, 33 34 Naoxuekang capsule, was approved as routine treatment for AICH 35 [22] 36 patients by the Chinese State Food and Drug Administration 37 38 (Naoxuekang capsule, register No. Z10960009). RBS herbal medicines 39 40 have been studied in AICH patients in more than 200 clinical studies over 41 42 the past 30 years, and they have gradually come to be considered a 43 [24] 44 regular therapy. AICH management guideline in China cited this 45 [25] 46 treatment. However, safety evidence in the early stage of AICH is 47 48 lacking. Some studies demonstrated that 30% of ICH patients suffered 49 [26] 50 continued bleeding within 6 h of onset . Some research has provided 51 52 low-level evidence of the safety of RBS herbal medicine for superacute 53 54 cerebral hemorrhage, but whether RBS herbal medicine administration in 55 56 an early-stage induced hematoma growth was not known because RBS 57 [27] 58 herbal medicine exhibits an anticoagulation effect. Marketed RBS 59 60 drugs that are clinically recognized and widely used did not illustrate a
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1 2 3 specific application time window. Early administration of RBS drugs 4 5 6 may cause hematoma expansion and increase the risk of death and serious 7 8 disability. The CRRICH trial was a prospective, double-blinded, 9 10 multicenter clinical trial that demonstrated that early administration of 11 12 RBS drugs did not increase hematoma growth but significantly increased 13 14 TEAEs. 15 16 The CRRICH trial is the largest clinical trial to investigate the safety 17 18 and efficacy ofFor a Chinese peer compound review formula in only patients with AICH. 19 20 Three other influential RCT trials of medical treatments with drugs, 21 22 including FAST, INTERACT2, and CHANT, that exhibit mechanisms 23 24 very different from those of RBS used similar methods to evaluate the 25 [28-30] 26 safety and efficacy and found no significant benefit. 27 28 Data from the clinical study suggested that the administration of 29 30 RBS herbal medicine should be avoided in AICH patients during the 31 32 initial 6-h time window from stroke onset to avoid the increased risk of 33 34 bleeding. Further clinical studies should be performed to confirm the 35 36 safety and efficacy of these agents beyond the 6 h of ICH onset. This 37 38 research suggests that the early administration of RBS herbal medicine in 39 40 ICH patients increases the risk of bleeding, such as gastrointestinal 41 42 bleeding, and hematoma growth. Some Chinese patent drugs 43 44 (Naoxuekang capsule (Z10960009), Naoxuekang pill (Z20050312) or 45 46 Naoxuekang drop pills (Z10980039)), which primarily consist of Hirudo 47 48 nipponica Whitman, should be reevaluated and used under supervision. 49 50 The relevant manufacturers should revise the drug instructions and add a 51 52 warning, “Do not use for superacute cerebral hemorrhage within 6 h from 53 54 onset”, if necessary. 55 56 This study had some limitations. First, there were no available data 57 58 to elucidate the mechanism of TEAEs or serious TEAEs. Second, there 59 60 was a significant difference in the number of patients among research
