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Effects of acupuncture for constipation in Parkinson's disease：study protocol for a multi-centre randomised controlled trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029841
Article Type: Protocol
Date Submitted by the 14-Feb-2019 Author:
Complete List of Authors: Li, kunshan; Shanghai University of Traditional Chinese Medicine, Xu, Shifen; Shanghai University of Traditional Chinese Medicine Wang, Zhaoqin; Shanghai University of Traditional Chinese Medicine Chen, Yiyi; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine Shen, Lirong; Shanghai Pudong New Area Hospital of Chinese Medicine Li, Zhongqiu; Shanghai University of Traditional Chinese Medicine Wu, Yiwen; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Yuan, Canxing; Longhua Hospital, Shanghai University of Traditional Chinese Medicine Huang, Yan; Key Laboratory of Acupuncture and Immunological Effects,
Shanghai University of Traditional Chinese Medicine http://bmjopen.bmj.com/ Wu, Luyi; Shanghai University of Traditional Chinese Medicine Bao, Chunhui; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine Wu, Huangan; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine
Constipation, Parkinson's disease, Acupuncture, Randomised controlled Keywords: trial
on September 27, 2021 by guest. Protected copyright.
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Effects of acupuncture for constipation in Parkinson's 5 6 disease ： study protocol for a multi-centre randomised 7 8 9 controlled trial 10 11 Kunshan Li,1* Shifen Xu,2* Zhaoqin Wang,1* Yiyi Chen,3 Lirong Shen,4 Zhongqiu Li,1 12 13 Yiwen Wu,5 Canxing Yuan,6 Yan Huang,7 Luyi Wu,1 Chunhui Bao,7 Huangan Wu3 14 15 16 17 18 Author affiliationsFor peer review only 19 20 1 21 Shanghai University of Traditional Chinese Medicine, Shanghai, China 22 23 2Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University 24 25 of Traditional Chinese Medicine, Shanghai, China 26 27 3 28 Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, 29 Shanghai University of Traditional Chinese Medicine, Shanghai, China 30 31 32 4Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai, China 33 34 5Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 35 36 China
37 http://bmjopen.bmj.com/ 38 6 39 Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 40 China 41 42 43 7 Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of 44 Traditional Chinese Medicine, Shanghai, China
45 on September 27, 2021 by guest. Protected copyright. 46 47 * Kunshan Li, Shifen Xu and Zhaoqin Wang contributed equally to this paper 48 49 50 51 52 Corresponding author: 53 54 55 Professor Huangan Wu,Yueyang Hospital of Integrated Traditional Chinese and 56 57 Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 58 110,Gan he road, Shanghai, China 59 60
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1 2 3 Tel: (021) 64644238 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Email: [email protected] 7 8 9 10 11 Co-authors: 12 13 14 Kunshan Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 15 Email: [email protected] 16 17 18 Shifen Xu: ShanghaiFor Municipal peer Hospital review of Traditional only Chinese Medicine, Shanghai 19 20 University of Traditional Chinese Medicine, Shanghai, China; 21 22 Email: [email protected] 23 24 25 Zhaoqin Wang: Shanghai University of Traditional Chinese Medicine, Shanghai, 26 China; 27 28 29 Email: [email protected] 30 31 Yiyi Chen: Department of Acupuncture-Moxibustion, Yueyang Hospital of Integrated 32 33 Traditional Chinese and Western Medicine, Shanghai University of Traditional 34 35 Chinese Medicine, Shanghai, China; 36
37 http://bmjopen.bmj.com/ 38 Email: [email protected] 39 40 Lirong Shen: Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai, 41 42 China; 43 44 Email: [email protected]
45 on September 27, 2021 by guest. Protected copyright. 46 47 Zhongqiu Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 48 49 Email: [email protected] 50 51 52 Yiwen Wu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 53 54 Shanghai, China; 55 56 Email:[email protected] 57 58 59 Canxing Yuan: Department of Neurology, Longhua Hospital, Shanghai University of 60
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1 2 3 Traditional Chinese Medicine, Shanghai, China; BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Email: [email protected] 7 8 Yan Huang: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 9 10 University of Traditional Chinese Medicine, Shanghai, China; 11 12 13 Email: [email protected] 14 15 Luyi Wu: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 16 17 18 Email:[email protected] peer review only 19 20 Chunhui Bao: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 21 22 University of Traditional Chinese Medicine, Shanghai, China; 23 24 Email:[email protected] 25 26 27 28 29 Version: 10-February- 2019 30 31 32 33 34 Word count: 4256 35 36 Keywords: Constipation; Parkinson's disease; Acupuncture; Randomised controlled
37 http://bmjopen.bmj.com/ 38 trial 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Introduction Constipation is one of the most common non-motor symptoms (NMSs) 7 8 in Parkinson's disease (PD). Medical treatment often targets the motor symptoms and 9 less attention is paid to the NMSs. Acupuncture has a certain effect on chronic 10 11 functional constipation and PD, but the clinical efficacy and safety for constipation in 12 13 PD have not yet been confirmed by high-quality clinical studies. Therefore, this study 14 is to evaluate the efficacy and safety of electroacupuncture (EA) for constipation in 15 16 PD. 17 18 For peer review only 19 Methods and analysis This study is a multi-center randomised controlled trial 20 (RCT). 126 constipation in PD patients will be randomly divided into intervention 21 22 group (received 12 weeks of EA + usual care) or waitlist control group (received 12 23 24 weeks of usual care). EA will be administered 3 times per week for weeks 1-8, 2 25 26 times per week for weeks 9-10, and 1 time for weeks 11-12. The primary outcome is 27 the change from baseline in mean spontaneous bowel movements (SBMs) per week in 28 29 weeks 8-9. The secondary outcomes are the change from baseline in mean SBMs 30 31 (excluding weeks 8-9), bowel movements, stool consistency, and straining score per 32 33 week. Defecation drugs used per week, Visual Analogue Scale, Sections II and III of 34 the Unified Parkinson Disease Rating Scale and the time and number of steps required 35 36 to walk 20 meters are also be observed. Efficacy is assessed in both groups at
37 http://bmjopen.bmj.com/ 38 baseline, week 4, week 8, and week 12. The intervention group also undergoes 39 efficacy evaluation during the follow-up period (week 16 and week 24). Adverse 40 41 events are reported. 42 43 44 Ethics and dissemination Ethics approval was obtained from the Ethical Review
45 Board in January 2019. The results of the study will be published in peer-reviewed on September 27, 2021 by guest. Protected copyright. 46 47 journals and will be disseminated through national and international conferences. 48 49 50 Trial registration number ChiCTR1900021053; Pre-results. 51 52 53 54 55 ARTICLE SUMMARY 56 57 Strengths and limitations of this study 58 59 60 This study is one of the rare RCT studies to observe the clinical efficacy of EA in
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1 2 3 the treatment of constipation in Parkinson's disease, and randomisation and BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 allocation concealment methods will be applied with data collectors and 6 7 statisticians blinded. 8 9 In order to optimize the authenticity and generalizability of the research results, a 10 11 multi-center trial is set up in this study, which will include 4 Tertiary A Hospitals 12 13 from Shanghai, China. 14 15 In addition to evaluating the clinical efficacy of EA in the treatment of 16 17 constipation in PD, this study also observed if EA can improve motor symptoms 18 For peer review only 19 of PD and its safety in this disease. 20 21 In this study the sham EA group is not established, so without blinding patients, it 22 23 can’t rule out the placebo effect of EA treatment. 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 With the global trends in aging, the incidence of Parkinson's disease (PD) is 7 8 increasing, and the prevalence rate of people with this disease over 65 years old is 9 1-3%.1 2 Previous studies often focused on the adjustment of motor symptoms in PD, 10 11 but in recent years, non-motor symptoms (NMSs) have received much attention. 12 3 13 Studies have shown that some NMSs can occur earlier than motor symptoms, 14 seriously affecting the patients’ quality of life. Constipation, as one of the most 15 16 common and earliest occurrence of NMSs, has been shown to occur as high as 80% in 17 18 PD,4-6 and 50% Forof patients peer have constipation review symptoms only 10 to 20 years before motor 19 7 20 symptoms occur. Moreover, studies indicate that constipation may be one of the risk 21 factors for PD. Several studies find that men or women afflicted with constipation (3 22 23 or fewer bowel movements per week) will be 2-5 times more likely to be diagnosed 24 25 with PD in the future than those who are without constipation.8-10 Drugs for treating 26 27 PD, such as dopamine agonists, anticholinergics and catechol-oxyl-methyltransferase 28 inhibitors, which are commonly used in clinical practice, can lead to a decrease in 29 30 intestinal motor function, thereby aggravating constipation symptoms. 31 32 33 The main cause of constipation in PD is slowed colonic transit or pelvic floor 34 35 and anal sphincter dysfunction.11 Therefore, the treatment of constipation in PD is 36
37 usually used laxative or prokinetic drugs. But in long-term treatment, http://bmjopen.bmj.com/ 38 39 treatment-related adverse events increased significantly. About 50% of patients are 40 41 dissatisfied with these drugs mainly due to their efficacy, inconsistent response to 42 43 constipation symptoms and adverse events.12 44
45 on September 27, 2021 by guest. Protected copyright. 46 A long-term practice in China, in recent decades, acupuncture’s efficacy has also 47 48 become increasingly popular in the world. Studies have shown that acupuncture can 49 13 14 50 improve stool frequency and stool consistency in functional constipation. In 51 15 16 52 addition, acupuncture also can slow down the development of PD to some extent, 53 54 especially in reducing the adverse reactions of medicine and improving non-motor 55 17-19 56 symptoms. But we have not yet found a high quality RCT study on acupuncture 57
58 treatment for constipation in PD. 59 60 Electroacupuncture (EA) as one of acupuncture therapies, combines acupuncture
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1 2 3 with electrical stimulation, conducts a small amount of electric current close to the BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 body's bioelectricity on the needle to treat diseases. The advantage of EA therapy is 6 7 that it can objectively control the amount of stimuli, and the frequency and intensity 8 of stimuli are more repeatable, ensuring that participants in clinical studies receive 9 10 similar stimuli. In addition, as a form of acupuncture, EA is often used to treat 11 12 constipation and PD.14 15 19 Based on our previous preliminary studies, we find 13 14 acupuncture treatment can improve the symptoms of constipation in Parkinson's 15 disease.20 Therefore, this study observed the efficacy of EA in treating constipation in 16 17 PD through a multi-center randomised controlled trial (RCT), in order to clarify the 18 For peer review only 19 feasibility and advantages of acupuncture treatment on constipation in PD. 20 21 22 23 24 METHODS AND ANALYSIS 25 26 Hypotheses 27 28 29 Compared with usual care (UC) alone (PD basic therapy + emergency defecation 30 31 medicine), EA + UC will increase the frequency of SBMs, improve stool consistency 32 33 and straining, and delay the progression of motor symptoms in PD. 34 35 36
37 http://bmjopen.bmj.com/ 38 Objectives 39 40 (1) By assessing the change from baseline in mean SBMs, BMs and the mean 41 42 frequency and dosage of emergency defecation drugs used according to the stool 43 44 diary per week to compare the improvement of the number of defecation between the
45 two groups. on September 27, 2021 by guest. Protected copyright. 46 47 48 (2) The difference of defecation status between the two groups are compared by 49 50 assessing VAS (the improvement of patient's Subjective stool symptoms) and the 51 change from baseline in mean stool consistency (according to Bristol Stool Form 52 53 Scale score), straining per week. 54 55 56 (3) The motor symptoms and quality of life of PD are compared between the 2 groups 57 by the UPDRS and the time and number of steps required to walk 20 meters. 58 59 60
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1 2 3 Study design BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 This study is a multi-center, data collector and statisticians blinded parallel 7 8 randomised controlled trial. It is estimated that 126 patients will be recruited and 9 randomly divided into intervention group (EA+UC) and waitlist control group (UC 10 11 alone) according to the ratio of 1:1 using hierarchical random method of variable 12 13 region. The participates in the 2 groups were treated for 12 weeks, and the 14 intervention group also received 12 weeks of follow-up. The flow chart of the trial is 15 16 shown in Figure 1. The research process and data collection are detailed in Table 1 17 18 and Figure 2. For peer review only 19 20 Table 1 Schedule of enrollment, interventions and assessments 21 22 23 24 Study period Enrollment Intervention period Follow-up period 25 Visit 1 2 3 4 5 6 26 27 Time point Week -2 0 Point Week 4 Week 8 Week 12 Week 16 Week 24 28 Basic information × 29 Medical history × 30 31 PD present history × 32 33 Constipation present history × Fill in the basic 34 information 35 H&Y stage × 36 Urine pregnancy test ×
37 http://bmjopen.bmj.com/ 38 MMSE × Classification of motor 39 × 40 symptoms in PD 41 42 Inclusion criteria × 43 Exclusion criteria × × 44 Sign consents ×
45 on September 27, 2021 by guest. Protected copyright. 46 Randomization × 47 Primary SBMs per week × × × × × × 48 outcome 49 (in the stool diary*) 50 BMs per week × × × × × × 51 52 (in the stool diary*) Stool consistency 53 Secondary × × × × × × 54 outcomes (in the stool diary*) 55 Straining × × × × × × 56 (in the stool diary*) 57 Emergency defecation drugs 58 Usage × × × × × × 59 60 (in the stool diary*)
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1 2
3 UPDRS-Ⅱ and UPDRS-Ⅲ × × × × BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Gait Speed (20 meter walk) × × × × 6 VAS × × × × × × 7 Intervention group × × × × × 8 AEs 9 Waitlist control group × × × 10 11 Compliance evaluation × 12 H&Y stage, Hoehn-Yahr stage; MMSE, Mini-mental State Examination; SBMs, spontaneous bowel movements; 13 14 BMs, bowel movements; VAS, Visual Analogue Scale; AEs, adverse events. 15 * 16 The stool diary records the patient's stool for 2 weeks. Therefore, each stool diary recording time is -2-0 weeks, 17 4-5weeks, 8-9weeks, 12-13 weeks, 16-17 weeks, and 23-24weeks. 18 For peer review only 19 20 21 22 Recruitment, setting and participants 23 24 The trial will be conducted at Yueyang Hospital of Integrated Traditional Chinese and 25 26 Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of Traditional 27 28 Chinese Medicine, Shuguang Hospital, which are all affiliated to Shanghai University 29 of Traditional Chinese Medicine. Potential will be recruited through publishing 30 31 newspapers, or posting recruitment notice on official network information platform 32 33 and bulletin board of each study site. Interested participants can contact the 34 35 researchers through the provided telephone numbers. After being informed of this 36 study protocol, voluntary participants are asked to sign consent forms, and
37 http://bmjopen.bmj.com/ 38 participants who meet the inclusion criteria will begin participation in the RCT. 39 40 Ethical approval and Clinical trial registration will be needed to obtain before 41 participants recruitment begins. 42 43 44 To be included in the trial, participants must meet the following criteria:
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 Inclusion criteria 50 51 52 The inclusion criteria are: (1) diagnosis of Parkinson’s disease according to the UK 53 Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria;21 (2) meeting 54 55 the diagnostic criteria of Roman IV diagnostic criteria for functional constipation;22 56 57 (3) aged between 40 and 80 years; (4) the course of PD is ≥6 months, and the course 58 # 59 of constipation is ≥3 months; (5) the number of SBMs per week <3 times ; (6) those 60
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1 2 3 who are not satisfied with current constipation treatment or who have not yet received BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 constipation treatment; (7) the Hoehn-Yahr (H&Y) stage belonging to 1-4; (8) those 6 7 who voluntarily participate in the study, willing receive relevant examinations and 8 treatments, and sign informed consent. 9 10 11 # The participants who does not meet the condition can be excluded according to the patient's -2-0 weeks stool 12 diary record. 13 14 15 16 17 Exclusion criteria 18 For peer review only 19 The exclusion criteria are: (1) patients with serious cardiovascular and 20 21 cerebrovascular diseases, hematopoietic diseases, malignant tumors or other serious 22 23 life-threatening diseases; (2) patients who have been diagnosed as schizophrenia, 24 major depression, or major depression (Mini-mental State Examination (MMSE): the 25 26 illiterate educational level is < 14 scores, the primary school educational level is < 20 27 28 scores, or the secondary school and above educational level is < 24 scores); (3) 29 patients with a history of laparotomy or anorectal surgery (except for hemorrhoid 30 31 surgery, one year after appendectomy, inguinal hernia repair) that may affect 32 33 intestinal transit; (4) patients who have been diagnosed with anal tumors, 34 35 malformations, suspected intestinal obstruction or other organic diseases leading to 36 constipation; (5) patients who can not be treated with EA with acupuncture points in
37 http://bmjopen.bmj.com/ 38 this study due to skin diseases, limb defects, or other conditions; (6) patients who 39 40 have received other clinical trials or acupuncture treatments within 30 days before 41 42 treatments which may affect the results of this study; (7) patients with acute 43 gastrointestinal disease within 2 weeks before treatments; (8) patients taking 44
45 antidepressants, analgesics, or antihistamines that affect PD symptoms within 2 weeks on September 27, 2021 by guest. Protected copyright. 46 47 before treatments; (9) pregnant or lactating women (female patients under 60 years 48 age need undergo urine pregnancy test). 49 50 51 52 53 54 Randomization and allocation concealment 55 56 Patients are randomly assigned to the intervention group or the waitlist control group 57 58 according to a 1:1 ratio using stratified random method with a variable block. The 59 60 stratification factors consider 2 aspects: (1) the severity of constipation (SBMs weekly
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1 2 3 = 2 times or SBMs weekly< 2 times); (2) study site. Independent statisticians provide BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 computer-generated random sequences and implement distribution through a central 6 7 web-based interactive randomization service system. 8 9 10 11 12 Blinding 13 14 This trial is not blind to patients and acupuncturists, but data collectors and 15 16 statisticians need to complete data collection or statistical analysis in a blind state. 17 18 Neither party knowFor the peer specific study review protocol nor patientsonly group. For better blind 19 20 evaluation, each sub-center has one acupuncturist and one data collector, the data 21 collection location is independent of the treatment room. More than that, data 22 23 collector will be given the relevant scale of this assessment every time they make the 24 25 assessment, and then the scale will be handed over to the supervisor of the 26 project team after each assessment. Patients and acupuncturists are advised not to 27 28 disclose the patient's grouping to the data collectors at any point during the trial. An 29 30 independent statistician will conduct the statistical analysis of the results. 31 32 33 34 35 Interventions 36
37 http://bmjopen.bmj.com/ 38 In the 12 weeks treatment period, both groups received UC, and participants 39 randomised to the intervention group will also receive EA. 40 41 42 43 44 UC treatment in both groups
45 on September 27, 2021 by guest. Protected copyright. 46 47 Treatment of PD 48 49 50 Considering the complexity of clinical manifestations of PD and the principles of 51 individualized treatment in PD clinical guidelines, the treatment for PD in this trial 52 53 will not be strictly standardized. However, if the participant has received PD medicine 54 55 treatment before enrollment, the treatment of medicine should not be changed 56 arbitrarily. The dose of different drugs can be converted to a total daily levodopa 57 58 equivalent dose (LED) according to the equivalence theory of levodopa.23 59 60
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1 2
3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Emergency treatment for constipation 7 8 If the patients are without BMs for 3 or more consecutive days they are allowed to use 9 10 emergency treatment, which is provided by the researchers. There are several options 11 available to patients. For patients with no defecation urge, it is recommended to first 12 13 take lactose solution orally, under the following protocol: take 15 ml of lactose 14 15 (lactose, H20171057, Abbott Healthcare Products B.V. 15ml/bag) orally at an interval 16 17 of 12 hours; if it is ineffective, take 30 ml of Lactose solution orally on the second 18 day at an intervalFor of 12 peerhours. For patientsreview who have onlyan urge but are unable to pass 19 20 stool, 20 ml Glycerol Enema (Glycerol Enema, H31021363, Shanghai Yunjia 21 22 Huangpu Pharmaceutical Co. Ltd.; 20 ml/bottle) by anus injection is recommended. A 23 24 combination of the 2 is recommended for patients who fail to respond to emergency 25 treatment for 2 days. Patients are advised not to use any other emergency treatments. 26 27 Each use of emergency treatment will be recorded in the stool diary. If there is any 28 29 other emergency treatment medications be used, it also need to be recorded in the 30 stool diary. 31 32 33 34 35 EA add-on treatment in the intervention group 36
37 A total of 30 EA sessions will be performed over a period of 12 weeks, 3 per week for http://bmjopen.bmj.com/ 38 39 the weeks 1-8, 2 per week for the weeks 9-10, and 1 per week for the weeks 11-12. 40 41 42 The acupuncturists who provide treatment are qualified doctors with a traditional 43 Chinese medicine qualification certificate and have at least 2 years of acupuncture 44
45 experience. They are required to be registered at the Chinese Medical Doctor on September 27, 2021 by guest. Protected copyright. 46 47 Association. All acupuncturists will receive one training before starting the study. 48 Acupuncturists need to explain to the patients the EA treatment process and to 49 50 describe any possible sensations during the treatment before starting to treat. A brief 51 52 interview will be conducted before each EA treatment to record whether the patient 53 54 has had an adverse reaction since the last treatment. 55 56 Each patient in the intervention group is treated at the bilateral acupoints of 57 58 Connect Qianding (GV21) to Xuanlu (GB5), Connect Qianshencong（EX-HN1）to 59 60 Xuanli (GB6), Tianshu (ST25), Fujie (SP14), Quchi (LI11), Hegu (LI4),
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1 2 3 Yanglingquan (GB34), Shangjuxu (ST37), Sanyinjiao (SP6), Zhaohai (KI6), and BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Taichong (LR3). When the patients are supine, they are treated with Single-use 6 7 stainless steel acupuncture needles (Jia Jian). Tianshu (ST25), Fujie (SP14) are used 8 with 0.30mm×50mm or 0.30mm×75mm needles (depending on the patient's body 9 10 type), slowly and vertically, until the muscle layer of the abdominal wall is pierced, 11 12 inserted approximately 45mm-70mm. Connect Qianding (GV21) to Xuanlu (GB 5), 13 14 Connect Qianshencong (EX-HN1) to Xuanli (GB6) (each bilateral Insert 2 needles), 15 Hegu (LI4), Zhaohai (KI6), and Taichong (LR3) use 0.25mm×25mm needles, 16 17 inserted approximately 10mm-20mm. Quchi (LI11), Yanglingquan (GB34), 18 For peer review only 19 Shangjuxu (ST37), and Sanyinjiao (SP6) use 0.25mm×40mm needles, inserted 20 21 approximately 30mm-35mm. Manipulations of twirling, lifting, and thrusting are 22 performed to reach de qi, which is a unique acupuncture feeling, including the 23 24 soreness, heaviness, and distension sensation. Connect Qianding (GV21) to Xuanlu 25 26 (GB5) (tremor type) or Connect Qianshencong (EX-HN1) to Xuanli (GB6)(Stiff type) 27 (1 group is selected according to the clinical manifestations of patients' motor 28 29 symptoms), Tianshu (ST25), Fujie (SP14) connected to the EA instrument (SDZ-III 30 31 EA device, Hua Tuo, Suzhou medical equipment). Frequency is 10/50Hz. Current 32 33 intensity is 2.0mA to 6.0mA, which is programmed to whatever level the patient can 34 tolerate. EA treatment lasts for 30 min. 35 36
37 http://bmjopen.bmj.com/ 38 39 Follow-ups 40 41 Only the intervention group participants received followed up at week 16 and week 42 43 24. The intervention group is still given UC treatment during follow-up. 44
45 Outcome measures and evaluation on September 27, 2021 by guest. Protected copyright. 46 47 48 Primary outcome 49 50 The primary outcome is the change from baseline in mean spontaneous bowel 51 52 movements (SBMs) per week according to the stool diary in the weeks 8-9. SBM 53 54 means a defecation that occurred in the past 24 hours without the use of rescue drugs 55 or other methods to help with defecation. The completion of the patient's bowel 56 57 movement diary card will be explained thoroughly to participants. 58 59 60
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1 2 3 Secondary outcome BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 The secondary outcome measures include the evaluation of constipation and PD:(1) 7 8 assessment of the efficacy of constipation: the change from baseline in mean SBMs 9 (excluding the weeks 8-9), BMs, stool consistency (according to Bristol Stool Form 10 11 Scale score), and straining score per week according to the stool diary; mean 12 13 frequency and mean dosage of emergency defecation drugs used per week according 14 to the stool diary; VAS: the improvement of patient's subjective stool symptoms are 15 16 assessed. (2) assessment of the efficacy of PD: sections II and III of UPDRS: UPDRS 17 18 II is about the For activity peer of daily life; review UPDRS III is only about the motion examination 19 20 evaluation; the scale is evaluated when the patients are under the good state of drug 21 treatment. If the patients appeared "on/off", the status of the patients in the "on" stage 22 23 are assessed. The time and number of steps required to walk 20 meters: measure step 24 25 speed and average step distance. The evaluation time point is shown in detail in figure 26 27 2. 28 29 Baseline data will be collected at the first visit by independent data collector, 30 31 including patient’s basic information, medical history review, present medical history 32 33 of PD and constipation, H&Y stage, urine pregnancy test, MMSE, inclusion and 34 exclusion criteria, and classification of motor symptoms in PD, as shown in table 35 36 1.The outcome assessment at baseline, treatment, and follow-up will be assessed by
37 http://bmjopen.bmj.com/ 38 the same data collector. 39 40 41 42 43 Safety assessment 44
45 To avoid the data collectors knowing the patient's grouping, all patients report any AE on September 27, 2021 by guest. Protected copyright. 46 47 to the acupuncturists. The acupuncturists are responsible for recording all details of 48 49 the AEs, including the time and severity of the occurrence. The relationship between 50 51 AEs and intervention method will be assessed according to the Standardized Case 52 Causality Assessment of the WHO Uppsala Monitoring Center Centre System. 53 54 Common AEs of acupuncture include fainting, local ecchymoses, dizzy and so on. 55 56 The details, processing progress and results of each AE will be recorded in the case 57 report form (CRF). The severe adverse event (SAE) is determined in accordance with 58 59 the International Conference on Harmonization harmonized tripartite guideline24 and 60
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1 2 3 must be reported to the Independent Data and Safety Monitoring Board (DSMB). BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 7 8 Data collection 9 10 11 Each sub-center has 1 data collector. The data collector can only access the relevant 12 13 content of this assessment at each evaluation time, and cannot obtain the results of the 14 last evaluation. Except for the stool diary, which is filled out by the patient, the other 15 16 efficacy indicators are filled out by the data collector after the patient is assessed and 17 18 evaluated. All dataFor collector peer will receive review training to learn only how to assess UPDRS and 19 20 other scales. 21 22 23 24 25 Data management 26 27 Data entry 28 29 30 The electronic data capture (EDC) system is used for data entry and data 31 32 management. Data entry is carried out by 1 data collector who is set up by each 33 sub-center. After the completion of the clinical raw data collection, the data collector 34 35 will give it to the supervisor of project team to monitor and review the data. Error 36 correction and data export are conducted by the supervisor, and finally after
37 http://bmjopen.bmj.com/ 38 verification, the database is locked and will undergo statistical analysis. Participants 39 40 information will be stored in the EDC system that researchers can access using a 41 42 password. Ethical Review Board and DSMB shall have the right to consult the 43 44 relevant records when necessary.
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 Interrogative data processing 50 51 When the data is in doubt, the data collector will be notified by the supervisor in the 52 53 form of a data question form. The answer of the data collector should be filled in the 54 55 data question form and returned to the statistician by the supervisor. 56 57 58 59 Missing data processing 60
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1 2 3 Based on the intention-to-treat (ITT) principle, when the data is missing, the last BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 observation will carry forward (LOCF). 6 7 8 Data monitoring 9 10 This study established an independent DSMB, which is independent from the sponsor 11 12 consisting of an acupuncturist, a rehabilitation specialist, and a statistician. The 13 14 DSMB supervised whether the trial follows the study design and standard guidelines, 15 examines the progress of the trial, the accuracy and authenticity of the results, and 16 17 examines whether the AEs and reason are well recorded. DSMB will have access to 18 For peer review only 19 the interim results. Acupuncturists need to assess, manage, and classify AEs within 24 20 hours. In the event of a SAE, it must be reported to the main researchers, Ethical 21 22 Review Board and DSMB within 24 hours of the occurrence. DSMB and the main 23 24 researchers will discuss it, Ethical Review Board and DSMB have right to terminate 25 26 the trial. 27 28 29 30 31 Sample size 32 33 In this study, the superior efficacy design is used. The results of H. Zheng25 EA 34 35 treatment of chronic functional constipation are used as a reference. We assume the 36 mean change of SBMs in the intervention group is 2.20, and the standard deviation
37 http://bmjopen.bmj.com/ 38 39 (SD) is 1.93. The mean number of spontaneous defecations in the control group is 40 1.23, and the SD is also 1.93. The test level is 0.05, and the test efficiency is 0.9. 41 42 Calculated by PASS software, 52 samples will be needed for a single group. 43 44 Considering the 20% drop-off rate, 63 samples will be needed for a single group, and
45 a total of 126 subjects will be enrolled. on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 Statistical analysis data set 52 53 Full analysis set, FAS 54 55 56 Based on the ITT principle, all patients are randomised to receive at least 1 treatments 57 and have a therapeutic evaluation after the treatments. 58 59 60
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1 2 3 Pre-protocol set, PPS BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Patients entering this data set at least meet the following criteria: (1) completion of 7 8 the efficacy evaluation for week 12; (2) good compliance, which means patients 9 without treatment times ≤ 6 times (the number of treatments reached 80% of the total 10 11 number of treatments). 12 13 14 15 16 Safety set, SS 17 18 For peer review only 19 All patients randomised into the group with at least 1 safety assessment record. 20 21 22 23 24 Statistical analysis 25 26 Statistical analysis is performed using SPSS24.0 for Windows. We use 2-sided at a 27 28 significance level of 0.05. The statistical description of the measurement data is mean 29 30 ± SD or Median (IQR), and the statistical description of the count data is N (%). 31 32 The distribution of enrollment, completion and FAS, PPS, SS cases of each 33 34 treatment group in each sub-center is included in the summary description. 35 36 The comparison between the groups of measurement data is performed by
37 http://bmjopen.bmj.com/ 38 independent sample t-test or non-parametric test, and the comparison within the group 39 40 is performed by paired t-test or non-parametric test. The hypothesis test of the 41 primary outcome needs to correct the central effect. Measurement data are compared 42 43 between groups at multiple time using a mixed-effects model. In order to meet the 44 applicable conditions of the hypothesis test, the variables need to be transformed if
45 on September 27, 2021 by guest. Protected copyright. 46 47 necessary. The hypothesis test of the count data uses the chi-square test or the Fisher 48 exact test. 49 50 51 52 53 Patient and public involvement 54 55 56 The Patient and public are not involved in the design of this research. 57 58 59 60
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1 2 3 Ethics and dissemination BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 This study protocol has been approved by the Ethical Review Board of Yueyang 7 8 Hospital of Integrated Traditional Chinese and Western Medicine in December 2018 9 (REB NO. 2018-121) and registered at Chinese Clinical Trials Registry (NO. 10 11 ChiCTR1900021053). This study conforms to the Declaration of Helsinki principles. 12 13 Written informed consent will be obtained from all participants who agree to take part 14 15 in this study. Any major modification of the protocol will be approved by the Ethical 16 Review Board and DSMB and documented on Chinese Clinical Trials Registry. 17 18 For peer review only 19 During data collection, the data stored in a password-protected database.We plan 20 21 the results of this study to be published in a peer-reviewed journal in a timely manner 22 and disseminated through national and international conferences. 23 24 25 26 27 DISCUSSION 28 29 30 NMSs in PD are increasingly being considered by physicians and researchers,26-29 the 31 32 efficacy of acupuncture in the treatment of NMSs in PD such as sleep disorders and 33 depression has already been confirmed.18 30 However, clinical research on 34 35 acupuncture treatment of constipation in PD is still insufficient. The efficacy of 36 acupuncture in the treatment of functional constipation has been valued by the
37 http://bmjopen.bmj.com/ 38 19 39 world, meanwhile previous studies have shown that acupuncture as an auxiliary 40 therapy for PD has the effect of reducing toxicity and increasing efficiency of 41 42 medicine when combined with medicine,30-32 so we puts forward the hypothesis that 43 44 “acupuncture therapy can treat constipation in PD”, but this hypothesis has not been
45 on September 27, 2021 by guest. Protected copyright. 46 supported by high-quality research. Therefore, we designed this RCT to provide better 47 evidence for acupuncture treatment of constipation in PD. 48 49 50 At present, the treatments of constipation in PD mostly include oral medication, 51 52 which can alleviate the clinical symptoms of functional constipation, but they are not 53 beneficial to PD itself.33-35 This study treats constipation and at the same time serves 54 55 as an intervention for motor symptoms. The main reasons are as follows. (1) We are 56 57 treating patients with constipation in PD, due to the characteristics of PD motor 58 symptoms, patients with constipation in PD are different from those of general 59 60 functional constipation. In addition, acupuncture treatment requires the patients to go
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1 2 3 to the hospital for treatments every week. Based on our preliminary pilot study, we BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 find the motor symptoms of PD will directly affect the patient's compliance with the 6 7 treatment. (2) Clinical studies have confirmed that severe constipation in PD patients 8 is caused by the loss of dopamine neurons of intestinal muscle,36 we suspect that 9 10 treatment of PD can assist in reducing the loss of dopaminergic neurons in the body to 11 12 a certain extent, which is helpful to treat constipation. Therefore, we have 13 14 individualized treatment for patients with motor symptoms mainly characterized by 15 tremor-dominant, or hypokinetic-rigid. 16 17 18 Clinical trialsFor of previous peer acupuncture review treatment onlyof PD have shown positive17 37 19 38 18 39 40 20 and negative results. By reading the related articles, we consider that the 21 negative results may be related to the small sample size, the long interval between 22 23 acupuncture treatment and the short treatment period, which may have resulted in an 24 25 insufficient amount of acupuncture stimulation. Different levels of stimuli may affect 26 41 42 27 the efficacy of acupuncture, potentially accounting for this inconsistency. 28 Therefore, in order to obtain a more accurate result, this study will include 126 29 30 patients, 3 times a week with EA treatment in weeks 1-8, and then take maintenance 31 32 treatments: 2 times a week in the weeks 9-10, once a week in the weeks 11-12. The 33 purpose of maintenance treatments is to observe whether reduction of treatment times 34 35 after a certain amount of acupuncture treatment can still maintain the therapeutic 36 effect. Maintenance treatments are in line with the actual situation of clinical
37 http://bmjopen.bmj.com/ 38 39 treatment, and can help reduce the economic burden of patients during clinical 40 treatment, reflecting the economic effects of acupuncture. We conducted 2 41 42 assessments during follow-up period, the first was 4 weeks after the end of treatment, 43 44 which is to observe the short-term efficacy of acupuncture treatment, and the second
45 on September 27, 2021 by guest. Protected copyright. 46 was 12 weeks after the end of treatment, which is to observe the long-term effect of 47 acupuncture treatment. 48 49 50 The vast majority of current researches on constipation are still based on the 51 52 diagnosis of Rome III. We use the diagnostic criteria for functional constipation in 53 Rome Ⅳ, which is newly revised in 2016. The differences between the diagnostic 54 55 criteria of Roman IV and Roman III for functional constipation are the frequency of 56 57 defecation, lumpy or hard stools, sensation of incomplete evacuation, anorectal 58 59 obstruction/ blockage, and manual maneuvers to facilitate are more stringent. Change 60
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1 2 3 from at least 25% of the incidence changes to more than 25%; the definition of lumpy BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 or hard stools is clearer which requires a score of 0 or 1 on the Bristol stool form 6 7 scale. 8 9 This study does not include the sham acupuncture group as control group. The 10 11 main reasons are as follows. (1) The primary outcome is the number of SBMs, which 12 13 is objective and less affected by the placebo effect. (2) In pilot study we have use 14 sham acupuncture treatment, but found that patients due to the limitations of motor 15 16 symptoms and constipation efficacy is not significant, the weekly treatment for 3 17 18 times is quite difficultFor and peer the rate of reviewshedding is too high. only 19 20 Because of the high frequency of treatment and long treatment period in this 21 22 study, in order to improve patient compliance, patients who are randomly assigned to 23 24 the intervention group will receive free EA treatment and emergency treatment for 25 26 constipation in the 24 weeks of the trial. In order to encourage patients to complete 27 the treatment and evaluation in the study, patients who finish relevant treatment and 28 29 evaluation at the week 8, week 12, week 16, and week 24 will respectively get 30 31 corresponding transportation subsidy. Patients in the waitlist control group will be 32 33 provide free emergency treatment for constipation during the 12 weeks of observation 34 and 12 free acupuncture treatment sessions after 12 weeks of observation; patients 35 36 who finish relevant evaluation at the 0 point, week 4, week 8, and week 12 will
37 http://bmjopen.bmj.com/ 38 respectively get corresponding transportation subsidy. 39 40 41 42 TRIAL STATUS 43 44
45 Patient recruitment will begin in February 2019 and is expected to finish at the end of on September 27, 2021 by guest. Protected copyright. 46 47 2022. 48 49 50 51 52 Acknowledgements We thank all participants and researchers at each sub-center for 53 54 their contribution throughout all stages of this research. 55 56 57 58 59 Author Contributions KSL, SFX and ZQW are joint first authors. KSL and SFX 60
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1 2 3 participated in the design of this study protocol and drafted the manuscript. LYW, BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 CHB, YH revised and edited this manuscript. YYC, ZQL participated in the 6 7 implementation of the project. ZQW, LRS, YWW, CXY helped recruit participants. 8 HGW conceived this research and is the research manager. All authors have read and 9 10 approved this final manuscript. 11 12 13 14 15 Funding This work was supported by Shanghai science and technology commission 16 17 scientific research project (grant number：18401970700). The funding agency has no 18 For peer review only 19 role in designing research and deciding to publish research results. 20 21 22 23 24 Competing interests The authors declare that they have no competing interests. 25 26 27 28 29 Ethical approval This study was approved by the Ethical Review Board of Yueyang 30 31 Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai 32 33 University of Traditional Chinese Medicine, Shanghai, China. 34 35 36
37 http://bmjopen.bmj.com/ 38 Data sharing statement Dataset available from the ResMan repository, 39 40 http://www.medresman.org. 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 1. Zaichick SV, McGrath KM, Caraveo G. The role of Ca2+ signaling in Parkinson's disease. Dis Model 7 8 Mech 2017;10(5):519-35. 9 10 2. de Rijk MC, Launer LJ, Berger K, et al. Prevalence of Parkinson's disease in Europe: A collaborative 11 study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 12 13 2000;54(11 Suppl 5):S21-3. 14 15 3. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features and risk 16 17 factors for Parkinson disease. Ann Neurol 2012;72(6):893-901. 18 For peer review only 19 4. Barichella M, Cereda E, Pezzoli G. Major nutritional issues in the management of Parkinson's 20 21 disease. Mov Disord 2009;24(13):1881-92. 22 23 5. Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson's disease. Lancet 24 25 Neurol 2015;14(6):625-39. 26 27 6. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson's disease. Mov 28 Disord 2015;30(12):1600-11. 29 30 31 7. Chen Y, Yu M, Liu X, et al. Clinical characteristics and peripheral T cell subsets in Parkinson's disease 32 patients with constipation. Int J Clin Exp Pathol 2015;8(3):2495-504. 33 34 35 8. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of 36 Parkinson's disease. Neurology 2001;57(3):456-62.