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1 2 3 centers. Third, the investigators preferred to study patients with minor 4 5 6 hematoma volume because they were afraid of the rebleed risk from the 7 8 herbal medicine. 9 10 Summary 11 12 This study demonstrates that ultra-early administration, namely, 13 14 within 6 h of ICH onset, of RBS herbal medicine for AICH patients 15 16 increased the risk of bleeding, such as gastrointestinal bleeding, and 17 18 hematoma growth.For This peer study also review shows that RBSonly herbal medicine did 19 20 not exert significantly beneficial effects on clinical outcomes in 21 22 hypertensive ICH patients in the ultra-early stage. These results support 23 24 the idea that the ultra-early administration of RBS herbal medicine is 25 26 unsafe and has a low efficacy. Future high-quality research should further 27 28 assess the efficacy and safety of RBS herbal medicine for intracerebral 29 30 hemorrhage beyond the 6- h time window. 31 32 33 Supplementary Material A complete list of supplementary material in the CCRICH 34 trial is provided in the Supplementary Appendix. 35 Data Sharing Statement No additional unpublished data are available. 36 Acknowledgments We thank the patients and families who volunteered for this 37 38 study; Zehuai Wen and Ouyang Wen for their assistance with data summarization; 39 and Yubo Lv for his guidance. The CRRICH trial was supported by an SATCM Grant 40 (No: ZDJX2012074) awarded to Dr. Jianwen Guo from the State Administration of 41 Traditional Chinese Medicine of the P.R.C. (SATCM). 42 Contributions JG, LZ, and JW organized the trial hypotheses, designed the trial, and 43 provided guidance about the data analysis and interpretation/presentation of the data. 44 JG is the subject primarily responsible of the clinical trial (CRRICH trial) and 45 46 provided a critical review of the manuscript. LZ drafted most sections of the 47 manuscript. JL, GC, YZ, SL, GH, QZ, GT and YW were involved in the design of the 48 study and contributed to writing and revising the manuscript. GT, JZ, ZX, RL, CC, 49 KZ, and HQ organized and managed the trial including trial start-up, data collection, 50 quality assurance, and trial close-out. XL provided the region of interest calculations 51 for all volumetric measurement results. JW and TH provided an independent review 52 53 and adjudication of all safety events. QZ, HL, BG, XC, YZ and ZW were involved in 54 the statistical analysis and data interpretation and contributed to the development of 55 and revisions to the manuscript. The CRRICH investigators contributed equally to the 56 identification and, when eligible, randomization of trial participants. 57 Funding The State Administration of Traditional Chinese Medicine of the P.R.C. 58 (SATCM) has allocated to Guangdong Provincial Hospital of TCM (GPHTCM): 59 SATCM Grant No: ZDJX2012074, JDZX2015048, and a Project of the Department 60
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1 2 3 of Science and Technology of Guangdong Province, Grant No. 2014A020221074. JG 4 is the subject primarily responsible. This report is an independent study supported by 5 6 the SATCM and conducted by the GPHTCM in the name of the SATCM–GPHTCM 7 partnership. The viewpoints stated in this manuscript are those of the authors and may 8 not be those of the SATCM, GPHTH or the Public Health Bureau. 9 Competing Interests None declared. 10 Ethics approval B2013-085-01; the CRRICH trial was approved by the institutional 11 review boards at all participating centers (specified in the text). 12 13 14 15 References 16 17 [1] Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009. 373(9675): 1632-44. 18 [2] Ng M, Fleming T, Robinson M, et al. Global, regional, and national prevalence of overweight and obesity in children and adultsFor during peer 1980-2013: a systematicreview analysis for theonly Global Burden of Disease Study 2013. 19 Lancet. 2014. 384(9945): 766-81. 20 [3] Feigin VL, Krishnamurthi RV, Parmar P, et al. Update on the Global Burden of Ischemic and Hemorrhagic 21 Stroke in 1990-2013: The GBD 2013 Study. Neuroepidemiology. 2015. 45(3): 161-76. 22 [4] Liu L, Wang D, Wong KS, Wang Y. Stroke and stroke care in China: huge burden, significant workload, 23 and a national priority. Stroke. 