37 http://bmjopen.bmj.com/ 38 39 9. Gao X, Chen H, Schwarzschild MA, et al. A prospective study of bowel movement frequency and risk 40 of Parkinson's disease. Am J Epidemiol 2011;174(5):546-51. 41 42 43 10. Adams-Carr KL, Bestwick JP, Shribman S, et al. Constipation preceding Parkinson's disease: a 44 systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2016;87(7):710-6.
45 on September 27, 2021 by guest. Protected copyright. 46 11. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Semin Neurol 2011;17(1):10-15. 47 48 49 12. Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharm 50 Ther 2010;25(5):599-608. 51 52 53 13. Zheng H, Liu ZS, Zhang W, et al. Acupuncture for patients with chronic functional constipation: A 54 randomized controlled trial. Neurogastroenterol Motil 2018;30(7):e13307. 55 56 57 14. Liu Z, Yan S, Wu J, et al. Acupuncture for Chronic Severe Functional Constipation: A Randomized 58 Trial. Ann Intern Med 2016;165(11):761-69. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 15. Lei H, Toosizadeh N, Schwenk M, et al. A Pilot Clinical Trial to Objectively Assess the Efficacy of 4 5 Electroacupuncture on Gait in Patients with Parkinson's Disease Using Body Worn Sensors. PLoS One 6 2016;11(5):e0155613. 7 8 9 16. Doo KH, Lee JH, Cho SY, et al. A Prospective Open-Label Study of Combined Treatment for 10 Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive 11 12 Treatment. J Altern Complement Med 2015;21(10):598-603. 13 14 17. Fukuda S, Kuriyama N, Tsuru H, et al. Immediate effects of acupuncture on tongue pressure 15 16 including swallowing reflex latency in Parkinson's disease. Acupunct Med 2016;34(1):59-61. 17 18 18. Zeng BY, ZhaoFor K. Effect ofpeer Acupuncture review on the Motor and only Nonmotor Symptoms in Parkinson's 19 20 Disease--A Review of Clinical Studies. CNS Neurosci Ther 2016;22(5):333-41. 21 22 19. Wang F, Sun L, Zhang XZ, et al. Effect and Potential Mechanism of Electroacupuncture Add-On 23 24 Treatment in Patients with Parkinson's Disease. Evidence-Based Complementray and Alternative 25 Medicine,2015,(2015-8-13) 2015;2015(7):692795. 26 27 20. Shen LR, Wang QD, Shen LP, et al. Therapeutic Observation of Acupuncture-moxibustion plus Ma 28 29 Ren Capsules for Constipation in Middle-Late Stage Parkinson Disease. Shanghai Journal of 30 31 Acupuncture and Moxibustion 2018;37(12):1381-85. 32 33 21. Rajput DR. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. Journal of Neurology 34 Neurosurgery & Psychiatry 1993;56(8):938-9. 35 36 22. Yun JY, Kim YE, Yang HJ, et al. Twice-Daily versus Once-Daily Pramipexole Extended Release
37 http://bmjopen.bmj.com/ 38 Dosage Regimens in Parkinson's Disease. Parkinsons Dis. 2017; 2017: 8518929. 39 40 41 23. Tomlinson CL, Rebecca S, Smitaa P, et al. Systematic review of levodopa dose equivalency 42 reporting in Parkinson's disease. Movement Disorders Official Journal of the Movement Disorder 43 44 Society 2010;25(15):2649-53.
45 on September 27, 2021 by guest. Protected copyright. 46 24. International Conference on Harmonisation of Techinical Requirements for Registration of 47 48 Pharmaceuticals for Human Use.ICH harmonised tripartite guideline: safety pharmacology studiesfor 49 human pharmaceuticals S7A. http://www. ich. org/ fileadmin/Public_ Web_ Site/ ICH_ Products/ 50 51 Guidelines/ Safety/ S7A/ Step4/ S7A_Guideline. pdf. 52 53 25. Zheng H, Liu ZS, Zhang W, et al. Acupuncture for patients with chronic functional constipation: A 54 55 randomized controlled trial. Neurogastroenterol Motil 2018;30(7):e13307. 56 57 26. Pfeiffer RF. Non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord 2016;22 Suppl 58 1:S119-22. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 27. Song R, Grabowska W, Park M, et al. The impact of Tai Chi and Qigong mind-body exercises on 4 5 motor and non-motor function and quality of life in Parkinson's disease: A systematic review and 6 meta-analysis. Parkinsonism Relat Disord 2017;41. 7 8 9 28. O’Brien C, Clemson L, Canning CG. Multiple factors, including non-motor impairments, influence 10 decision making with regard to exercise participation in Parkinson’s disease: a qualitative enquiry. 11 12 Disability & Rehabilitation 2016;38(5):472-81. 13 14 29. Fox SH, Regina K, Shen-Yang L, et al. The Movement Disorder Society Evidence-Based Medicine 15 16 Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord 17 2011;26(S3):S2-S41. 18 For peer review only 19 20 30. Zhuang XL, Wang LL. Acupuncture Treatment of Parkinson’s Disease System—System A Report of 21 29 Cases. J Tradit Chin Med 2000;20(4):265-67. 22 23 24 31. Chen FP, Chang CM, Shiu JH, et al. A Clinical Study of Integrating Acupuncture and Western 25 Medicine in Treating Patients with Parkinson's Disease. Am J Chin Med 2015;43(03):407-23. 26 27 32. Lee SH, Lim S. Clinical effectiveness of acupuncture on Parkinson disease: A PRISMA-compliant 28 29 systematic review and meta-analysis. Medicine 2017;96(3):e5836. 30 31 33. Parkinson Study Group. A randomized trial of relamorelin for constipation in Parkinson's disease 32 33 (MOVE-PD): Trial results and lessons learned. Parkinsonism Relat Disord 2017;37:101-5. 34 35 34. Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated 36 with Parkinson disease: An RCT. Neurology 2016;87(12):1274.
37 http://bmjopen.bmj.com/ 38 39 35. Ondo WG, Kenney C, Sullivan K, et al. Placebo-controlled trial of lubiprostone for constipation 40 41 associated with Parkinson disease. Neurology 2012;78(21):1650-54. 42 43 36. C Singaram M, Gaumnitz, E. A, C Torbey M, et al. Dopaminergic defect of enteric nervous system 44 in Parkinson's disease patients with chronic constipation. Lancet 1995;346(8979):861.
45 on September 27, 2021 by guest. Protected copyright. 46 47 37. Doo KH, Lee JH, Cho SY, et al. A Prospective Open-Label Study of Combined Treatment for 48 Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive 49 50 Treatment. Journal of Alternative & Complementary Medicine 2015;21(10):598. 51 52 38. Seung-Yeon C, So-Ra S, Hak Young R, et al. Effectiveness of acupuncture and bee venom 53 54 acupuncture in idiopathic Parkinson's disease. Parkinsonism Relat Disord 2013;333(8):e115-e15. 55 56 39. Cristian A, Katz ME, Walker RH. Evaluation of acupuncture in the treatment of Parkinson's disease: 57 58 a double-blind pilot study. Mov Disord 2010;20(9):1185-88. 59 60 40. Kluger BM, Rakowski D, Christian M, et al. Randomized, Controlled Trial of Acupuncture for
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from Fatigue in Parkinson's Disease. Mov Disord 2016;31(7):1027-32. 4 5 6 41. SjöLund BH. Acupuncture or acupuncture? Pain 2005;114(3):311-12. 7 8 42. Meng ZH. The quantity-effect relationship of acupuncture. World Chinese Medicine 9 10 2014(12):1581-85. 11 12 13 14 15 16 17 Figure legends 18 For peer review only 19 20 Figure 1 Flow chart 21 22 23 Figure 2 Outcome evaluation time point 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 participantes 2 recruitment 3 4 5 6 screening
7 exclusion or UnwillingBMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 8 to participate 9 10 sign consents 11 -2 week 12 13 14 exclude on the 15 stool diary 16 17 18 0 point Baseline assessment（n=126） 19 hierarchical random（1:1） 20 21 For peer review only 22 23 24 25 26 waitlist control group(n=63) intervention group(n=63) 27 PD basic therapy + emergency EA+PD basic therapy + emergency 28 29 defecation medicine defecation medicine 30 31 32 33 34 35 Intervention for 12 weeks 36 EA will be administered 3 times per week for 37 38 the 1-8 weeks, 2 times per week for the 9- 39 10 weeks, and 1 time for the 11-12 weeks. 40 41 42 http://bmjopen.bmj.com/ 43 44 evaluation in the intervention period evaluation in the follow-up period 45 46 47 48 49
Week 4 Week 8 Week 12 Week 16 on September 27, 2021 by guest. Protected copyright. Week 24 50 51 52 53 54 55 Safety assessment 56 57 58 59 60 statistical analysis
Figure 1 Flow chart
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UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ 1 VAS 2 Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS VAS VAS VAS 3 4 5 6 -1-2 0 point 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 (week) 7 8 stool stool stool stool stool stool 9 diary diary diary diary diary diary 10 11 12 Figure 2 Outcome evaluation time point 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 http://bmjopen.bmj.com/ 25 26 27 28 29 30 31 32 on September 27, 2021 by guest. Protected copyright. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 6 7 8 9 10 11 12 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents* 20 21 22 23 Section/item Item Description Addressed on 24 No page number 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 Administrative information 29 30 31 Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______1______32 33 34 Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _____3,15______35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 2b All items from the World Health Organization Trial Registration Data Set _____3,15______6 7 8 Protocol version 3 Date and version identifier ______1______9 10 11 Funding 4 Sources and types of financial, material, and other support ______18______12 For peer review only 13 14 Roles and 5a Names, affiliations, and roles of protocol contributors _____1,18______15 16 responsibilities 17 http://bmjopen.bmj.com/ 5b Name and contact information for the trial sponsor ______1______18 19 20 5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and 21 22 interpretation of data; writing of the report; and the decision to submit the report for publication, including 23 ______18______whether they will have ultimate authority over any of these activities 24 25 on September 27, 2021 by guest. Protected copyright. 26 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication ______13______27 28 committee, data management team, and other individuals or groups overseeing the trial, if applicable (see 29 Item 21a for data monitoring committee) 30 31 32 33 34 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 6 Introduction 7 8 9 Background and 6a Description of research question and justification for undertaking the trial, including summary of relevant _____5,6______10 rationale studies (published and unpublished) examining benefits and harms for each intervention 11 12 For peer review only 13 6b Explanation for choice of comparators ______10______14 15 16
Objectives 7 Specific objectives or hypotheses http://bmjopen.bmj.com/ ______6______17 18 19 Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), 20 21 allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 22 _____6,14______23 24 25 on September 27, 2021 by guest. Protected copyright. Methods: Participants, interventions, and outcomes 26 27 28 Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will _____8______29 30 be collected. Reference to where list of study sites can be obtained 31 32 33 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and ____8-9,11______34 individuals who will perform the interventions (eg, surgeons, psychotherapists) 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be _____10,11_____ 6 7 administered 8 9 10 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose ____12-13,14____ 11 change in response to harms, participant request, or improving/worsening disease) 12 For peer review only 13 14 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence _____17,18_____ 15 16 (eg, drug tablet return, laboratory tests) 17 http://bmjopen.bmj.com/ 18 19 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____10______20 21 22 Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood 23 pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, 24 _____12______25 median, proportion), and time point for each outcome. Explanation of the clinical on September 27, 2021 by guest. Protected copyright. relevance of chosen 26 efficacy and harm outcomes is strongly recommended 27 28 29 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for ___7(table 1)____ 30 31 participants. A schematic diagram is highly recommended (see Figure) 32 33 34 Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including _____14______35 clinical and statistical assumptions supporting any sample size calculations 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______8______6 7 8 9 Methods: Assignment of interventions (for controlled trials) 10 11 12 Allocation: For peer review only 13 14 15 Sequence 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any _____9______16 17 generation factors for stratification. To reduce predictability of a random sequence, details of anyhttp://bmjopen.bmj.com/ planned restriction (eg, 18 blocking) should be provided in a separate document that is unavailable to those who enrol participants or 19 20 assign interventions 21 22 23 Allocation 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, _____9______24 concealment sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 25 on September 27, 2021 by guest. Protected copyright. 26 mechanism 27 28 29 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to _____9______30 interventions 31 32 33 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome ______9______34 35 assessors, data analysts), and how 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s _Not applicable, 6 7 allocated intervention during the trial data collectors and 8 statisticians are 9 10 11 blinded _____ 12 For peer review only 13 14 Methods: Data collection, management, and analysis 15 16 17 http://bmjopen.bmj.com/ Data collection 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related ____12,13______18 19 methods processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of 20 study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. 21 22 Reference to where data collection forms can be found, if not in the protocol 23 24 25 18b Plans to promote participant retention and complete follow-up, including list of any on September 27, 2021 by guest. Protected copyright. outcome data to be ____17-18______26 collected for participants who discontinue or deviate from intervention protocols 27 28 29 Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality _____13______30 31 (eg, double data entry; range checks for data values). Reference to where details of data management 32 procedures can be found, if not in the protocol 33 34 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the _____15______6 7 statistical analysis plan can be found, if not in the protocol 8 9 10 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______15_____ 11 12 For peer review only 13 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any 14 statistical methods to handle missing data (eg, multiple imputation) 15 ____14,15______16 17 http://bmjopen.bmj.com/ 18 19 Methods: Monitoring 20 21 22 Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of ______14_____ 23 whether it is independent from the sponsor and competing interests; and reference to where further details 24 25 about its charter can be found, if not in the protocol. Alternatively, an explanation on September 27, 2021 by guest. Protected copyright. of why a DMC is not 26 needed 27 28 29 30 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim _____14______31 results and make the final decision to terminate the trial 32 33 34 Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse ____12-13______35 36 events and other unintended effects of trial interventions or trial conduct 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent _____13,14_____ 6 7 from investigators and the sponsor 8 9 10 Ethics and dissemination 11 12 For peer review only 13 Research ethics 24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ______15______14 15 approval 16 17 http://bmjopen.bmj.com/ 18 Protocol 25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, ______15______19 amendments analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, 20 21 regulators) 22 23 24 Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and ______8______25 on September 27, 2021 by guest. Protected copyright. how (see Item 32) 26 27 28 26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary _Not applicable__ 29 30 studies, if applicable 31 32 33 Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained _____13______34 35 in order to protect confidentiality before, during, and after the trial 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Declaration of 28 Financial and other competing interests for principal investigators for the overall trial and each study site _____18______6 7 interests 8 9 10 Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that _____14,18_____ 11 limit such access for investigators 12 For peer review only 13 14 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial _____10______15 16 post-trial care participation 17 http://bmjopen.bmj.com/ 18 19 Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the _____15______20 public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing 21 22 arrangements), including any publication restrictions 23 24 25 31b Authorship eligibility guidelines and any intended use of professional writers on September 27, 2021 by guest. Protected copyright. _ Not applicable__ 26 27 28 31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______18______29 30 31 32 Appendices 33 34 35 Informed consent 32 Model consent form and other related documentation given to participants and authorised surrogates _Not applicable__ 36 materials 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Biological 33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular _Not applicable__ 6 7 specimens analysis in the current trial and for future use in ancillary studies, if applicable 8 9 10 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification 11 on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 12 For peer review only 13 Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 14 15 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 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 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
Efficacy of acupuncture for the treatment of constipation in Parkinson's disease：study protocol for a multi-centre randomised controlled trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029841.R1
Article Type: Protocol
Date Submitted by the 03-Jul-2019 Author:
Complete List of Authors: Li, kunshan; Shanghai University of Traditional Chinese Medicine, Wang, Zhaoqin; Shanghai University of Traditional Chinese Medicine Chen, Yiyi; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine Shen, Lirong; Shanghai Pudong New Area Hospital of Chinese Medicine Li, Zhongqiu; Shanghai University of Traditional Chinese Medicine Wu, Yiwen; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Yuan, Canxing; Longhua Hospital, Shanghai University of Traditional Chinese Medicine Huang, Yan; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine
Wu, Luyi; Shanghai University of Traditional Chinese Medicine http://bmjopen.bmj.com/ Bao, Chunhui; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine Xu, Shifen; Shanghai University of Traditional Chinese Medicine Wu, Huangan; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine
Primary Subject Complementary medicine Heading:
Secondary Subject Heading: Neurology, Gastroenterology and hepatology on September 27, 2021 by guest. Protected copyright.