2011. 42(12): 3651-4. 24 [5] van Asch CJ, Luitse MJ, Rinkel GJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. 25 Lancet Neurol. 2010. 9(2): 167-76. 26 [6] Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the Management of Spontaneous 27 Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart 28 Association/American Stroke Association. Stroke. 2015. 46(7): 2032-60. 29 [7] Rabinstein AA. Intracerebral haemorrhage: no good treatment but treatment helps. Lancet. 2017. 30 389(10069): 575-576. [8] Tsai CF, Thomas B, Sudlow CL. Epidemiology of stroke and its subtypes in Chinese vs white populations: 31 a systematic review. Neurology. 2013. 81(3): 264-72. 32 [9] Li HQ, Wei JJ, Xia W, et al. Promoting blood circulation for removing blood stasis therapy for acute 33 intracerebral hemorrhage: a systematic review and meta-analysis. Acta Pharmacol Sin. 2015. 36(6): 659-75. 34 [10] Wang YQ, Shi Q, Wang WP. Clinical study of xuefuzhuyu decoction on hypertensive intracerebral 35 hemorrhage. J Emerg Tradit Chin Med 2013; 22: 1686-7, 1689. Chinese . 36 [11] Zhang ZZ, Zhang BH, Chen M. The study of Danshen Injection for prevention and treatment of brain edema in acute intracerebral hemorrhage. Zhejiang J Integr Tradit Chin West Med 2003; 13: 355-7. Chinese . 37 [12] Monreal M, Costa J, Salva P. Pharmacological properties of hirudin and its derivatives. Potential clinical 38 advantages over heparin. Drugs Aging. 1996. 8(3): 171-82. 39 [13] Brott T, Broderick J, Kothari R, et al. Early hemorrhage growth in patients with intracerebral hemorrhage. 40 Stroke. 1997. 28(1): 1-5. 41 [14] Xu Y, Guo J, Liu X. Can Herbal Medicine Cause Hematoma Enlargement of Hypertensive Intracerebral 42 Hemorrhage within 24 hrs Time Window? A Retrospective Study of 256 Cases from a Single Center in 43 China. Evid Based Complement Alternat Med. 2015. 2015: 868731. [15] Zeng L, Guo J, Wang J. Clinical re-evaluation of removing blood stasis therapy in treating acute intracerebral 44 hemorrhage safety and efficacy: a protocol for a randomized, controlled, multicenter study (CRRICH Trial). 45 Springerplus. 2016. 5(1): 1466. 46 [16] Kothari RU, Brott T, Broderick JP, et al. The ABCs of measuring intracerebral hemorrhage volumes. Stroke. 47 1996. 27(8): 1304-5. 48 [17] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 49 intracerebral hemorrhage. N Engl J Med. 2008. 358(20): 2127-37 . [18] Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, et al. Prediction of haematoma growth and outcome in 50 patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective 51 observational study. Lancet Neurol. 2012. 11(4): 307-14. 52 [19] Davis SM, Broderick J, Hennerici M, et al. Hematoma growth is a determinant of mortality and poor outcome 53 after intracerebral hemorrhage. Neurology. 2006. 66(8): 1175-81. 54 [20] Mayer SA. Ultra-early hemostatic therapy for intracerebral hemorrhage. Stroke. 2003. 34(1): 224-9. 55 [21] Wartenberg KE, Mayer SA. Ultra-Early Hemostatic Therapy for Intracerebral Hemorrhage: Future Directions. Front Neurol Neurosci. 2015. 37: 107-29. 56 [22] Chinese Pharmacopoeia Committee. Chinese Pharmacopoeia. Beijing:China Medical Science and 57 Technology Press. 2010: 111-113 . 58 [23] Si GZ. preliminary clinical study of herbal medicine on hemorrhagic stroke: Removing Blood Stasis 59 Therapy. Tianjin Medical Journal.1982;08: 473-476.Chinese . 60 [24] The Professional Board of Neurology Department of Chinese Association of Integrative Medicine in Beijing，