Constipation, Parkinson's disease, Acupuncture, Randomised controlled Keywords: trial
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Efficacy of acupuncture for the treatment of constipation in 5 6 Parkinson's disease ： study protocol for a multi-center 7 8 9 randomised controlled trial 10 11 Kunshan Li,1* Zhaoqin Wang,1* Yiyi Chen,2 Lirong Shen,3 Zhongqiu Li,1 Yiwen Wu,4 12 13 Canxing Yuan,5 Yan Huang,6 Luyi Wu,1 Chunhui Bao,6 Shifen Xu,7 Huangan Wu2 14 15 16 17 18 Author affiliationsFor peer review only 19 20 1Shanghai University of Traditional Chinese Medicine, Shanghai, China 21 22 2 Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, 23 24 Shanghai University of Traditional Chinese Medicine, Shanghai, China 25 26 3 27 Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai, China 28 29 4Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 30 31 China 32 33 5 Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 34 35 China 36 6 37 Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of http://bmjopen.bmj.com/ 38 39 Traditional Chinese Medicine, Shanghai, China 40 41 7Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University 42 43 of Traditional Chinese Medicine, Shanghai, China 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 * Kunshan Li and Zhaoqin Wang contributed equally to this paper 49 50 51 52 53 Corresponding author: 54 55 Professor Huangan Wu,Yueyang Hospital of Integrated Traditional Chinese and 56 57 Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 58 110,Gan he road, Shanghai, China 59 60
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1 2 3 Tel: +86 021-64644238 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Email: [email protected] 7 8 9 10 Doctor Shifen Xu, Shanghai Municipal Hospital of Traditional Chinese Medicine, 11 12 Shanghai University of Traditional Chinese Medicine, No. 274, Middle Zhi jiang 13 14 road, Shanghai, China 15 16 Tel: +86 13761931393 17 18 For peer review only 19 Email: [email protected] 20 21 22 23 Co-authors: 24 25 26 Kunshan Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 27 28 Email: [email protected] 29 30 Zhaoqin Wang: Shanghai University of Traditional Chinese Medicine, Shanghai, 31 32 China; 33 34 Email: [email protected] 35 36 Yiyi Chen: Department of Acupuncture-Moxibustion, Yueyang Hospital of Integrated
37 http://bmjopen.bmj.com/ 38 Traditional Chinese and Western Medicine, Shanghai University of Traditional 39 40 Chinese Medicine, Shanghai, China; 41 42 Email: [email protected] 43 44 Lirong Shen: Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai,
45 on September 27, 2021 by guest. Protected copyright. 46 China; 47 48 49 Email: [email protected] 50 51 Zhongqiu Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 52 53 54 Email: [email protected] 55 56 Yiwen Wu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 57 58 Shanghai, China; 59 60 Email:[email protected]
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1 2 3 Canxing Yuan: Department of Neurology, Longhua Hospital, Shanghai University of BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Traditional Chinese Medicine, Shanghai, China; 6 7 Email: [email protected] 8 9 10 Yan Huang: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 11 12 University of Traditional Chinese Medicine, Shanghai, China; 13 14 Email: [email protected] 15 16 Luyi Wu: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 17 18 For peer review only 19 Email:[email protected] 20 21 Chunhui Bao: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 22 23 University of Traditional Chinese Medicine, Shanghai, China; 24 25 Email:[email protected] 26 27 28 29 Version: 25-June-2019 30 31 32 33 34 Word count: 4701 35 36 Keywords: Constipation; Parkinson's disease; Acupuncture; Randomised controlled
37 http://bmjopen.bmj.com/ 38 trial 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Introduction Constipation is one of the most common non-motor symptoms (NMSs) 7 of Parkinson's disease (PD). Acupuncture has a certain effect on chronic functional 8 9 constipation and PD, but its clinical efficacy for the treatment of constipation in PD 10 11 has not yet been confirmed by high-quality clinical studies. Therefore, this study will 12 13 aim to evaluate the efficacy and safety of electroacupuncture (EA) for treating 14 constipation in PD. 15 16 17 Methods and analysis: This study is a multi-centre randomised controlled trial 18 (RCT). For theFor trial, 134 peer PD patients review suffering from only constipation will be randomly 19 20 divided into the intervention group (will receive 12 weeks of EA + usual care) or the 21 22 waitlist control group (will receive 12 weeks of usual care). EA will be performed 23 24 three times per week from weeks 1 to 8, two times per week for weeks 9 and 10, and 25 once a week for weeks 11 and 12. The primary outcome is the change from baseline 26 27 in mean spontaneous bowel movements (SBMs) per week, in weeks 8 and 9. The 28 29 secondary outcomes are the change from baseline in mean bowel movements, stool 30 31 consistency, and straining per week. Defecation drugs used per week, Visual 32 Analogue Scale, Sections II and III of the Unified Parkinson Disease Rating Scale, 33 34 and the time and number of steps required to walk 20 meters will also be observed. 35 36 Efficacy will be assessed in both groups at baseline, week 4, week 8, and week 12.
37 The intervention group will undergo efficacy evaluations during the follow-up period http://bmjopen.bmj.com/ 38 39 (week 16 and week 24). Adverse events will be reported. 40 41 42 Ethics and dissemination Ethical approval has been obtained from the Ethics 43 Committees of the four centres. The results of the study will be published in 44
45 peer-reviewed journals and will be disseminated through national and international on September 27, 2021 by guest. Protected copyright. 46 47 conferences. 48 49 Trial registration number ChiCTR1900021053; Pre-results. 50 51 52 53 54 ARTICLE SUMMARY 55 56 Strengths and limitations of this study 57 58 59 This study will be one of the rare RCT studies to assess the clinical efficacy of 60
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1 2 3 electroacupuncture (EA) in the treatment of constipation in Parkinson's disease BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 (PD); a randomisation and allocation concealment methods will be applied with 6 7 all data collectors blinded to the procedure. 8 9 In order to optimize the authenticity and generalizability of the research results, a 10 11 multi-centre trial will be utilised for this study, which will include four Tertiary A 12 13 Hospitals located in Shanghai, China. 14 15 In addition to evaluating the clinical efficacy of EA in the treatment of 16 17 constipation in PD patients, this study also will investigate if EA can play a role 18 in maintenanceFor therapy. peer review only 19 20 21 In this study, a sham EA group will not be included, so without blinding patients, 22 23 the placebo effect of EA treatment cannot be ruled out. 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 As the percentage of aging people in the global population increases, the incidence of 7 Parkinson's disease (PD) is also increasing. Incidence of this disease the percentage of 8 9 people over 65 years old disease is 1-3% in the world’s population.1 2 The incidence 10 11 of this disease is 1-3% among the elderly over 65 years old in the world. Previous 12 13 studies often focused on the adjustment of motor symptoms in PD. However, 14 non-motor symptoms (NMSs) have received increased attention in recent years. 15 16 Studies have shown that some NMSs can occur earlier than motor symptoms,3 17 18 seriously affectingFor the patients’ peer quality review of life. Constipation only is one of the most 19 common and earliest occurrence of NMSs, with a prevalence of up to 80% among PD 20 21 patients.4-6 50% of patients present constipation symptoms 10 to 20 years before the 22 23 motor symptoms appear.7 Moreover, studies indicate that constipation may be one of 24 25 the risk factors for PD. Several studies find that men or women afflicted with 26 constipation (three or fewer bowel movements per week) are two to five times more 27 28 likely to be diagnosed with PD in the future than those who do not suffer from 29 30 constipation.8-10 Common drugs used for treating PD, such as dopamine agonists, 31 32 anticholinergics, and catechol-oxyl-methyltransferase inhibitors can aggravate 33 constipation symptoms. 34 35 36 The main cause of constipation in PD is slow colonic transit or pelvic floor and
37 http://bmjopen.bmj.com/ 38 anal sphincter dysfunction.11 Therefore, the treatment of constipation in PD usually 39 40 involves the use of laxative or prokinetic drugs. However, in long-term treatment, 41 42 treatment-related adverse events increase significantly. About 50% of patients are 43 44 unsatisfied with these drugs mainly due to their low efficacy, inconsistent response to
45 on September 27, 2021 by guest. Protected copyright. 46 constipation symptoms and their associated adverse events.12 47 48 49 Acupuncture is an age-old practice in China, which in recent decades has 50 51 become increasingly popular in different parts of the world. Studies have shown that 52 53 acupuncture can increase stool frequency and improve stool consistency in functional 54 13 14 55 constipation. In addition, acupuncture can slow down the deterioration of PD to 56 15 16 57 some extent. It plays an important role in reducing adverse reactions to medicine 58 17-19 59 and in improving non-motor symptoms. Nevertheless, we have not yet found a 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
4 high-quality RCT study on acupuncture treatment for constipation in PD patients. 5 6 Electroacupuncture (EA) is a form of acupuncture therapy that combines 7 8 traditional acupuncture with electrical stimulation. The advantage of EA therapy is 9 that the amount of stimulation can be objectively controlled, and the frequency and 10 11 intensity of stimulation are repeatable, ensuring that participants in clinical studies 12 13 receive similar stimulation. In addition, as a form of acupuncture, EA is often used to 14 14 15 19 15 treat constipation and PD. Based on our previous preliminary studies, we found 16 that acupuncture treatment can ameliorate the symptoms of constipation in PD.20 17 18 Therefore, this studyFor will peer investigate reviewthe efficacy of EA only in treating constipation in PD 19 20 through a multi-centre randomised controlled trial (RCT), in order to clarify the 21 feasibility and advantages of acupuncture treatment for constipation in PD. 22 23 24 25 26 METHODS AND ANALYSIS 27 28 29 Objectives 30 31 Our primary objective is to demonstrate that compared with usual care (UC) alone 32 33 (PD basic therapy + emergency defecation medicine), EA + UC will increase the 34 frequency of defecation, ameliorate stool consistency and straining. The secondary 35 36 objective is to investigate the maintenance treatment effects of EA + UC administered
37 http://bmjopen.bmj.com/ 38 three times a week for eight weeks followed by reduced frequency of EA treatment 39 40 for four weeks compared to UC alone. 41 42 43 44 Study design
45 on September 27, 2021 by guest. Protected copyright. 46 47 This study is a multi-centre, parallel, randomised controlled trial with blinded data 48 49 collectors. It is estimated that 134 patients will be recruited and randomly divided into 50 the intervention group (EA+UC) or the waitlist control group (UC alone) in a ratio of 51 52 1:1 using a stratified random sampling method. The participants in the two groups 53 54 will be treated for 12 weeks, but the intervention group will receive 12 weeks of 55 follow-up as well. The flow chart of the trial is shown in Figure 1. The research 56 57 process and data collection are described in detail in Table 1 and Figure 2. 58 59 60
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1 2 3 Table 1 Schedule of enrollment, interventions and assessments BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 7 Study period Enrollment Intervention period Follow-up period 8 Visit 1 2 3 4 5 6 9 Time point Week -2 0-Point Week 4 Week 8 Week 12 Week 16 Week 24 10 11 Basic information × 12 Medical history × 13 14 PD present history × 15 Constipation present history × 16 Fill in the basic 17 information H&Y stage × 18 For peer review only 19 Urine pregnancy test × 20 MMSE × 21 Classification of motor 22 × 23 symptoms in PD 24 Inclusion criteria × 25 26 Exclusion criteria × × 27 Sign consents × 28 29 Randomization × 30 Primary SBMs per week 31 × × × × × × outcome (in the stool diary*) 32 33 BMs per week × × × × × × 34 (in the stool diary*) 35 Stool consistency 36 × × × × × × (in the stool diary*)
37 http://bmjopen.bmj.com/ 38 Straining Secondary × × × × × × 39 (in the stool diary*) 40 outcomes Emergency defecation drugs 41 Usage × × × × × × 42 (in the stool diary*) 43 Ⅱ Ⅲ 44 UPDRS- and UPDRS- × × × ×
45 Gait Speed (20 meter walk) × × × × on September 27, 2021 by guest. Protected copyright. 46 VAS × × × × × × 47 48 Intervention group × × × × × 49 AEs Waitlist control group × × × 50 51 Compliance evaluation × 52 53 H&Y stage, Hoehn-Yahr stage; MMSE, Mini-mental State Examination; SBMs, spontaneous bowel movements; 54 BMs, bowel movements; Unified Parkinson Disease Rating Scale, UPDRS; VAS, Visual Analogue Scale; AEs, 55 adverse events. 56 57 * The stool diary records the patient's stool for 2 weeks. Therefore, each stool diary recording time is -2-0 weeks, 58 4-5weeks, 8-9weeks, 12-13 weeks, 16-17 weeks, and 23-24weeks. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Recruitment, setting and participants 7 8 9 The trial will be conducted at Yueyang Hospital of Integrated Traditional Chinese and 10 Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of Traditional 11 12 Chinese Medicine, and Shuguang Hospital, which are all affiliated to Shanghai 13 14 University of Traditional Chinese Medicine. The participants will be recruited 15 through published advertisements in newspapers or by posting recruitment notices on 16 17 the official network information platforms and the bulletin boards of each study site. 18 For peer review only 19 Interested participants can contact the researchers through the provided telephone 20 21 numbers. Then an independent researcher will conduct a face-to-face interview with 22 the participants to explain the study and voluntary participants will be required to sign 23 24 consent forms (see online supplementary file 1). After a baseline screening visit， 25 26 participants who meet the eligibility criteria will participate in the study. 27 28 29 Inclusion criteria 30 31 To be included in the trial, participants must: (1) have a diagnosis of idiopathic 32 33 Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank 34 21 35 Clinical Diagnostic Criteria; (2) meet the diagnostic criteria of Roman IV diagnostic 36 criteria for functional constipation;22 (3) be aged between 40 and 80 years; (4) have a
37 http://bmjopen.bmj.com/ 38 course of PD ≥6 months and a course of constipation ≥3 months; (5) have 39 40 spontaneous bowel movements (SBMs) <3 times# per week; (6) be unsatisfied with 41 42 their current constipation treatment or must have not received constipation treatment 43 yet; (7) be in stage to 1 to 4 of the Hoehn-Yahr (H&Y) scale; (8) be a voluntary 44
45 participant in the study, agree to receive relevant examinations and treatments, and on September 27, 2021 by guest. Protected copyright. 46 47 sign the informed consent form. 48 49 # The participants who meet this condition based on the patient's -2-0 weeks stool diary record. 50 51 52 53 Exclusion criteria 54 55 56 The exclusion criteria are as follows: (1) patients with serious cardiovascular and 57 58 cerebrovascular diseases, hematopoietic diseases, malignant tumours, or other serious 59 60 life-threatening diseases; (2) patients who have been diagnosed as suffering from
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 schizophrenia, major depression, or cognition impairment (Cognition impairment is 5 6 defined based on the Mini-mental State Examination (MMSE), which categorises 7 8 cognitive impairment based on different educational levels. The definition of the 9 10 criteria are as follows: people who were illiterate, only received primary school 11 12 education, or had formal education higher than primary education will be classified as 13 14 having cognitive impairment if they score less than 14, 20, and 24 respectively on the 15 16 MMSE); (3) patients with a history of laparotomy or anorectal surgery (except for 17 18 haemorrhoid surgery,For appendectomy peer review in the last one year,only or inguinal hernia repair) 19 20 that may affect intestinal transit; (4) patients who have been diagnosed with anal 21 22 tumours, malformations, suspected intestinal obstruction, or other organic diseases 23 24 leading to constipation; (5) patients who cannot be treated with EA on acupuncture 25 26 points in this study due to skin diseases, limb defects, or other conditions; (6) patients 27 28 who have been involved in other clinical trials or who have received acupuncture 29 30 treatments within 30 days before treatments which may affect the results of this study; 31 32 (7) patients diagnosed with acute gastrointestinal disease within two weeks before 33 34 treatments; (8) patients who are allergic to lactose solution or glycerine enema; (9) 35 36 pregnant or lactating women (female patients under 60 years age will need to undergo
37 http://bmjopen.bmj.com/ 38 a urine pregnancy test). 39 40 41 42 Randomisation and allocation concealment 43 44 Patients will be randomly assigned to the intervention group or the waitlist control
45 on September 27, 2021 by guest. Protected copyright. 46 group in a 1:1 ratio using a stratified random sampling method. The stratification will 47 48 be based on two factors: (1) the severity of constipation (SBMs weekly = 2 times or 49 50 SBMs weekly < 2 times); (2) study site. Independent statisticians will provide 51 computer-generated random sequences and each strata will be generated from a 52 53 separate random sequence. Distribution will be done by a central web-based 54 55 interactive randomization service system. To prevent the researcher from guessing the 56 grouping situation of the next patient, we conducted the variable block random 57 58 method (block size is four or six). When a participant is eligible, the researcher who 59 60 conducted the random grouping needs to log on the website to know the