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1 2 3 GAO L ． Expert consensus on hypertensive intracerebral hemorrhage in acute stage in diagnosis and 4 treatment combining traditional Chinese medicine and Western medicine［J］. Chinese General Practice， 5 2016，19 (30): 3641 －3648. Chinese . 6 [25] Zou YH, Ma Bin. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for 7 healthcare professionals from the China Association of Chinese Medicine.Chinese traditional Chinese 8 medicine modern remote education.2011.9(23): 110-112.Chinese . 9 [26] Brouwers HB, Falcone GJ, McNamara KA, et al. CTA spot sign predicts hematoma expansion in patients with delayed presentation after intracerebral hemorrhage. Neurocrit Care. 2012. 17(3): 421-8. 10 [27] L.Bin, L Jian. Clinical observation of early use promoting blood circulation and removing blood stasis herbal 11 injection to treat acute intracerebral hemorrhage. Shandong Journal of Traditional Chinese Medicine. 2000; 12 19(8):461-462.Chinese . 13 [28] Mayer SA, Brun NC, Begtrup K, et al. Efficacy and safety of recombinant activated factor VII for acute 14 intracerebral hemorrhage. N Engl J Med. 2008. 358(20): 2127-37. 15 [29] Anderson CS, Heeley E, Huang Y, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013. 368(25): 2355-65. 16 [30] Lyden PD, Shuaib A, Lees KR, et al. Safety and tolerability of NXY-059 for acute intracerebral hemorrhage: 17 the CHANT Trial. Stroke. 2007. 38(8): 2262-9. 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 Figure 1. Enrollment and Follow-up. AEs, adverse events; FAS, full analysis set; PPS, per-protocol population 33 set; RBS, removing blood stasis; ICH denotes intracerebral hemorrhage; ICH-1 denotes herbal medicine 34 with RBS herbals hirudo and tabanus (8 herbals); ICH-2 denotes herbal medicine without RBS herbals 35 hirudo or tabanus (6 herbals). 36 172x136mm (300 x 300 DPI) 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 20 of 29
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 Figure2 Clinical Outcome at 90 Days According to the Modified Rankin Scale. The modified Rankin Scale evaluates global disability and handicap. Scores range from 0 (no symptoms or disability) to 6 (death). 28 There were no significant differences among the three groups. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 21 of 29 BMJ Open
1 2 3 4 Supplemental Material 5 6 S1 Table: study inclusion and exclusion criteria 7 8 Study inclusion and exclusion criteria 9 10 Inclusion Criteria: 11 12 13 ages eligible for Study: 18 years or older 14 genders eligible for Study: Both 15 16 AICH confirmed by craniocerebral CT scan 17 within 6 hours after the onset of symptom 18 For peer review only 19 GCS≥6 20 sign the informed consent form 21 22 Exclusion Criteria: 23 24 secondary intracerebral hemorrhage resulting from trauma, brain tumor, blood 25 diseases, arteriovenous malformation or aneurysm, etc; 26 27 patients with severe heart, liver or kidney disease. 28 Intolerance to herbal medicine, 29 30 patients with allergies 31 patients planning a surgical evacuation of hematoma with severe cerebral hernia 32 33 at super-early stage 34 patients with poor compliance 35 36 TCM,Chinese Medicine. AICH, acute intracerebral hemorrhage.CT, computed tomography; GCS, 37 Glasgow coma scale. 38 39 40 S2 Table : Full list of Principle investigators and study centers 41 Number of 42 Centre Centre address, zip code 43 Principle Investigator patients NO. 44 randomized 45 Zhangyong Xia, Rui Liaocheng People's Hospital, Liaocheng, 46 1 39 47 Zhang, Guangzeng Li Shandong Province, China, 252000 48 Guangsheng Chen, Boluo County People's Hospital, 49 2 Bochang Lin, Weiming Huizhou, Guangdong, China, 514610 32 50 51 Zhu 52 Qianshan Zhao, Richao Jiangmen Wuyi Traditional Chinese Medicine 53 3 Chen, Yongtong He Hospital, Jiangmen, Guangdong, China, 9 54 55 529000 56 Jiexia Li, Xiaomei Huang, The hospital of Chinese Medicine of Conghua 4 27 57 Mengxin Huang City, Conghua, Guangdong, China, 5109000 58 59 60
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1 2 3 Chaojun Chen, Jianfang Guangzhou Hospital of Integrated traditional 4 5 5 Hu, Peiqun Yang and west medicine, Guangzhou, Guangdong, 2 6 China, 510800 7 Yongbo Zhang, Quanliang Shouguang City People's Hospital, 8 6 21 9 Wang, Xiulan Huang Shouguang, Shandong, China, 262700 10 Gan Huang, Lianying Li, Yangjiang Hospital of Traditional Chinese 11 12 7 Yanchun Li Medicine, Yangjiang, Guangdong, China, 13 13 529500 14 Kaiyun Zhu, Ningping Liu, Panyu Hospital of Chinese Medicine 15 8 1 16 Yinghong Zhang Guangzhou, Guangdong, China, 511400 17 Saihua Luo ,Zai Liang, Lianjiang People's hospital, Lianjiang, 9 19 18 Bing QiuFor peer Guangdong,review China, 524400only 19 Guanghai Tang, Kai Zhao, Shenyang No.2 traditional Chinese medical 20 10 54 21 Guang Yang hospital, Shenyang, Liaoning, China, 110000 22 Jianbin Zhong, Simin Boji-affiliated Hospital of Sun Yat-sen 23 11 Zhong, Sijun Zhang University, zengcheng, Guangdong, China, 42 24 25 511300 26 Jianwen Guo, Liling Zeng, Guangdong Provincial Hospital of Chinese 27 12 Jing Wang Medicine, Guangzhou, Guangdong, China, 42 28 29 510120 30 Yue Wang, Wenjun Liu, Zhongshan Hospital of Hubei Province, 13 9 31 Jing Zuo Wuhan, Hubei, China,430032 32 Tao Huang, Ronming Lin, Guangzhou Charity Hospital, Guangzhou, 33 14 14 34 Qixin Zhang Guangdong, China,510000 35 36 37 S1 Fig: Study design 38 39 40 Stroke onset 0-6h 41 42 43 Screening 44 and Arriving at treating hospital 45 46 Randomization 47 48 Perform CT, Baseline NIHSS,GCS 49 ≤ 50 6 hours post stroke 51 52 No 53 Subject not consider 54 Hemorrhage? for study 55 56 Yes 57 No 58 59 Does subject meet all Subject not consider for 60 entry criteria study
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1 2 3 4 Yes 5 6 7 Randomize 8 9 10 11 Group Placebo 12 Group ICH-2 Group ICH-1 13 14 15 16 17 Perform CT ,NIHSS,GCS after 24h of onset 18 For peer review only 19 Treatment period 20 Yes 21 Perform CT, NIHSS, 22 10 days Reccurence of hemorrhage between 24h and 10-14 days 23 of onset? GCS, BI, mRS 24 25 No 26 27 Perform CT ,NIHSS,GC,BI,mRS after 10-14 days of 28 29 onset 30 Follow-up period 31 3 months 32 90 days follow-up , Perform NIHSS,GCS,BI,mRS 33 34 35 36 S1 Fig. Study design diagram. Subjects who had suffered hypertensive intracerebral hemorrhage 37 were randomized to receive placebo, ICH-1, ICH-2in a 1:1 :1ratio within 6 hours following the 38 stroke onset. The trial consisted of a screening period (up to 6 hours), followed by a randomized 39 treatment period (up to2 weeks treatment period), ending with a 3-month efficacy follow-up 40 41 period (where subjects were allowed to undergo treatment in accordance with standard clinical 42 practice).CT, computed tomography; CTA, computed tomography angiography; NIHSS, National 43 Institutes of Health Stroke Scale; mRS, modified Rankin Scale; BI, Barthel Index; GCS, Glasgow 44 45 coma scale. 46 47 S3 Table : Groups and Interventions 48 49 Groups Interventions Direction 50 51 8 herbal, including 2 herbals of RBS (Hirudo one dose, bid, by oral or 52 ICH-1 nipponica Whitman and Tabanus bivittatus nasogastric tube for 10 days 53 Matsumura) 54 6 herbals(removed the 2 herbals of RBS from the one dose, bid, by oral or 55 ICH-2 56 ICH-1 formula) nasogastric tube for 10 days 57 Placebo placebo herbal medicine (with dextrin, farina and one dose, bid, by oral or 58 Comparator so on) nasogastric tube for 10 days 59 60