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1 2 3 grouping situation of this participant. BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 7 8 Blinding 9 10 This trial is not blind to patients and acupuncturists, but data collectors need to 11 12 complete data collection in a blind state. They will not know the grouping situation. 13 14 For better blind evaluation, each sub-centre has one acupuncturist and one data 15 16 collector and the data collection location is independent of the treatment room. More 17 than that, data collectors will be given the relevant scale of this assessment every time 18 For peer review only 19 they make the assessment, then the scale will be handed over to the supervisor of the 20 21 project team after each assessment. Patients and acupuncturists will be advised not to 22 23 disclose the patient's grouping to the data collectors at any point during the trial. An 24 independent statistician will conduct the statistical analyses of the results. 25 26 27 28 29 Interventions 30 31 In the 12-week treatment period, both groups will usual care (UC) and participants 32 33 randomly assigned to the intervention group will receive electroacupuncture (EA) as 34 35 well. 36
37 http://bmjopen.bmj.com/ 38 39 40 UC treatment in both groups 41 42 Treatment of PD 43 44 Considering the complexity of the clinical manifestations of PD and the principles of
45 on September 27, 2021 by guest. Protected copyright. 46 individualized treatment in PD clinical guidelines, the treatment for PD in this trial 47 48 will not be strictly standardized. However, if the participant has received PD 49 50 medication before enrolment, the dosage of the medicine should not be changed 51 arbitrarily. The dose of different drugs can be converted to a total daily levodopa 52 53 equivalent dose (LED) according to the equivalence theory of levodopa.23 54 55 56 57 58 Emergency treatment for constipation 59 60
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1 2 3 If the patients have no BMs for three or more consecutive days, they will be allowed BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 to use an emergency treatment, which will be provided by the researchers. There are 6 7 several options available to patients. For patients with no defecation urge, it will be 8 recommended that they first take lactose solution orally under the following protocol: 9 10 15 ml of lactose solution (lactose solution orally, H20171057, Abbott Healthcare 11 12 Products B.V. 15ml/bag) taken orally at an interval of 12 hours; if it is ineffective, 30 13 14 ml of lactose solution should be taken orally on the second day at an interval of 12 15 hours. For patients who have an urge to defecate but are unable to pass stool, 20 ml 16 17 glycerine enema (glycerine enema, H31021363, Shanghai Yunjia Huangpu 18 For peer review only 19 Pharmaceutical Co. Ltd.; 20 ml/bottle) by anal injection will be recommended. A 20 21 combination of the two treatment regimens will be recommended for patients who fail 22 to respond to emergency treatment for two days. Patients will be advised not to use 23 24 any other emergency treatments. Each use of emergency treatment will be recorded in 25 26 the stool diary. If there is any other emergency treatment medication being used, it 27 also needs to be recorded in the stool diary. 28 29 30 31 32 EA add-on treatment in the intervention group 33 34 Thirty EA sessions will be performed over a period of 12 weeks, three sessions per 35 36 week from weeks 1 to 8, two sessions per week for weeks 9 and 10, and one session
37 http://bmjopen.bmj.com/ 38 per week for weeks 11 and 12. 39 40 The acupuncturists who will provide treatment are qualified doctors with a 41 42 Traditional Chinese Medicine qualification certificate and have at least two years of 43 acupuncture experience. They are required to be registered with the Chinese Medical 44
45 Doctor Association. All acupuncturists will receive one training before starting the on September 27, 2021 by guest. Protected copyright. 46 47 study. Acupuncturists need to explain the EA treatment process to the patients and 48 49 should describe any possible sensations during the treatment before starting the 50 procedure. A brief interview will be conducted before each EA treatment to record 51 52 whether the patient has had an adverse reaction since the last treatment. 53 54 55 Each patient in the intervention group will be treated at the bilateral acupoints of 56 57 Connect Qianding (GV21) to Xuanlu (GB5), Connect Qianshencong（EX-HN1）to 58 59 Xuanli (GB6), Tianshu (ST25), Fujie (SP14), Quchi (LI11), Hegu (LI4), 60
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1 2 3 Yanglingquan (GB34), Shangjuxu (ST37), Sanyinjiao (SP6), Zhaohai (KI6), and BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Taichong (LR3). When the patients are supine, they are to be treated with single-use 6 7 stainless steel acupuncture needles (Hwato). Acupuncture on Tianshu (ST25), Fujie 8 (SP14) will be done with 0.30 mm × 50 mm or 0.30 mm × 75 mm needles (depending 9 10 on the patient's body type), inserted slowly and vertically approximately 11 12 45mm-70mm until the muscle layer of the abdominal wall is pierced. Acupuncture on 13 14 the bilateral lines from Qianding (GV21) to Xuanlu (GB 5), the bilateral lines from 15 Qianshencong (EX-HN1) to Xuanli (GB6) (for each line, two needles will be 16 17 inserted), Hegu (LI4), Zhaohai (KI6), and Taichong (LR3) will be punctured with 18 For peer review only 19 0.25 mm × 25 mm needles, inserted approximately 10mm-20mm deep. Quchi (LI11), 20 21 Yanglingquan (GB34), Shangjuxu (ST37), and Sanyinjiao (SP6) will be punctured 22 using 0.25mm×40mm needles inserted approximately 30mm-35 mm deep. 23 24 Manipulations of twirling, lifting, and thrusting will be performed to reach de qi, 25 26 which is the unique acupuncture feeling that includes soreness, heaviness, and 27 distension sensation. Paired alligator clips from the EA instrument (SDZ-III EA 28 29 device, Hua Tuo, Suzhou medical equipment) will be connected to Qianding (GV21) 30 31 to Xuanlu (GB5) (tremor type) or Connect Qianshencong (EX-HN1) to Xuanli (GB6) 32 33 (Stiff type) (one group is selected according to the clinical manifestations of patients' 34 motor symptoms; the left acupoint is connected to the left acupoint, the right acupoint 35 36 is connected to the right acupoint), and bilateral Tianshu (ST25), Fujie (SP14) will be
37 http://bmjopen.bmj.com/ 38 connected transversely to the EA instrument. The frequency of the wave is 10/50Hz; 39 40 10Hz lasts for five seconds, 50Hz lasts for ten seconds. The output pulse width is 0.2 41 ms ± 30%. Current intensity will be between 0.1 mA and 10 mA, depending on 42 43 whatever level the patients feel comfortable without feeling pain. EA treatment will 44 last for 30 minutes.
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 Follow-ups 49 50 Only the intervention group participants will have scheduled follow-up at week 16 51 and week 24. The intervention group will still be given usual care treatment during 52 53 follow-up. 54 55 Outcome measures and evaluation 56 57 58 Primary outcome 59 60
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1 2 3 The primary outcome is the change in mean spontaneous bowel movements (SBMs) BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 from baseline per week, according to the data in the stool diary in weeks 8 and 9. It 6 7 means the total amount of SBMs during weeks 8-9 and weeks -2-0 will be divided by 8 two respectively, then the average of weeks 8-9 minus the average of weeks-2-0. 9 10 SBM is define as defecation occurred in the past 24 hours without the use of rescue 11 12 drugs or other methods that can aid defecation. The data collectors will explain how 13 14 to fill out the stool diary to the patients. 15 16 17 Secondary outcome 18 For peer review only 19 The secondary outcome measures include the evaluation of constipation and PD with 20 21 the following protocol: (1) assessment of constipation: change in mean BMs, stool 22 consistency (according to Bristol Stool Form Scale score), and straining score from 23 24 baseline per week based on the stool diary; mean frequency and mean dosage of 25 26 emergency defecation drugs used per week based on the stool diary; VAS: the 27 28 amelioration of patient's subjective stool symptoms will be assessed; (2) assessment 29 of the PD: sections II and III of the Unified Parkinson Disease Rating Scale (UPDRS) 30 31 (UPDRS II is about the activities of daily life; UPDRS III is about the motion 32 33 examination evaluation) will be used for evaluation when the patients are under the 34 influence of drug treatment. If the patients appeared "on/off", the status of the patients 35 36 in the "on" stage is assessed. The time and number of steps required to walk 20 meters
37 http://bmjopen.bmj.com/ 38 (measured step speed and average step distance). The evaluation time-point is 39 40 shown in detail in Figure 2. 41 42 Baseline data will be collected at the first visit by an independent data collector 43 44 and will include patient’s basic information, medical history review, present medical
45 history of PD and constipation, Hoehn-Yahr stage, urine pregnancy test(if it is on September 27, 2021 by guest. Protected copyright. 46 47 needed), Mini-mental State Examination, inclusion and exclusion criteria, and 48 49 classification of motor symptoms in PD, as shown in Table 1. The outcome 50 51 assessment at baseline, treatment, and follow-up will be evaluated by the same data 52 collector. 53 54 55 56 57 Safety assessment 58 59 60 All patients will report any adverse event (AE)to the acupuncturists; this will be done
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1 2 3 to avoid making the data collectors aware of the patient's grouping. The BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 acupuncturists will be responsible for recording all details of the AEs, including the 6 7 time and severity of the occurrence. The relationships between AEs and intervention 8 methods will be assessed according to the Standardized Case Causality Assessment of 9 10 the World Health Organization Uppsala Monitoring Centre System. Common AEs of 11 12 acupuncture include fainting, local ecchymoses, dizziness and so on. The details, 13 14 processing progress and results of each AE will be recorded in the case report form 15 (CRF). Any severe adverse event (SAE) will be determined in accordance with the 16 17 International Conference on Harmonization harmonized tripartite guideline24 and must 18 For peer review only 19 be reported to the Independent Data and Safety Monitoring Board (DSMB). 20 21 22 23 24 Data collection 25 26 Each sub-centre will have one data collector. The data collector can only access the 27 28 relevant content of this assessment at each evaluation time and cannot obtain the 29 results of the last evaluation. Except for the stool diary, which will be filled out by the 30 31 patient, the other efficacy indicators will be filled out by the data collector after the 32 33 patient is assessed and evaluated. All data collectors will receive training to learn how 34 35 to assess UPDRS and other scales. 36
37 http://bmjopen.bmj.com/ 38 39 Data management 40 41 42 Data entry 43 44 The electronic data capture (EDC) system will beused for data entry and data
45 on September 27, 2021 by guest. Protected copyright. 46 management. Data entry will be carried out by one data collector who will be 47 48 allocated to each sub-centre. After the completion of the clinical raw data collection, 49 the data collectors will give it to the supervisor of the project team monitoring and 50 51 review. Error correction and data export will be conducted by the supervisor, and 52 53 finally after verification, the database is locked and will undergo statistical analysis. 54 55 Participants’ information will be stored in the EDC system that researchers can access 56 using a password. The Ethical Review Boards and DSMB shall have the right to 57 58 consult the relevant records when necessary. 59 60
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1 2
3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Interrogative data processing 7 8 If the authenticity of the data is questioned, the data collector will be notified by the 9 10 supervisor in the form of a data question form. The data collector’s answer will be 11 12 filled in the data question form and returned to the statistician by the supervisor. 13 14 15 16 Missing data processing 17 18 Missing data willFor assumed peer to be under review the missing-at-random only assumption and will be 19 20 imputed using multiple imputation. 21 22 23 24 25 Data monitoring 26 27 This study established an independent Data and Safety Monitoring Board (DSMB), 28 29 which is independent of the sponsor, consisting of an acupuncturist, a rehabilitation 30 31 specialist, and a statistician. The DSMB supervised whether the trial follows the study 32 design and standard guidelines, will monitor the progress of the trial, and observe 33 34 whether AEs and aetiologies are well recorded. The DSMB will have access to the 35 36 interim results. Acupuncturists will need to assess, manage, and classify AEs within
37 24 hours. In the event of a SAE, it must be reported to the main researchers, Ethics http://bmjopen.bmj.com/ 38 39 Committees and the DSMB within 24 hours of the occurrence. The DSMB and the 40 41 main researchers will discuss it, however, the Ethics Committees and the DSMB have 42 43 right to terminate the trial. 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 Sample size 48 49 50 In this study, the superior trial is used. Based on the results of H. Zheng25 EA 51 52 treatment of chronic functional constipation, we estimate the change in mean 53 spontaneous bowel movements (SBMs) from baseline per week is 2.20, with a 54 55 standard deviation (SD) of 1.93 in the intervention group. The mean change from 56 57 baseline in SBMs is 0.97, also with a SD of 1.93 in the control group. We use power 58 analysis and sample size (PASS) software to determine the sample size. When the 59 60 power is 90% and 2-sided significance level is 5%, the sample size is 53 participants
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1 2 3 in each group. Considering the 20% dropout rate, the sample size is increased to 67 in BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 each group, and a total of 134 participants is needed. 6 7 8 9 10 Statistical analysis data set 11 12 Full analysis set, FAS (Modified ITT) 13 14 15 All patients will be randomised to receive at least one treatment and to have a 16 therapeutic evaluation after the treatments. 17 18 For peer review only 19 20 21 Per-protocol set, PPS 22 23 Patients entering this data set should at least meet the following criteria: (1) the 24 25 patients in both groups should complete efficacy evaluation for week 12; (2) if the 26 27 patients are in the intervention group, they should reach the good compliance level, 28 29 which means patients without electroacupuncture treatment times ≤ 6 times (i.e. the 30 31 number of electroacupuncture treatments reached 80% of the total of 30 EA sessions). 32 33 34 35 Safety set, SS 36
37 http://bmjopen.bmj.com/ 38 All patients randomised into the group will have at least one safety assessment record. 39 40 41 42 43 Statistical analysis 44
45 Statistical analysis will be performed using SAS 9.4 with a 2-sided P value of less on September 27, 2021 by guest. Protected copyright. 46 47 than 0.05 considered significance. The measurement data will be described as mean 48 and standard deviation or median and interquartile range, and the count data as 49 50 frequency and corresponding percentage. 51 52 53 The demographic data and other baseline data will be analyzed in full analysis 54 set. Continuous variables will be examined by independent sample t-test or Wilcoxon 55 56 rank-sum test, and categorical variables will be compared by chi-square test or 57 58 Fisher’s exact test. The significance of grade variables will be obtained by CMH 59 chi-square test. 60
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1 2 3 The primary outcome is the change from baseline in mean spontaneous bowel BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 movements (SBMs) per week in the weeks 8-9. It means the total amount of SBMs 6 7 during weeks 8-9 and weeks -2-0 will be divided by two respectively, then the mean 8 of weeks 8-9 minus the mean of weeks-2-0. The analysis is based on the full analysis 9 10 set and per-protocol set simultaneously. We will assess primary outcome by a random 11 12 effect generalized linear model with possible covariates such as group, baseline, study 13 14 site, visit, rescue medicine, other defecation aids, etc. 15 16 The analysis on the secondary outcomes are based on the full analysis set. The 17 18 outcomes includeFor the changepeer from review baseline in mean only bowel movements, stool 19 consistency (according to Bristol Stool Form Scale score), and straining score per 20 21 week; mean frequency and mean dosage of emergency defecation drugs used per 22 23 week; VAS; sections II and III of Unified Parkinson Disease Rating Scale (UPDRS); 24 25 The time and number of steps required to walk 20 meters: measure step speed and 26 average step distance. The same statistical methods as primary outcome are used for 27 28 mean bowel movements, stool consistency, straining score per week, step speed and 29 30 average step distance, VAS and UPDRS. In addition, mean dosage of emergency 31 32 defecation drugs used per week will be compared between the two groups with 33 independent sample t-test or Wilcoxon rank-sum test, and mean frequency of them 34 35 will be compared by chi-square test or Fisher’s exact test 36
37 The evaluation of the safety are based on the safety set. Adverse events (AEs) http://bmjopen.bmj.com/ 38 39 and serious adverse events between the two groups will be compared by chi-square 40 41 test or Fisher’s exact test. 42 43 44
45 Patient and public involvement on September 27, 2021 by guest. Protected copyright. 46 47 The patient and public are not involved in the design of this research. 48 49 50 51 52 Ethics and dissemination 53 54 This study protocol has been approved by four local Ethics Committees including: 55 56 Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (Approval 57 58 NO. 2018-121), Longhua Hospital (Approval NO. 2019LCSY034), Shanghai 59 60 Municipal Hospital of Traditional Chinese Medicine (Approval NO.
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1 2 3 2019SHL-KY-07-02), and Shuguang Hospital (Approval NO. 2019-676-31-01). This BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 study conforms to the Declaration of Helsinki principles. Written informed consent 6 7 will be obtained from all participants who agree to take part in this study. Any major 8 9 modification of the protocol will be approved by the Ethical Review Board and the 10 DSMB and will be documented on Chinese Clinical Trials Registry. 11 12 13 During data collection, the data will be stored in a password-protected database. 14 We plan to have the results of this study published in a peer-reviewed journal on time 15 16 and disseminated through national and international conferences. 17 18 For peer review only 19 20 21 DISCUSSION 22 23 Non-motor symptoms (NMSs) in PD are increasingly getting attention by physicians 24 25 and researchers,26-29 and the efficacy of acupuncture in the treatment of NMSs in PD 26 18 30 27 such as sleep disorders and depression has already been confirmed. However, 28 clinical research on acupuncture treatment for constipation in PD is still insufficient. 29 30 The efficacy of acupuncture in the treatment of functional constipation has been 31 32 valued all over the world,19 meanwhile previous studies have shown that acupuncture 33 34 as an auxiliary therapy for PD has the effect of reducing toxicity and increasing 35 efficacy when combined with medicine.30-32 Therefore, we proposed the hypothesis 36
37 that acupuncture therapy can ameliorate constipation in PD, but this hypothesis has http://bmjopen.bmj.com/ 38 39 not been supported by high-quality research. We designed this randomised controlled 40 trial to provide better evidence of the efficacy of acupuncture treatment for 41 42 constipation in PD. 43 44
45 At present, treatments for constipation in PD mostly include oral medications, on September 27, 2021 by guest. Protected copyright. 46 47 which can alleviate the clinical symptoms of functional constipation, but they are not 48 49 beneficial to PD itself.33-35 This study scrutinises constipation and at the same time 50 51 examines motor symptoms as well. The main reasons are as follows: Constipation in 52 53 PD patients is different from simple functional constipation. Motor symptoms and 54 55 constipation of PD interact. The aggravation of motor symptoms leads to a decrease 56 57 in patients' activities and an increase in drug dosage, both of which may aggravate 58 59 constipation. Clinical studies have confirmed that severe constipation in PD patients is 60
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1 2
3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 36 4 caused by loss of the dopamine neurons of the intestinal muscles. We believe that 5 6 treatment of PD may assist in reducing the loss of dopaminergic neurons in the body 7 8 to a certain extent, which will be helpful in treating constipation. On the other hand, 9 8-10 10 constipation is a risk factor for the development of PD. The aggravation of 11 12 constipation leads to the weakening of gastrointestinal function, which may reduce 13 14 the absorption of drugs and is detrimental to the improvement of motor symptoms. If 15 16 patients' motor symptoms become worse, they may need to increase the dosage of 17 18 their drugs; someFor drugs aggravatepeer the review symptoms of constipation, only which in turn creates 19 20 a vicious circle. To some extent, the treatment of motor symptoms also helps to 21 22 improve the symptoms of constipation. 23 24 Clinical trials of previous acupuncture treatments of PD have shown positive17 37 25 26 38 and negative18 39 40 results. By reading the related articles, we consider that the 27 28 negative results may be related to the long interval between acupuncture treatment 29 30 and the short treatment period, which may have resulted in an insufficient amount of 31 32 acupuncture stimulation. Different amounts of stimulation may affect the efficacy of 33 34 acupuncture,41 which may account for this inconsistency.42 Therefore, in order to 35 36 obtain a more accurate result, this study will include 134 patients, 3 sessions a week
37 http://bmjopen.bmj.com/ 38 with EA treatment from weeks 1 to 8. Maintenance treatments will be administered as 39 40 well: two sessions a week in the weeks 9 and 10, one sessions a week in the weeks 11 41 42 and 12. Maintenance treatments serve two purposes. One is to observe whether 43 44 reducing the treatment frequency can maintain the therapeutic effect after acupuncture
45 on September 27, 2021 by guest. Protected copyright. 46 has achieved a certain therapeutic effect. This will prevent excessive treatment caused 47 48 by increasing the number of patients' visits. The other is from the perspective of 49 50 economics. If reduced frequency of acupuncture can play a role in maintaining 51 52 treatment, the economic burden of patients can be reduced in clinical application. In a 53 54 word, we designed this study to provide guidance for clinical treatment. 55 56 This study will not use the sham acupuncture group as control group. The main 57 58 reasons are as follows: (1) The primary outcome is the number of spontaneous bowel 59 60 movements (SBMs), which is objective and less affected by the placebo effect. (2) In
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1 2 3 the pilot study, we used sham acupuncture treatment but found that patients, due to BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 the limitations of motor symptoms and constipation improvements that were 6 7 significant, the three sessions per week treatments was quite difficult for them to stick 8 to and the drop-out rate was too high. 9 10 11 Because of the high frequency of treatment and long treatment period in this 12 13 study, to improve patient compliance, patients who are randomly assigned to the 14 intervention group will receive free EA treatment and emergency treatment for 15 16 constipation throughout the 24 weeks of the trial. When they finish the relevant 17 18 treatment and evaluationFor peer at week 8, weekreview 12, week 16, only and week 24, they will get an 19 adequate transportation subsidy. Patients in the waitlist control group will be provided 20 21 free emergency treatment for constipation during the 12 weeks of observation and 12 22 23 free acupuncture treatment sessions after 12 weeks of observation. When they finish 24 25 the relevant evaluation at the 0-point, week 4, week 8, and week 12, they will get an 26 adequate transportation subsidy. 27 28 29 30 31 TRIAL STATUS 32 33 34 Patient recruitment will begin in July 2019 and is expected to finish at the end of 35 2022. 36
37 http://bmjopen.bmj.com/ 38 39 40 Acknowledgements We thank all participants and researchers at each sub-center for 41 42 their contribution throughout all stages of this research. 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 Author Contributions KSL and ZQW are joint first authors. KSL participated in 48 the design of this study and drafted the manuscript. LYW, CHB, YH revised and 49 50 edited this manuscript. YYC, ZQL participated in the implementation of the project. 51 52 ZQW, LRS, YWW, CXY will help recruit participants. SFX contributed to the design 53 of this study and critical revision of the manuscript. HGW conceived this research and 54 55 is the research manager. All authors have read and approved this final manuscript. 56 57 58 59 60 Funding This work was supported by Shanghai Science and Technology Committee
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1 2 3 (grant number：18401970700), National Key Basic Research Program of China (grant BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 number ： 2015CB554501) and Shanghai Municipal Commission of Health and 6 7 Family Planning (grant number：2018Y0143). The funding agencies have no role in 8 9 designing research and deciding to publish research results. 10 11 12 13 14 Competing interests The authors declare that they have no competing interests. 15 16 17 18 For peer review only 19 Ethical approval This study protocol has been approved by four local Ethics 20 Committees including: Yueyang Hospital of Integrated Traditional Chinese and 21 22 Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of Traditional 23 24 Chinese Medicine, and Shuguang Hospital. 25 26 27 28 29 Data sharing statement We plan to share the results of the study within six months 30 after publication of the research results. Dataset available from the ResMan repository, 31 32 http://www.medresman.org/login.aspx. The basic information of participators is not 33 open to the public. 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 1. Zaichick SV, McGrath KM, Caraveo G. The role of Ca2+ signaling in Parkinson's disease. Dis Model 7 8 Mech 2017;10(5):519-35. 9 10 11 2. de Rijk MC, Launer LJ, Berger K, et al. Prevalence of Parkinson's disease in Europe: A collaborative 12 13 study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 14 15 2000;54(11 Suppl 5):S21-3. 16 17 3. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features and risk 18 For peer review only 19 factors for Parkinson disease. Ann Neurol 2012;72(6):893-901. 20 21 22 4. Barichella M, Cereda E, Pezzoli G. Major nutritional issues in the management of Parkinson's 23 24 disease. Mov Disord 2009;24(13):1881-92. 25 26 27 5. Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson's disease. Lancet 28 29 Neurol 2015;14(6):625-39. 30 31 6. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson's disease. Mov 32 33 Disord 2015;30(12):1600-11. 34 35 36 7. Chen Y, Yu M, Liu X, et al. Clinical characteristics and peripheral T cell subsets in Parkinson's disease
37 http://bmjopen.bmj.com/ 38 patients with constipation. Int J Clin Exp Pathol 2015;8(3):2495-504. 39 40 41 8. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk of 42 43 Parkinson's disease. Neurology 2001;57(3):456-62. 44
45 9. Gao X, Chen H, Schwarzschild MA, et al. A prospective study of bowel movement frequency and risk on September 27, 2021 by guest. Protected copyright. 46 47 of Parkinson's disease. Am J Epidemiol 2011;174(5):546-51. 48 49 50 10. Adams-Carr KL, Bestwick JP, Shribman S, et al. Constipation preceding Parkinson's disease: a 51 52 systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2016;87(7):710-6. 53 54 55 11. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Semin Neurol 2011;17(1):10-15. 56 57 12. Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharm 58 59 Ther 2010;25(5):599-608. 60
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37 http://bmjopen.bmj.com/ 38 Treatment in Patients with Parkinson's Disease. Evidence-Based Complementray and Alternative 39 40 Medicine 2015;2015:692795. 41 42 20. Shen LR, Wang QD, Shen LP, et al. Therapeutic Observation of Acupuncture-moxibustion plus Ma 43 44 Ren Capsules for Constipation in Middle-Late Stage Parkinson Disease. Shanghai Journal of
45 on September 27, 2021 by guest. Protected copyright. 46 Acupuncture and Moxibustion 2018;37(12):1381-85. 47 48 49 21. Rajput DR. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. Journal of Neurology 50 51 Neurosurgery & Psychiatry 1993;56(8):938-9. 52 53 54 22. Yun JY, Kim YE, Yang HJ, et al. Twice-Daily versus Once-Daily Pramipexole Extended Release 55
56 Dosage Regimens in Parkinson's Disease. Parkinsons Dis. 2017; 2017: 8518929. 57 58 23. Tomlinson CL, Rebecca S, Smitaa P, et al. Systematic review of levodopa dose equivalency 59 60 reporting in Parkinson's disease. Movement Disorders Official Journal of the Movement Disorder
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Society 2010;25(15):2649-53. 5 6 24. International Conference on Harmonisation of Techinical Requirements for Registration of 7 8 Pharmaceuticals for Human Use.ICH harmonised tripartite guideline: safety pharmacology studiesfor 9 10 human pharmaceuticals S7A. http://www. ich. org/ fileadmin/Public_ Web_ Site/ ICH_ Products/ 11 12 Guidelines/ Safety/ S7A/ Step4/ S7A_Guideline. pdf. 13 14 15 25. Zheng H, Liu ZS, Zhang W, et al. Acupuncture for patients with chronic functional constipation: A 16 17 randomized controlled trial. Neurogastroenterol Motil 2018;30(7):e13307. 18 For peer review only 19 20 26. Pfeiffer RF. Non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord 2016;22 Suppl 21 22 1:S119-22. 23 24 27. Song R, Grabowska W, Park M, et al. The impact of Tai Chi and Qigong mind-body exercises on 25 26 motor and non-motor function and quality of life in Parkinson's disease: A systematic review and 27 28 meta-analysis. Parkinsonism Relat Disord 2017;41. 29 30 31 28. O’Brien C, Clemson L, Canning CG. Multiple factors, including non-motor impairments, influence 32 33 decision making with regard to exercise participation in Parkinson’s disease: a qualitative enquiry. 34 35 Disability & Rehabilitation 2016;38(5):472-81. 36
37 http://bmjopen.bmj.com/ 38 29. Fox SH, Regina K, Shen-Yang L, et al. The Movement Disorder Society Evidence-Based Medicine 39 40 Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov Disord 41 42 2011;26(S3):S2-S41. 43 44 30. Zhuang XL, Wang LL. Acupuncture Treatment of Parkinson’s Disease System—System A Report of
45 on September 27, 2021 by guest. Protected copyright. 46 29 Cases. J Tradit Chin Med 2000;20(4):265-67. 47 48 49 31. Chen FP, Chang CM, Shiu JH, et al. A Clinical Study of Integrating Acupuncture and Western 50 51 Medicine in Treating Patients with Parkinson's Disease. Am J Chin Med 2015;43(03):407-23. 52 53 54 32. Lee SH, Lim S. Clinical effectiveness of acupuncture on Parkinson disease: A PRISMA-compliant 55 56 systematic review and meta-analysis. Medicine 2017;96(3):e5836. 57 58 33. Parkinson Study Group. A randomized trial of relamorelin for constipation in Parkinson's disease 59 60 (MOVE-PD): Trial results and lessons learned. Parkinsonism Relat Disord 2017;37:101-5.
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 34. Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation associated 5 6 with Parkinson disease: An RCT. Neurology 2016;87(12):1274. 7 8 35. Ondo WG, Kenney C, Sullivan K, et al. Placebo-controlled trial of lubiprostone for constipation 9 10 associated with Parkinson disease. Neurology 2012;78(21):1650-54. 11 12 13 36. C Singaram M, Gaumnitz, E. A, C Torbey M, et al. Dopaminergic defect of enteric nervous system 14 15 in Parkinson's disease patients with chronic constipation. Lancet 1995;346(8979):861. 16 17 18 37. Doo KH, Lee For JH, Cho SY, peer et al. A Prospective review Open-Label only Study of Combined Treatment for 19 20 Idiopathic Parkinson's Disease Using Acupuncture and Bee Venom Acupuncture as an Adjunctive 21 22 Treatment. Journal of Alternative & Complementary Medicine 2015;21(10):598. 23 24 38. Seung-Yeon C, So-Ra S, Hak Young R, et al. Effectiveness of acupuncture and bee venom 25 26 acupuncture in idiopathic Parkinson's disease. Parkinsonism Relat Disord 2013;333(8):e115-e15. 27 28 29 39. Cristian A, Katz ME, Walker RH. Evaluation of acupuncture in the treatment of Parkinson's disease: 30 31 a double-blind pilot study. Mov Disord 2010;20(9):1185-88. 32 33 34 40. Kluger BM, Rakowski D, Christian M, et al. Randomized, Controlled Trial of Acupuncture for 35 36 Fatigue in Parkinson's Disease. Mov Disord 2016;31(7):1027-32.
37 http://bmjopen.bmj.com/ 38 41. SjöLund BH. Acupuncture or acupuncture? Pain 2005;114(3):311-12. 39 40 41 42. Meng ZH. The quantity-effect relationship of acupuncture. World Chinese Medicine 42 43 2014(12):1581-85. 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 Figure legends 51 52 53 Figure 1 Flow chart 54 55 Figure 2 Outcome evaluation time point 56 57 58 59 60
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1 participantes 2 recruitment 3 4 5 6 screening
7 exclusion or UnwillingBMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 8 to participate 9 10 sign consents 11 -2 week 12 13 14 exclude on the 15 stool diary 16 17 18 0 point Baseline assessment（n=134） 19 hierarchical random（1:1） 20 21 For peer review only 22 23 24 25 waitlist control group(n=63) 26 intervention group(n=63) PD basic therapy + emergency 27 EA+PD basic therapy + emergency 28 defecation medicine 29 defecation medicine 30 31 32 33 34 35 Intervention for 12 weeks 36 EA will be administered 3 times per week for 37 38 the 1-8 weeks, 2 times per week for the 9- 39 10 weeks, and 1 time for the 11-12 weeks. 40 41 42 http://bmjopen.bmj.com/ 43 44 evaluation in the intervention period evaluation in the follow-up period 45 46 47 48 49
Week 4 Week 8 Week 12 Week 16 on September 27, 2021 by guest. Protected copyright. Week 24 50 51 52 53 54 55 Safety assessment 56 57 58 59 60 statistical analysis
Figure 1 Flow chart
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UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ 1 VAS 2 Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS VAS VAS VAS 3 4 5 6 -1-2 0 point 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 (week) 7 8 stool stool stool stool stool stool 9 diary diary diary diary diary diary 10 11 12 Figure 2 Outcome evaluation time point 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 http://bmjopen.bmj.com/ 25 26 27 28 29 30 31 32 on September 27, 2021 by guest. Protected copyright. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 51 52 53 54 55 56 57 58 59 60 Page 29 of 43 BMJ Open
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Informed Consent Form-Information Page 5 6 7 Dear participant: 8 9 Your doctor has diagnosed you with constipation associated with Parkinson's 10 disease. 11 12 You are invited to participate in a study titled “Efficacy of acupuncture for the 13 14 treatment of constipation in Parkinson's disease：a multi-centre randomised controlled 15 trial”. 16 17 Please read the following information as carefully as possible before you decide 18 For peer review only 19 whether to participate in this study. It can help you understand why this study is being 20 done, the procedures and duration of the study, the benefits, the risks you may face, 21 22 and the discomfort you may experience if you participate in the study. You can 23 discuss it with your relatives, friends, or ask your doctor for an explanation to help 24 25 you make a decision. 26 27 1. Study background and objectives 28 29 Parkinson's disease (PD) is a kind of progressive neurodegenerative disease 30 commonly seen in people over 50 years old. With the increased aging of the world's 31 32 population, the incidence of the disease is increasing as well. In recent years, PD 33 related non-motor symptoms have attracted more attention than ever. Constipation is 34 35 the most common and earliest non-motion symptom of PD that seriously affects the 36 quality of life of patients. Meanwhile, studies have shown that constipation may be
37 one of the risk factors for the occurrence and development of PD. Furthermore, the http://bmjopen.bmj.com/ 38 39 common drugs used for treating PD, such as dopamine agonists, anticholinergics and 40 catechol-oxyl-methyltransferase inhibitors, may aggravate constipation. 41 42 Acupuncture, as a green treatment method, has been recognized all over the 43 44 world in recent decades. To some extent, studies have shown that acupuncture can
45 slow down the development of PD, especially by reducing adverse reactions to on September 27, 2021 by guest. Protected copyright. 46 47 western medicine and treating non-motor symptoms. Electroacupuncture is often used 48 for treating PD, and it has a good therapeutic effect in the treatment of constipation as 49 50 well. However, no large randomised controlled trial on the use of acupuncture for the 51 treatment of constipation in PD has been found so far. Therefore, this study will 52 observe the efficacy of acupuncture in treating constipation in PD through a 53 54 multi-centre randomised controlled trial. 55 56 This study is supported by Shanghai Science and Technology Commission 57 Scientific Research Project and will be conducted at Yueyang Hospital of Integrated 58 59 Traditional Chinese and Western Medicine, Longhua Hospital, Shanghai Municipal 60 Hospital of Traditional Chinese Medicine, and Shuguang Hospital, which are all
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 affiliated to Shanghai University of Traditional Chinese Medicine. 5 6 If you agree to take part in the study, you will need to do the following: 7 8 1. Before you are enrolled in the study, you will undergo the following 9 examinations to determine whether you can participate in the study. The doctor will 10 11 ask for and record your medical history; a general physical examination will be 12 conducted as well. 13 14 2. If you meet the inclusion criteria for the above examinations, the researchers 15 16 will arrange for you to be assigned to the waitlist control group or the intervention 17 group for treatment according to the random sampling results. Patients in the study 18 have a 50 percentFor chance peer of being assigned review to either group. only 19 20 21 Waitlist Control group: Administration of conventional medications will be done 22 for the treatment of PD. If the patients are without bowel movements for three or 23 more consecutive days, they will be allowed to take lactose solution orally and take 24 25 glycerine enema as well. Patients need be assessed before treatment, at week 4, 26 week 8, and week 12. 27 28 Intervention group: Electroacupuncture will be performed in the same manner as 29 30 in the waitlist control group: three times per week from week 0 to week 8, two times 31 per week for weeks 9 and 10, and one time per week for weeks 11 and 12. Patients 32 33 need be assessed before treatment, at week 4, week 8, and week 12, and during the 34 follow-up period ( week16 and week24 after treatment). 35 36 3. Possible benefits of participating in the study
37 http://bmjopen.bmj.com/ 38 You and society at large will likely benefit from this research. Such benefits include 39 40 an improvement in your condition and quality of life; this study may have a good 41 guiding effect on clinical treatment, making acupuncture better for patients with PD. 42 43 However, it is not excluded that this trial may not improve your condition. 44 4. Possible adverse reactions, risks, discomfort, and inconvenience of
45 on September 27, 2021 by guest. Protected copyright. 46 participating in the study 47 48 If you experience any discomfort during the study period, new changes in your 49 50 condition, or any unexpected circumstances, whether or not related to treatment, you 51 should inform your doctor immediately, who will make a judgment call and initiate 52 53 medical treatment as needed. During acupuncture clinical trials, some adverse events 54 may occur, such as fainting (during the acupuncture process, patients may suffer from 55 palpitation, sweating, nausea, vomiting or even fainting), stagnation of needles 56 57 (difficulty in needle extraction, and pain in patients) and so on. When fainting occurs, 58 the needle will be removed immediately. The participant will be asked to lie flat with 59 60 his/her head slightly lower than their body. The participant will be given warm boiled
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 water or sugar water. In general, the participant will recover after lying for a while. 5 When the hysteresis needle occurs, position of the needle will be gently tapped to 6 relieve the tense skin and muscles, or moxibustion will be applied on the hilt of the 7 8 needle or another needle will be used to puncture the skin near the needle. If the 9 unidirectional twist is too large, the needle will be twisted in the opposite direction. 10 11 During the study period, you need to come to our outpatient service on time for 12 13 treatment and follow-up, and do some physical and chemical tests, which may cause 14 trouble or inconvenience to you. 15 16 5. Is personal information confidential? 17 18 Your medical recordsFor (CRF, peer physical review and chemical examination only reports, etc.) will be 19 20 kept in the hospital. Researchers, sponsor representatives, and ethics committees will 21 be allowed access to your medical records. Any public report on this study will not 22 23 disclose your personal identity. We will make every effort to protect the privacy of 24 your personal medical data within the scope permitted by law. 25 26 6. You may voluntarily choose to participate in the study or drop out of the study. 27 28 Participation in the study depends entirely on your willingness. You may refuse to 29 30 participate in the study or withdraw from the study at any time during the study 31 without affecting your relationship with your doctor, and without the loss of your 32 33 medical treatment or other benefits. 34 35 Your doctor or researcher may discontinue your participation in this study at any 36 time for your best interest.