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1 2 3 *RBS, removing blood stasis. 4 5 6 S4 Table: Composition of the ICH-1formula 7 8 Plant/animal TCM ID Condition dosage(gram) dosage form 9 parts included 10 11 Hirudo nipponica entire body dry 1.0 granules 12 Whitman 13 Tabanus bivittatus 14 entire body dry 1.0 granules 15 Matsumura 16 17 Rheum officinale Baill rhizome dry 1.5 granules 18 For peer review only 19 Typha angustifolia L pollen dry 1.5 granules 20 21 Trichosanthes seed dry 1.5 granules 22 kirilowii Maxim. 23 Panax notoginseng 24 rhizome dry 1.0 granules 25 （Burk.）F. H. Chen 26 Acorus tatarinowii 27 rhizome dry 1.0 granules 28 Schott 29 Chinemys reevesii 30 shell dry 1.5 granules 31 (Gray) 32 33 34 35 S5 Table : All primary, secondary and safety endpoints 36 37 Primary 38 Hematoma enlargement:the percent change in the volume of hematoma at 24 hours,on 10-14th day 39 40 Secondary 41 Between-group differences in the NIHSS at 3 months 42 Mortality on the 10th-14th day, 3 months 43 44 Poor prognosis popularly as defined by mRS score≥5 at 3 months 45 Adverse events 46 NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin Scale. 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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Checklist of Items for Reporting Trials of Chinese Herbal Medicine Formulas* 1 2 Section/Topic Item Standard CONSORT Checklist Item Extension for CHM Formulas 珈ਤ⊀ʤ㦠珈⁀ 3 4 Number ⊀R Page 5 Number 6 7 8 Title, abstract, and 1a I⁀珈R㦠ifica㦠i⊀R as a ʤaR⁀⊀miz珈⁀ 㦠ʤial iR 㦠h珈 㦠i㦠l珈 Statement of whether the trial targets a TCM Pa㦠㦠珈ʤR, a Western P1 9 keywords medicine–defined disease, or a Western medicine–defined disease with a 10 11 specific TCM Pa㦠㦠珈ʤR, if applicable 12 For peer review only 13 1b S㦠ʤuc㦠uʤ珈⁀ summaʤy ⊀f 㦠ʤial ⁀珈sigR, m珈㦠h⊀⁀s, ʤ珈sul㦠s, aR⁀ c⊀Rclusi⊀Rs Illustration of the name and form of the formula used, and the TCM P1-3 14 (f⊀ʤ sਤ珈cific gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ abs㦠ʤac㦠s [26, 27]) Pa㦠㦠珈ʤR applied, if applicable 15 16 17 1c Determination of appropriate keywords, including “Chinese herbal P3 18 medicine formula” and “randomized controlled trial” 19 20 Introduction 21 22 23 Backgʤ⊀uR⁀ aR⁀ 2a Sci珈R㦠ific backgʤ⊀uR⁀ aR⁀ 珈xਤlaRa㦠i⊀R ⊀f ʤa㦠i⊀Ral珈 Statement with biomedical science approaches and/or TCM approaches P4 24 ⊀bj珈c㦠iv珈s 25 2b Sਤ珈cific ⊀bj珈c㦠iv珈s ⊀ʤ hyਤ⊀㦠h珈s珈s Statement of whether the formula targets a Western medicine–defined P5 26 disease, a TCM Pa㦠㦠珈ʤR, or a Western medicine–defined disease with a 27 28 specific TCM Pa㦠㦠珈ʤR 29 30 Methods 31 32 Tʤial ⁀珈sigR 3a D珈scʤiਤ㦠i⊀R ⊀f 㦠ʤial ⁀珈sigR (such as ਤaʤall珈l, fac㦠⊀ʤial), iRclu⁀iRg P5 33 34 all⊀ca㦠i⊀R ʤa㦠i⊀ 35 36 3b Imਤ⊀ʤ㦠aR㦠 chaRg珈s 㦠⊀ m珈㦠h⊀⁀s af㦠珈ʤ 㦠ʤial c⊀mm珈Rc珈m珈R㦠 (such as P5 37 38 珈ligibili㦠y cʤi㦠珈ʤia), wi㦠h ʤ珈as⊀Rs 39 40 Paʤ㦠iciਤaR㦠s 4a Eligibili㦠y cʤi㦠珈ʤia f⊀ʤ ਤaʤ㦠iciਤaR㦠s Statement of whether participants with a specific TCM Pa㦠㦠珈ʤR were P5-6 41 recruited, in terms of 1) diagnostic criteria and 2) inclusion and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 26 of 29
1 exclusion criteria. All criteria used should be universally recognized, or 2 reference given to where detailed explanation can be found. 3 4 5 4b S珈㦠㦠iRgs aR⁀ l⊀ca㦠i⊀Rs wh珈ʤ珈 㦠h珈 ⁀a㦠a w珈ʤ珈 c⊀ll珈c㦠珈⁀ P6 6 7 IR㦠珈ʤv珈R㦠i⊀Rs 5 Th珈 iR㦠珈ʤv珈R㦠i⊀Rs f⊀ʤ 珈ach gʤ⊀uਤ wi㦠h suffici珈R㦠 ⁀珈㦠ails 㦠⊀ all⊀w Description(s) for different types of formulas should include the P6-8 8 ʤ珈ਤlica㦠i⊀R, iRclu⁀iRg h⊀w aR⁀ wh珈R 㦠h珈y w珈ʤ珈 ac㦠ually a⁀miRis㦠珈ʤ珈⁀ following: 9 10 5a. For fixed CHM formulas 11 1. Name, source, and dosage form (e.g., decoctions, granules, 12 For peer review only 13 powders) 14 2. Name, source, processing method, and dosage of each medical 15 16 substance. Names of substances should be presented in at least 2 17 languages: Chinese (PiRyiR), Latin, or English. Names of the parts of 18 19 the substances used should be specified. 