37 http://bmjopen.bmj.com/ 38 If you withdraw from the study for any reason, you may be asked about the 39 40 treatment you are taking in the study. You may also be asked to perform physical 41 examinations if your doctor thinks it is needed. 42 43 If you do not participate in this study, or withdraw from the study, there are many 44 other alternatives, such as exercise therapy, surgery, and so on. You do not have to
45 on September 27, 2021 by guest. Protected copyright. 46 choose to participate in this study in order to treat your illness. 47 48 If you choose to participate in this study, we hope that you will be able to 49 50 complete the entire study process. 51 52 53 54 55 56 57 58 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Informed Consent Form-Signature Page 5 6 7 Clinical study project name: Efficacy of acupuncture for the treatment of 8 constipation in Parkinson's disease：a multi-centre randomised controlled trial 9 10 Research unit: Yueyang Hospital of Integrated Traditional Chinese and Western 11 12 Medicine, Shanghai University of Traditional Chinese Medicine 13 14 Longhua Hospital, Shanghai University of Traditional Chinese 15 Medicine 16 17 Shanghai Municipal Hospital of Traditional Chinese Medicine, 18 For peer review only 19 Shanghai University of Traditional Chinese Medicine 20 21 Shuguang Hospital, Shanghai University of Traditional Chinese 22 Medicine 23 24 25 Approval number : 2018-121 26 27 2019LCSY034 28 29 2019SHL-KY-07-02 30 31 2019-676-31-01 32 33 Fill in the corresponding Research unit and Approval number according to 34 different centres. 35 36 Voluntary Subject Statement:
37 http://bmjopen.bmj.com/ 38 39 I have read the above introduction to this study and have had the opportunity to 40 discuss and ask questions about this study with my doctor. All my questions were 41 satisfactorily answered. 42 43 44 I am aware of the risks and benefits of participating in this study. I understand
45 that participation in the study is voluntary. I confirm that there is sufficient time to on September 27, 2021 by guest. Protected copyright. 46 consider this and I understand that: 47 48 49 I can always ask my doctor for more information. 50 51 I can withdraw from the study at any time without being discriminated against or 52 penalised and my medical rights and treatment will not be affected. 53 54 I am also aware that if I drop out of the study, especially if I drop out of the study 55 56 due to treatment reasons, it will be very beneficial to me and the study as a whole if I 57 tell the doctor about the change in my condition and complete the required physical 58 examination. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 If I need to take any other treatment due to the change in my condition, I will 5 consult my doctor in advance or inform him/her afterwards. 6 7 I grant access to my research materials to the ethics committee or the sponsor's 8 representative. 9 10 11 I will receive a signed and dated copy of the informed consent. In the end, I 12 agree to participate in the study and will try to follow my doctor's advice. 13 14 15 16 Subject’s signature: Date: 17 18 For peer review only 19 20 Subject contact number: 21 22 23 24 25 Signature of subject’s guardian: Date: 26 27 28 29 Guardian’s contact number: 30 31 32 33 Subject’s guardian is required to sign the informed consent if necessary. 34 35 36
37 Doctor's declaration http://bmjopen.bmj.com/ 38 39 I have fully explained this study in detail to the above participant, including 40 41 his/her rights and possible benefits and risks, and I have answered all his/her 42 questions. To the best of my knowledge, the participant has been informed adequately 43 44 and has consented to the trial.
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 Doctor’s signature: Date: 49 50 51 52 Doctor contact number: 53 54 55 56 In the event of inconsistency or discrepancy between the Chinese version and the 57 58 English version, the Chinese language version shall prevail. 59 60
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1 2 3 4 5 6 7 8 9 10 11 12 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents* 20 21 22 23 Section/item Item Description Addressed on 24 No page number 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 Administrative information 29 30 31 Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______2______32 33 34 Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _____ 5______35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 2b All items from the World Health Organization Trial Registration Data Set _____ 5______6 7 8 Protocol version 3 Date and version identifier ______4______9 10 11 Funding 4 Sources and types of financial, material, and other support _____22-23 ____ 12 For peer review only 13 14 Roles and 5a Names, affiliations, and roles of protocol contributors _____2,22______15 16 responsibilities 17 http://bmjopen.bmj.com/ 5b Name and contact information for the trial sponsor ______2______18 19 20 5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and 21 22 interpretation of data; writing of the report; and the decision to submit the report for publication, including 23 ______22______whether they will have ultimate authority over any of these activities 24 25 on September 27, 2021 by guest. Protected copyright. 26 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication ______17______27 28 committee, data management team, and other individuals or groups overseeing the trial, if applicable (see 29 Item 21a for data monitoring committee) 30 31 32 33 34 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 6 Introduction 7 8 9 Background and 6a Description of research question and justification for undertaking the trial, including summary of relevant _____7-8______10 rationale studies (published and unpublished) examining benefits and harms for each intervention 11 12 For peer review only 13 6b Explanation for choice of comparators __12-13,21-22__ 14 15 16
Objectives 7 Specific objectives or hypotheses http://bmjopen.bmj.com/ ______8______17 18 19 Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), 20 21 allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 22 _____8,17______23 24 25 on September 27, 2021 by guest. Protected copyright. Methods: Participants, interventions, and outcomes 26 27 28 Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will _____10______29 30 be collected. Reference to where list of study sites can be obtained 31 32 33 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and ___10-11,13____ 34 individuals who will perform the interventions (eg, surgeons, psychotherapists) 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be _____12-14_____ 6 7 administered 8 9 10 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose ___15-16,17____ 11 change in response to harms, participant request, or improving/worsening disease) 12 For peer review only 13 14 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence _____ 22 _____ 15 16 (eg, drug tablet return, laboratory tests) 17 http://bmjopen.bmj.com/ 18 19 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial ____12-13_____ 20 21 22 Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood 23 pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, 24 ____14-15______25 median, proportion), and time point for each outcome. Explanation of the clinical on September 27, 2021 by guest. Protected copyright. relevance of chosen 26 efficacy and harm outcomes is strongly recommended 27 28 29 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for ___9(table 1)____ 30 31 participants. A schematic diagram is highly recommended (see Figure) 32 33 34 Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including ____ 17-18_____ 35 clinical and statistical assumptions supporting any sample size calculations 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______10______6 7 8 9 Methods: Assignment of interventions (for controlled trials) 10 11 12 Allocation: For peer review only 13 14 15 Sequence 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any _____11______16 17 generation factors for stratification. To reduce predictability of a random sequence, details of anyhttp://bmjopen.bmj.com/ planned restriction (eg, 18 blocking) should be provided in a separate document that is unavailable to those who enrol participants or 19 20 assign interventions 21 22 23 Allocation 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, _____11______24 concealment sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 25 on September 27, 2021 by guest. Protected copyright. 26 mechanism 27 28 29 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to ____10,11____ 30 interventions 31 32 33 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome ______11______34 35 assessors, data analysts), and how 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s _Not applicable, 6 7 allocated intervention during the trial data collectors and 8 statisticians are 9 10 11 blinded _____ 12 For peer review only 13 14 Methods: Data collection, management, and analysis 15 16 17 http://bmjopen.bmj.com/ Data collection 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related ___14-15,16___ 18 19 methods processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of 20 study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. 21 22 Reference to where data collection forms can be found, if not in the protocol 23 24 25 18b Plans to promote participant retention and complete follow-up, including list of any on September 27, 2021 by guest. Protected copyright. outcome data to be ____ 22______26 collected for participants who discontinue or deviate from intervention protocols 27 28 29 Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality _____16______30 31 (eg, double data entry; range checks for data values). Reference to where details of data management 32 procedures can be found, if not in the protocol 33 34 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the ____18-19_____ 6 7 statistical analysis plan can be found, if not in the protocol 8 9 10 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______19_____ 11 12 For peer review only 13 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any 14 statistical methods to handle missing data (eg, multiple imputation) 15 ____17,18______16 17 http://bmjopen.bmj.com/ 18 19 Methods: Monitoring 20 21 22 Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of ______17_____ 23 whether it is independent from the sponsor and competing interests; and reference to where further details 24 25 about its charter can be found, if not in the protocol. Alternatively, an explanation on September 27, 2021 by guest. Protected copyright. of why a DMC is not 26 needed 27 28 29 30 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim _____17______31 results and make the final decision to terminate the trial 32 33 34 Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse ____15-16______35 36 events and other unintended effects of trial interventions or trial conduct 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent _____17_____ 6 7 from investigators and the sponsor 8 9 10 Ethics and dissemination 11 12 For peer review only 13 Research ethics 24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ___19-20,23____ 14 15 approval 16 17 http://bmjopen.bmj.com/ 18 Protocol 25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, ______19______19 amendments analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, 20 21 regulators) 22 23 24 Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and ______10______25 on September 27, 2021 by guest. Protected copyright. how (see Item 32) 26 27 28 26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary _Not applicable__ 29 30 studies, if applicable 31 32 33 Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained _____23______34 35 in order to protect confidentiality before, during, and after the trial 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Declaration of 28 Financial and other competing interests for principal investigators for the overall trial and each study site _____23______6 7 interests 8 9 10 Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that _____17,23_____ 11 limit such access for investigators 12 For peer review only 13 14 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial _____16______15 16 post-trial care participation 17 http://bmjopen.bmj.com/ 18 19 Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the _____20______20 public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing 21 22 arrangements), including any publication restrictions 23 24 25 31b Authorship eligibility guidelines and any intended use of professional writers on September 27, 2021 by guest. Protected copyright. _ Not applicable__ 26 27 28 31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______23______29 30 31 32 Appendices 33 34 35 Informed consent 32 Model consent form and other related documentation given to participants and authorised surrogates 10 36 materials 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Biological 33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular _Not applicable__ 6 7 specimens analysis in the current trial and for future use in ancillary studies, if applicable 8 9 10 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification 11 on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 12 For peer review only 13 Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 14 15 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 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 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
Efficacy of electroacupuncture for the treatment of constipation in Parkinson's disease：study protocol for a multi-centre randomised controlled trial ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2019-029841.R2
Article Type: Protocol
Date Submitted by the 27-Aug-2019 Author:
Complete List of Authors: Li, kunshan; Shanghai University of Traditional Chinese Medicine, Wang, Zhaoqin; Shanghai University of Traditional Chinese Medicine Chen, Yiyi; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine Shen, Lirong; Shanghai Pudong New Area Hospital of Chinese Medicine Li, Zhongqiu; Shanghai University of Traditional Chinese Medicine Wu, Yiwen; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine Yuan, Canxing; Longhua Hospital, Shanghai University of Traditional Chinese Medicine Huang, Yan; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine
Wu, Luyi; Shanghai University of Traditional Chinese Medicine http://bmjopen.bmj.com/ Bao, Chunhui; Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of Traditional Chinese Medicine Zhang, wei; Fudan University, Departement of Biostatistics, School of Public Health Xu, Shifen; Shanghai University of Traditional Chinese Medicine Wu, Huangan; Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine
Primary Subject
Complementary medicine on September 27, 2021 by guest. Protected copyright. Heading:
Secondary Subject Heading: Neurology, Gastroenterology and hepatology
Constipation, Parkinson's disease, Acupuncture, Randomised controlled Keywords: trial
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Efficacy of electroacupuncture for the treatment of 5 6 constipation in Parkinson's disease ： study protocol for a 7 8 9 multi-centre randomised controlled trial 10 Kunshan Li,1* Zhaoqin Wang,1* Yiyi Chen,2 Lirong Shen,3 Zhongqiu Li,1 Yiwen Wu,4 11 12 Canxing Yuan,5 Yan Huang,6 Luyi Wu,1 Chunhui Bao,6 Wei Zhang7, Shifen Xu,8 13 14 Huangan Wu2 15 16 17 Author affiliations 18 For peer review only 19 1Shanghai University of Traditional Chinese Medicine, Shanghai, China 20 21 2Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, 22 23 Shanghai University of Traditional Chinese Medicine, Shanghai, China 24 3Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai, China 25 26 4Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 27 28 China 29 5Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 30 31 China 32 33 6Key Laboratory of Acupuncture and Immunological Effects, Shanghai University of 34 35 Traditional Chinese Medicine, Shanghai, China 36 7Departement of Biostatistics, School of Public Health, Fudan University, Shanghai,
37 http://bmjopen.bmj.com/ 38 China 39 40 8Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University 41 42 of Traditional Chinese Medicine, Shanghai, China 43 44
45 * Kunshan Li and Zhaoqin Wang contributed equally to this paper on September 27, 2021 by guest. Protected copyright. 46 47 48 Corresponding authors: 49 50 Professor Huangan Wu,Yueyang Hospital of Integrated Traditional Chinese and 51 52 Western Medicine, Shanghai University of Traditional Chinese Medicine, No. 53 54 110,Gan he road, Shanghai, China 55 Tel: +86 021-64644238 56 57 Email: [email protected] 58 59 60
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1 2 3 Doctor Shifen Xu, Shanghai Municipal Hospital of Traditional Chinese Medicine, BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Shanghai University of Traditional Chinese Medicine, No. 274, Middle Zhi jiang 6 7 road, Shanghai, China 8 Tel: +86 13761931393 9 10 Email: [email protected] 11 12 13 14 Co-authors: 15 Kunshan Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 16 17 Email: [email protected] 18 For peer review only 19 Zhaoqin Wang: Shanghai University of Traditional Chinese Medicine, Shanghai, 20 21 China; 22 Email: [email protected] 23 24 Yiyi Chen: Department of Acupuncture-Moxibustion, Yueyang Hospital of Integrated 25 26 Traditional Chinese and Western Medicine, Shanghai University of Traditional 27 Chinese Medicine, Shanghai, China; 28 29 Email: [email protected] 30 31 Lirong Shen: Shanghai Pudong New Area Hospital of Chinese Medicine, Shanghai, 32 33 China; 34 Email: [email protected] 35 36 Zhongqiu Li: Shanghai University of Traditional Chinese Medicine, Shanghai, China;
37 http://bmjopen.bmj.com/ 38 Email: [email protected] 39 40 Yiwen Wu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 41 Shanghai, China; 42 43 Email:[email protected] 44 Canxing Yuan: Department of Neurology, Longhua Hospital, Shanghai University of
45 on September 27, 2021 by guest. Protected copyright. 46 Traditional Chinese Medicine, Shanghai, China; 47 48 Email: [email protected] 49 50 Yan Huang: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 51 52 University of Traditional Chinese Medicine, Shanghai, China; 53 Email: [email protected] 54 55 Luyi Wu: Shanghai University of Traditional Chinese Medicine, Shanghai, China; 56 57 Email:[email protected] 58 Chunhui Bao: Key Laboratory of Acupuncture and Immunological Effects, Shanghai 59 60 University of Traditional Chinese Medicine, Shanghai, China;
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1 2 3 Email:[email protected] BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Wei Zhang: Departement of Biostatistics, School of Public Health, Fudan University, 6 7 Shanghai, China; 8 Email:[email protected] 9 10 11 12 Version: 20-August-2019 13 14 15 Word count: 4495 16 17 Keywords: Constipation; Parkinson's disease; Acupuncture; Randomised controlled 18 For peer review only 19 trial 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
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1 2 3 ABSTRACT BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Introduction Constipation is one of the most common non-motor symptoms (NMSs) 6 7 in Parkinson's disease (PD). Acupuncture can have a positive on chronic functional 8 constipation and PD, but its efficacy for the treatment of constipation in PD has not 9 10 yet been confirmed by high-quality clinical trials. Therefore, this study aims to 11 12 evaluate the efficacy and safety of electroacupuncture (EA) in the treatment of 13 14 constipation in PD. 15 Methods and analysis: This study is a multi-centre randomised controlled trial. A 16 17 total of 124 qualified PD patients with constipation will be randomly divided into the 18 For peer review only 19 intervention group (62 participants will receive 12 weeks of EA + usual care) or the 20 21 waitlist control group (62 participants will receive 12 weeks of usual care). EA will be 22 performed three times per week from weeks 1 to 8, two times per week during weeks 23 24 9 and 10, and once a week during weeks 11 and 12. The primary outcome is the 25 26 change in mean weekly spontaneous bowel movements from baseline to weeks 8 and 27 9. The secondary outcomes are the changes from baseline in mean weekly bowel 28 29 movements, mean weekly stool consistency, and mean weekly straining. Other 30 31 secondary outcomes include the weekly doses of defecation drugs, Visual Analogue 32 33 Scale for subjective improvements in stool symptoms, Unified Parkinson’s Disease 34 Rating Scale, and the time and number of steps required to walk 20 metres. Outcomes 35 36 will be assessed at baseline; week 4, week 8, and week 12 (intervention period); as
37 http://bmjopen.bmj.com/ 38 well as at week 16, and week 24 (follow-up period). 39 40 Ethics and dissemination Ethical approval has been obtained from four local ethics 41 committees. The results of the study will be published in peer-reviewed journals and 42 43 will be disseminated through national and international conferences. 44 Trial registration number ChiCTR1900021053; Pre-results.