20 3. Authentication method of each ingredient and how, when, where, 21 22 and by whom it was conducted; statement of whether any voucher 23 specimen was retained, and if so, where they were kept and whether 24 25 they are accessible 26 4. Principles, rationale, and interpretation of forming the formula 27 28 5. Reference(s) as to the efficacy of the formula, if any 29 6. Pharmacologic study results of the formula, if any 30 31 7. Production method of the formula, if any 32 8. Quality control of each ingredient and of the product of the 33 34 formula, if any. This would include any quantitative and/or 35 qualitative testing method(s); when, where, how, and by whom these 36 37 tests were conducted; whether the original data and samples were 38 kept, and, if so, whether they are accessible. 39 40 9. Safety assessment of the formula, including tests for heavy metals 41 and toxic elements, pesticide residues, microbial limit, and 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 27 of 29 BMJ Open
1 acute/chronic toxicity, if any. If yes, it should be stated when, where, 2 how, and by whom these tests were conducted; if the original data 3 4 and samples were kept; and, if so, whether they are accessible. 5 10. Dosage of the formula, and how the dosage was determined 6 7 11. Administration route (e.g., oral, external) 8 5b. For individualized CHM formulas 9 10 1. See recommendations 5a 1–11 11 2. Additional information: how, when, and by whom the formula was 12 For peer review only 13 modified 14 5c. For patent proprietary CHM formulas 15 16 1. Reference to publicly available materials, such as pharmacopeia, 17 for the details about the composition, dosage, efficacy, safety, and 18 19 quality control of the formula 20 2. Illustration of the details of the formula, namely 1) the proprietary 21 22 product name (i.e., brand name), 2) name of manufacturer, 3) lot 23 number, 4) production date and expiry date, 5) name and percentage 24 25 of added materials, and 6) whether any additional quality control 26 measures were conducted 27 28 3. Statement of whether the patent proprietary formula used in the 29 trial is for a condition that is identical to the publicly available 30 31 reference 32 5d. Control groups 33 34 Placebo control 35 1. Name and amount of each ingredient 36 37 2. Description of the similarity of placebo with the intervention 38 (e.g., color, smell, taste, appearance, packaging) 39 40 3. Quality control and safety assessment, if any 41 4. Administration route, regimen, and dosage 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 28 of 29
1 5. Production information: where, when, how, and by whom the 2 placebo was produced 3 4 Active control 5 1. If a CHM formula was used, see recommendations 5a–5c 6 7 2. If a chemical drug was used, see item 5 of the CONSORT 8 Statement (24) 9 10 11 Ou㦠c⊀m珈s 6a C⊀mਤl珈㦠珈ly ⁀珈fiR珈⁀, ਤʤ珈sਤ珈cifi珈⁀ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈 Illustration of outcome measures with Pa㦠㦠珈ʤR in detail P8-9 12 m珈asuʤ珈s, iRclu⁀iRgFor h⊀w aR⁀ wh珈R peer 㦠h珈y w珈ʤ珈 ass珈ss珈⁀ review only 13 14 6b ARy chaRg珈s 㦠⊀ 㦠ʤial ⊀u㦠c⊀m珈s af㦠珈ʤ 㦠h珈 㦠ʤial c⊀mm珈Rc珈⁀, wi㦠h ʤ珈as⊀Rs P8-9 15 16 17 Samਤl珈 siz珈 7a H⊀w samਤl珈 siz珈 was ⁀珈㦠珈ʤmiR珈⁀ P10 18 19 7b Wh珈R aਤਤlicabl珈, 珈xਤlaRa㦠i⊀R ⊀f aRy iR㦠珈ʤim aRalys珈s aR⁀ s㦠⊀ਤਤiRg 20 gui⁀珈liR珈s 21 22 23 aR⁀⊀miza㦠i⊀R 24 25 S珈qu珈Rc珈 8a M珈㦠h⊀⁀ us珈⁀ 㦠⊀ g珈R珈ʤa㦠珈 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 P6 26 g珈R珈ʤa㦠i⊀R 27 8b Tyਤ珈 ⊀f ʤaR⁀⊀miza㦠i⊀R; ⁀珈㦠ails ⊀f aRy ʤ珈s㦠ʤic㦠i⊀R (such as bl⊀ckiRg aR⁀ P6 28 29 bl⊀ck siz珈) 30 31 All⊀ca㦠i⊀R 9 M珈chaRism us珈⁀ 㦠⊀ imਤl珈m珈R㦠 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈 (such P6 32 c⊀Rc珈alm珈R㦠 as s珈qu珈R㦠ially Rumb珈ʤ珈⁀ c⊀R㦠aiR珈ʤs), ⁀珈scʤibiRg aRy s㦠珈ਤs 㦠ak珈R 㦠⊀ 33 34 m珈chaRism c⊀Rc珈al 㦠h珈 s珈qu珈Rc珈 uR㦠il iR㦠珈ʤv珈R㦠i⊀Rs w珈ʤ珈 assigR珈⁀ 35 36 Imਤl珈m珈R㦠a㦠i⊀R 10 Wh⊀ g珈R珈ʤa㦠珈⁀ 㦠h珈 ʤaR⁀⊀m all⊀ca㦠i⊀R s珈qu珈Rc珈, wh⊀ 珈Rʤ⊀ll珈⁀ P6-8 37 38 ਤaʤ㦠iciਤaR㦠s, aR⁀ wh⊀ assigR珈⁀ ਤaʤ㦠iciਤaR㦠s 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs 39 40 BliR⁀iRg 11a If ⁀⊀R珈, wh⊀ was bliR⁀珈⁀ af㦠珈ʤ assigRm珈R㦠 㦠⊀ iR㦠珈ʤv珈R㦠i⊀Rs (f⊀ʤ P6 41 珈xamਤl珈, ਤaʤ㦠iciਤaR㦠s, caʤ珈 ਤʤ⊀vi⁀珈ʤs, 㦠h⊀s珈 ass珈ssiRg ⊀u㦠c⊀m珈s) aR⁀ 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 29 of 29 BMJ Open
1 h⊀w 2 3 11b If ʤ珈l珈vaR㦠, ⁀珈scʤiਤ㦠i⊀R ⊀f 㦠h珈 similaʤi㦠y ⊀f iR㦠珈ʤv珈R㦠i⊀Rs P6-7 4 5 S㦠a㦠is㦠ical 12a S㦠a㦠is㦠ical m珈㦠h⊀⁀s us珈⁀ 㦠⊀ c⊀mਤaʤ珈 gʤ⊀uਤs f⊀ʤ ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy P9-10 6 7 m珈㦠h⊀⁀s ⊀u㦠c⊀m珈s 8 9 12b M珈㦠h⊀⁀s f⊀ʤ a⁀⁀i㦠i⊀Ral aRalys珈s, such as subgʤ⊀uਤ aRalys珈s aR⁀ P9-10 10 11 a⁀jus㦠珈⁀ aRalys珈s 12 For peer review only 13 Results 14 15 Paʤ㦠iciਤaR㦠 fl⊀w 13a F⊀ʤ 珈ach gʤ⊀uਤ, 㦠h珈 Rumb珈ʤs ⊀f ਤaʤ㦠iciਤaR㦠s wh⊀ w珈ʤ珈 ʤaR⁀⊀mly P11-13 16 17 (a ⁀iagʤam is assigR珈⁀, ʤ珈c珈iv珈⁀ iR㦠珈R⁀珈⁀ 㦠ʤ珈a㦠m珈R㦠, aR⁀ w珈ʤ珈 aRalyz珈⁀ f⊀ʤ 㦠h珈 18 s㦠ʤ⊀Rgly ਤʤimaʤy ⊀u㦠c⊀m珈 19 20 ʤ珈c⊀mm珈R⁀珈⁀) 13b F⊀ʤ 珈ach gʤ⊀uਤ, l⊀ss珈s aR⁀ 珈xclusi⊀Rs af㦠珈ʤ ʤaR⁀⊀miza㦠i⊀R, 㦠⊀g珈㦠h珈ʤ P11-13 21 22 wi㦠h ʤ珈as⊀Rs 23 24 珈cʤui㦠m珈R㦠 14a Da㦠珈s ⁀珈fiRiRg 㦠h珈 ਤ珈ʤi⊀⁀s ⊀f ʤ珈cʤui㦠m珈R㦠 aR⁀ f⊀ll⊀w-uਤ P7 25 26 14b Why 㦠h珈 㦠ʤial 珈R⁀珈⁀ ⊀ʤ was s㦠⊀ਤਤ珈⁀ P22 27 28 29 Bas珈liR珈 ⁀a㦠a 15 A 㦠abl珈 sh⊀wiRg bas珈liR珈 ⁀珈m⊀gʤaਤhic aR⁀ cliRical chaʤac㦠珈ʤis㦠ics f⊀ʤ P13-14 30 珈ach gʤ⊀uਤ 31 32 Numb珈ʤs 16 F⊀ʤ 珈ach gʤ⊀uਤ, Rumb珈ʤ ⊀f ਤaʤ㦠iciਤaR㦠s (⁀珈R⊀miRa㦠⊀ʤ) iRclu⁀珈⁀ iR 珈ach P14-17 33 34 aRalyz珈⁀ aRalysis aR⁀ wh珈㦠h珈ʤ 㦠h珈 aRalysis was by ⊀ʤigiRal assigR珈⁀ gʤ⊀uਤs 35 36 Ou㦠c⊀m珈s aR⁀ 17a F⊀ʤ 珈ach ਤʤimaʤy aR⁀ s珈c⊀R⁀aʤy ⊀u㦠c⊀m珈, ʤ珈sul㦠s f⊀ʤ 珈ach gʤ⊀uਤ, aR⁀ P14-17 37 38 珈s㦠ima㦠i⊀R 㦠h珈 珈s㦠ima㦠珈⁀ 珈ff珈c㦠 siz珈 aR⁀ i㦠s ਤʤ珈cisi⊀R (such as 95% c⊀Rfi⁀珈Rc珈 39 iR㦠珈ʤval) 40 41 17b F⊀ʤ biRaʤy ⊀u㦠c⊀m珈s, ਤʤ珈s珈R㦠a㦠i⊀R ⊀f b⊀㦠h abs⊀lu㦠珈 aR⁀ ʤ珈la㦠iv珈 珈ff珈c㦠 P14-17 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 30 of 29
1 siz珈s is ʤ珈c⊀mm珈R⁀珈⁀ 2 3 ARcillaʤy 18 珈sul㦠s ⊀f aRy ⊀㦠h珈ʤ aRalys珈s ਤ珈ʤf⊀ʤm珈⁀, iRclu⁀iRg subgʤ⊀uਤ aRalys珈s P17 4 5 aRalys珈s aR⁀ a⁀jus㦠珈⁀ aRalys珈s, ⁀is㦠iRguishiRg ਤʤ珈sਤ珈cifi珈⁀ fʤ⊀m 珈xਤl⊀ʤa㦠⊀ʤy 6 7 Haʤms 19 All imਤ⊀ʤ㦠aR㦠 haʤms ⊀ʤ uRiR㦠珈R⁀珈⁀ 珈ff珈c㦠s iR 珈ach gʤ⊀uਤ (f⊀ʤ sਤ珈cific (There is no extension for this item) P15-17 8 gui⁀aRc珈, s珈珈 CONSO T f⊀ʤ haʤms [28]) 9 10 11 Discussion 12 For peer review only 13 Limi㦠a㦠i⊀Rs 20 Tʤial limi㦠a㦠i⊀Rs; a⁀⁀ʤ珈ssiRg s⊀uʤc珈s ⊀f ਤ⊀㦠珈R㦠ial bias; imਤʤ珈cisi⊀R; aR⁀, P22 14 if ʤ珈l珈vaR㦠, mul㦠iਤlici㦠y ⊀f aRalys珈s 15 16 17 G珈R珈ʤalizabili㦠y 21 G珈R珈ʤalizabili㦠y (珈x㦠珈ʤRal vali⁀i㦠y, aਤਤlicabili㦠y) ⊀f 㦠h珈 㦠ʤial fiR⁀iRgs Discussion of how the formula works on different TCM Pa㦠㦠珈ʤRs or P20-21 18 diseases 19 20 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R 22 IR㦠珈ʤਤʤ珈㦠a㦠i⊀R c⊀Rsis㦠珈R㦠 wi㦠h ʤ珈sul㦠s, balaRciRg b珈R珈fi㦠s aR⁀ haʤms, Interpretation with TCM theory P17-21 21 22 aR⁀ c⊀Rsi⁀珈ʤiRg ⊀㦠h珈ʤ ʤ珈l珈vaR㦠 珈vi⁀珈Rc珈 23 24 Other information 25 26 珈gis㦠ʤa㦠i⊀R 23 珈gis㦠ʤa㦠i⊀R Rumb珈ʤ aR⁀ Ram珈 ⊀f 㦠ʤial ʤ珈gis㦠ʤy P2 27 28 29 Pʤ⊀㦠⊀c⊀l 24 Wh珈ʤ珈 㦠h珈 full 㦠ʤial ਤʤ⊀㦠⊀c⊀l caR b珈 acc珈ss珈⁀, if availabl珈 P5 30 31 FuR⁀iRg 25 S⊀uʤc珈s ⊀f fuR⁀iRg aR⁀ ⊀㦠h珈ʤ suਤਤ⊀ʤ㦠 (such as suਤਤly ⊀f ⁀ʤugs), ʤ⊀l珈 ⊀f P10 32 33 fuR⁀珈ʤs 34 35 CHM = ChiR珈s珈 h珈ʤbal m珈⁀iciR珈; CONSO T = C⊀Rs⊀li⁀a㦠珈⁀ S㦠aR⁀aʤ⁀s ⊀f 珈ਤ⊀ʤ㦠iRg Tʤials; TCM = 㦠ʤa⁀i㦠i⊀Ral ChiR珈s珈 m珈⁀iciR珈. 36 * Th珈 ⊀ʤigiRal CONSO T i㦠珈ms aʤ珈 ਤʤ⊀vi⁀珈⁀; 珈lab⊀ʤa㦠i⊀Rs f⊀ʤ CHM f⊀ʤmulas aʤ珈 iR i㦠aliciz珈⁀ 㦠珈x㦠. W珈 s㦠ʤ⊀Rgly ʤ珈c⊀mm珈R⁀ ʤ珈a⁀iRg 㦠his ch珈cklis㦠 iR c⊀RjuRc㦠i⊀R wi㦠h 㦠h珈 CONSO T 2010 37 38 ExਤlaRa㦠i⊀R aR⁀ Elab⊀ʤa㦠i⊀R (29) f⊀ʤ imਤ⊀ʤ㦠aR㦠 claʤifica㦠i⊀Rs ⊀R all ⊀ʤigiRal i㦠珈ms ⊀f CONSO T S㦠a㦠珈m珈R㦠. 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60