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 ARTICLE SUMMARY BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Strengths and limitations of this study 6 7 This study will be one of the rare randomised controlled trials to assess the 8 clinical efficacy of electroacupuncture (EA) in the treatment of constipation in 9 10 Parkinson's disease (PD). 11 12 In order to optimise the credibility of the research results, a multi-centre trial will 13 14 be utilised for this study. 15 In addition to evaluating the clinical efficacy of EA in the treatment of 16 17 constipation in PD, this study will also investigate whether EA can play a role in 18 For peer review only 19 maintenance therapy. 20 21 This study will not include a sham EA group. Without blinding patients, the 22 placebo effect of EA treatment cannot be ruled out. 23 24 25 26 27 28 29 30 31 32 33 34 35 36
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1 2 3 INTRODUCTION BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 With the increase in the percentage of ageing people in the global population, the 6 7 incidence of Parkinson's disease (PD) is also increasing. The global prevalence rate of 8 PD in the over-65 cohort is 1-3%.1 2 Previous studies have often focused on the 9 10 management in motor symptoms of PD. However, non-motor symptoms (NMSs) 11 12 have received increased attention in recent years. Studies have shown that some 13 3 14 NMSs can occur earlier than motor symptoms, and can seriously affecting the 15 patients’ quality of life. Constipation is one of the most common and earliest NMSs, 16 17 with a prevalence of up to 80% among PD patients.4-6 Fifty percent of patients present 18 For peer review only 19 constipation symptoms 10 to 20 years before the motor symptoms appear.7 Moreover, 20 21 studies indicate that constipation may be one of the risk factors for PD because men 22 or women afflicted with constipation (three or less bowel movements per week) are 23 24 two to five times more likely to be diagnosed with PD in the future compared to those 25 8-10 26 who do not experience from constipation. Furthermore, common drugs used to 27 treat PD, such as dopamine agonists, anticholinergics, and 28 29 catechol-oxyl-methyltransferase inhibitors, can aggravate constipation symptoms. 30 31 The main cause of constipation in PD is slow colonic transit or pelvic floor and 32 11 33 anal sphincter dysfunction. Therefore, the treatment of constipation in PD usually 34 involves the use of laxative or prokinetic drugs. However, long-term treatment 35 36 increases the likelihood of treatment-related adverse events. Approximately 50% of
37 http://bmjopen.bmj.com/ 38 patients are unsatisfied with these drugs mainly due to their low efficacy, 39 12 40 inconsistency, or associated adverse events. 41 Acupuncture is an age-old practice in China, which has gained global popularity 42 43 in recent decades. Studies have shown that acupuncture can increase stool frequency 44 and improve stool consistency in functional constipation.13 14 In addition, acupuncture
45 on September 27, 2021 by guest. Protected copyright. 46 can delay the progression of PD to some extent.15 16 It can play an important role in 47 48 reducing adverse reactions to medicine and improving non-motor symptoms.17-19 49 50 Nevertheless, we have not yet found a high-quality randomised controlled trial (RCT) 51 52 study on acupuncture treatment for constipation in PD patients. 53 Electroacupuncture (EA) is a form of acupuncture therapy that combines 54 55 traditional acupuncture with electrical stimulation. The advantage of EA therapy is 56 57 that the amount of stimulation can be objectively controlled, and the frequency and 58 intensity of stimulation is replicable, ensuring that participants in clinical studies 59 60 receive similar stimulation. In addition, as a form of acupuncture, EA is often used to
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1 2 3 treat constipation and PD.14 15 19 Based on our previous studies, we have found that BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 acupuncture treatment can ameliorate the symptoms of constipation in PD.20 6 7 Therefore, this study will investigate the efficacy of EA for treating constipation in 8 PD through a multi-centre RCT, in order to verify the feasibility and advantages of 9 10 acupuncture treatment for constipation in PD. 11 12 13 14 METHODS AND ANALYSIS 15 Hypothesis 16 17 Compared with usual care (UC) alone (PD basic therapy + emergency defecation 18 For peer review only 19 medicine), EA + UC will increase the frequency of defecation, ameliorate stool 20 21 consistency and straining. 22 23 24 Study design 25 26 This study is a multi-centre, parallel design RCT with blinded data collectors. It is 27 estimated that 124 patients will be recruited and randomly divided into the 28 29 intervention group (EA+UC) or the waitlist control group (UC alone) in a 1:1 ratio 30 31 using stratified randomisation. The participants in the two groups will be treated for 32 33 12 weeks, and will then be followed-up for 12 weeks. The flow chart of the trial 34 process is shown in Figure 1. The research process and data collection are described 35 36 in detail in Table 1 and Figure 2.
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1 2 3 Table 1 Schedule of enrolment, interventions and assessments BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Study period Enrollment Intervention period Follow-up period 7 8 Time point Week -2 0-Point Week 4 Week 8 Week 12 Week 16 Week 24 9 Eligibility screening × × 10 Informed consent × 11 12 Randomization × 13 Primary outcome Mean weekly SBMs* × × × × × × 14 15 Mean weekly BMs* × × × × × × 16 Mean weekly stool 17 × × × × × × consistency* 18 For peer review only 19 Mean weekly straining * × × × × × × 20 Secondary outcomes Weekly emergency 21 defecation drugs Usage * × × × × × × 22 23 UPDRS-Ⅱ and UPDRS-Ⅲ × × × × 24 25 Gait Speed (20 metres walk) × × × × 26 VAS × × × × × × 27 28 AEs × × × × × 29 30 Compliance evaluation × × × × × 31 H&Y stage, Hoehn-Yahr stage; MMSE, Mini-Mental State Examination; SBMs, spontaneous bowel movements; 32 BMs, bowel movements; Unified Parkinson’s Disease Rating Scale, UPDRS; VAS, Visual Analogue Scale; AEs, 33 34 adverse events. 35 * The results are based on the stool diary, which records the patient's stool for 2 weeks. Therefore, each stool diary 36 recording time is -2-0 weeks, 4-5 weeks, 8-9 weeks, 12-13 weeks, 16-17 weeks, and 23-24 weeks.
37 http://bmjopen.bmj.com/ 38 39 Recruitment, setting, and participants 40 41 The trial will be conducted at Yueyang Hospital of Integrated Traditional Chinese and 42 Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of Traditional 43 44 Chinese Medicine, and Shuguang Hospital, all of which are affiliated with Shanghai
45 on September 27, 2021 by guest. Protected copyright. 46 University of Traditional Chinese Medicine. The participants will be recruited 47 48 through published advertisements in newspapers or by recruitment notices posted on 49 the official network information platforms and the bulletin boards of each study site. 50 51 Interested participants can contact the researchers through the provided telephone 52 53 numbers. An independent researcher will conduct face-to-face interviews with the 54 55 participants to explain the study, and those who volunteer to participate will be 56 required to sign consent forms (see online supplementary file 1). After a baseline 57 58 screening visit, participants who meet the eligibility criteria will be able to participate 59 60 in the study.
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1 2 3 Inclusion criteria BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 To be included in the trial, participants must (1) have a diagnosis of idiopathic 6 7 Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank 8 Clinical Diagnostic Criteria;21 (2) meet the diagnostic criteria of Roman IV diagnostic 9 10 criteria for functional constipation;22 (3) be aged between 40 and 80 years; (4) have 11 12 PD for ≥6 months and constipation for ≥3 months; (5) have mean weekly spontaneous 13 # 14 bowel movements (SBMs) <3 times ; (6) be unsatisfied with their current 15 constipation treatment or have not yet received constipation treatment; (7) be in stages 16 17 1 to 4 of the Hoehn and Yahr (H&Y) scale; (8) be a voluntary participant in the study, 18 For peer review only 19 agree to undergo relevant examinations and treatments, and sign the informed consent 20 21 form. 22 # Based on the patient's -2 and 0 weeks stool diary record. 23 24 25 Exclusion criteria 26 27 The exclusion criteria are as follows: (1) serious cardiovascular and cerebrovascular 28 diseases, hematopoietic diseases, malignant tumours, or other serious life-threatening 29 30 diseases; (2) diagnosis of schizophrenia, major depression, or cognitive impairment 31 32 (Cognitive impairment is defined based on the Mini-Mental State Examination 33 [MMSE], which categorises cognitive impairment based on different educational 34 35 levels. The definition of these criteria are as follows: people who are illiterate, have 36
37 only received primary school education, or have formal education higher than primary http://bmjopen.bmj.com/ 38 39 education will be classified as having cognitive impairment if they score less than 14, 40 20, or 24 respectively on the MMSE); (3) history of laparotomy or anorectal surgery 41 42 (except for haemorrhoid surgery, appendectomy in the last year, or inguinal hernia 43 44 repair) that may affect intestinal transit; (4) anal tumours, malformations, suspected
45 on September 27, 2021 by guest. Protected copyright. 46 intestinal obstruction, or other organic diseases leading to constipation; (5) EA cannot 47 be performed on acupuncture points due to skin diseases, limb defects, or other 48 49 conditions; (6) involvement in other clinical trials or having undergone acupuncture 50 51 treatment within 30 days before participantion, which may affect the results of this 52 study; (7) acute gastrointestinal disease diagnosed within two weeks before treatment; 53 54 (8) allergy to lactulose solution or glycerine enema; and (9) pregnancy or lactation 55 56 (under 60-year-old females will need to undergo a urine pregnancy test). 57 58 59 Randomisation and allocation concealment 60
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1 2 3 Patients will be randomly assigned to the intervention group or the waitlist control BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 group in a 1:1 ratio using stratified randomisation. The stratification will be based on 6 7 two factors: (1) the severity of constipation (SBMs weekly = 2 times or SBMs weekly 8 <2 times); and (2) the study site. Independent statisticians will provide 9 10 computer-generated random sequences and each stratum will be generated from a 11 12 separate random sequence. Distribution will be conducted by a central web-based 13 14 interactive randomisation service system. To prevent the researcher from predicting 15 which group the next patient is allocated to, we will use the variable block 16 17 randomisation method (block size of four or six). When a participant is eligible, the 18 For peer review only 19 researcher who conducted the random grouping will need to log onto the website to 20 21 see the grouping situation of this participant. 22 23 24 Blinding 25 26 This trial is not blind to patients and acupuncturists, however data collectors will be 27 blinded. To improve blinding, each centre will have one acupuncturist and one data 28 29 collector. The data collection location is independent of the treatment room. Patients 30 31 and acupuncturists will be required to not disclose the patient's group allocation to the 32 33 data collectors at any point during the trial. An independent statistician will conduct 34 the statistical analyses of the results. 35 36
37 http://bmjopen.bmj.com/ 38 Interventions 39 40 During the trial, both groups will receive usual care (UC). In the intervention group, 41 participants will receive electroacupuncture (EA) during weeks 1 to 12. In the waitlist 42 43 control group, participants have the option to receive 24 true acupuncture bonus 44 sessions upon conclusion of the study (i.e. after week 24).
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 UC treatments in both groups 49 50 Treatment of PD 51 52 Considering the complexity of the clinical manifestations of PD and the principles of 53 individualised treatment in PD clinical guidelines, the treatment for PD in this trial 54 55 will not be strictly standardised. However, if the participant has received PD 56 57 medication before enrolment, the dosage of the medicine should not be changed 58 arbitrarily. The dose of different drugs can be converted to a total daily levodopa 59 60 equivalent dose (LED).23
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1 2 3 Emergency treatment for constipation BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 If patients have no BMs for three or more consecutive days, they will be permitted to 6 7 use an emergency treatment, which will be provided by the researchers. There are 8 several options available to patients. For patients with no urge to defecate, it will be 9 10 recommended that they first take oral lactulose solutions under the following 11 12 protocol: 15 mL of oral lactulose solutions (oral lactulose solution, H20171057, 13 14 Abbott Healthcare Products B.V. 15 mL/bag) taken at 12-hour intervals; if 15 ineffective, 30 mL of oral lactulose solutions should be taken on the second day at 16 17 12-hour intervals. For patients who have an urge to defecate but are unable to pass 18 For peer review only 19 stool, 20 mL of glycerine enemas (glycerine enema, H31021363, Shanghai Yunjia 20 21 Huangpu Pharmaceutical Co. Ltd.; 20 mL/bottle) by rectal injection will be 22 recommended. A combination of the two treatments will be recommended for patients 23 24 who fail to respond to emergency treatment for two days. Patients will be advised not 25 26 to use any other emergency treatments. Each use of emergency treatment will be 27 recorded in the stool diary. If any other emergency treatment medication is used, this 28 29 will also be recorded in the stool diary. 30 31 32 33 EA add-on treatment in the intervention group 34 Thirty EA sessions will be performed over a period of 12 weeks, with three sessions 35 36 per week from weeks 1 to 8, two sessions per week during weeks 9 and 10, and one
37 http://bmjopen.bmj.com/ 38 session per week during weeks 11 and 12. 39 40 The acupuncturists who will provide treatment are qualified doctors with a 41 qualification certificate in Traditional Chinese Medicine and at least two years of 42 43 acupuncture experience. They are required to be registered with the Chinese Medical 44 Doctor Association. All acupuncturists will receive one training session before
45 on September 27, 2021 by guest. Protected copyright. 46 commencing the study. Acupuncturists need to explain the EA treatment process to 47 48 the patients and should describe any possible sensations during the treatment before 49 50 starting the procedure. 51 52 Each patient in the intervention group will be treated at the bilateral acupoints of 53 Connection Qianding (GV21) to Xuanlu (GB5), Connect Qianshencong (EX-HN1) to 54 55 Xuanli (GB6), Tianshu (ST25), Fujie (SP14), Quchi (LI11), Hegu (LI4), 56 57 Yanglingquan (GB34), Shangjuxu (ST37), Sanyinjiao (SP6), Zhaohai (KI6), and 58 Taichong (LR3). When the patients are supine, they are to be treated with single-use 59 60 stainless steel acupuncture needles (Hwato). Acupuncture on Tianshu (ST25) and
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1 2 3 Fujie (SP14) will be performed with 0.30 mm × 50 mm or 0.30 mm × 75 mm needles BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 (depending on the patient's body type), inserted slowly and vertically approximately 6 7 45 mm - 65mm until the muscle layer of the abdominal wall is pierced. Acupuncture 8 on the bilateral lines from Qianding (GV21) to Xuanlu (GB 5), the bilateral lines from 9 10 Qianshencong (EX-HN1) to Xuanli (GB6) (for each line, two needles will be 11 12 inserted), Hegu (LI4), Zhaohai (KI6), and Taichong (LR3) will be punctured with 13 14 0.25 mm × 25 mm needles, inserted approximately 10 mm - 20 mm deep. Quchi 15 (LI11), Yanglingquan (GB34), Shangjuxu (ST37), and Sanyinjiao (SP6) will be 16 17 punctured using 0.25 mm × 40 mm needles inserted approximately 30 mm - 35 mm 18 For peer review only 19 deep. Manipulations such as twirling, lifting, and thrusting will be performed to reach 20 21 de qi, which is the sensation unique to acupuncture that includes soreness, heaviness, 22 and distension. Paired alligator clips from the EA instrument (SDZ-III EA device, 23 24 Hua Tuo, Suzhou medical equipment) will be connected to Qianding (GV21) to 25 26 Xuanlu (GB5; tremor type) or Connect Qianshencong (EX-HN1) to Xuanli (GB6; 27 stiff type). In this case, either pairing may be selected according to the clinical 28 29 manifestation of the patient’s motor symptoms. The left acupoint is paired with the 30 31 left acupoint, and the right acupoint is paired with the right acupoint. Finally, the 32 33 bilateral points Tianshu (ST25) and Fujie (SP14) will be connected transversely to the 34 EA instrument. The frequency of the wave is 10/50 Hz; 10 Hz lasts for five seconds, 35 36 while 50 Hz lasts for ten seconds. The output pulse width is 0.2 ms ± 30%. The
37 http://bmjopen.bmj.com/ 38 intensity of the current will be between 1 mA and 10 mA, depending on the level the 39 40 patient feels comfortable without feeling pain. EA treatment will last for 30 minutes. 41 42 43 Outcome measures and evaluation 44 Primary outcome
45 on September 27, 2021 by guest. Protected copyright. 46 The primary outcome is the change in mean weekly spontaneous bowel movements 47 48 (SBMs) from baseline to weeks 8 and 9. SBM is defined as the number of times 49 50 defecation has occurred in the past 24 hours without the use of emergency drugs or 51 52 other methods to aid defecation. The data collectors will inform patients how to 53 complete the stool diary. 54 55 56 57 Secondary outcomes 58 The secondary outcomes include the evaluation of constipation and PD with the 59 60 following protocol: (1) Assessment of constipation: changes from baseline in mean
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1 2 3 weekly BMs, mean weekly stool consistency (according to the Bristol Stool Form BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Scale score), and mean weekly straining score based on the stool diary; mean weekly 6 7 frequency and mean dosage of emergency defecation drugs based on the stool diary; 8 and use of visual analogue scale (VAS) to measure improvements in the patient's 9 10 subjective stool symptoms. (2) Assessment of PD symptoms: sections II (motor 11 12 experiences of daily living) and III (motor examination) of the Unified Parkinson’s 13 14 Disease Rating Scale (UPDRS) are used. If the patients appear "on/off", the status of 15 the patients in the "on" stage is assessed. The time and number of steps required to 16 17 walk 20 metres (including step speed and average step distance) is also observed. 18 For peer review only 19 Evaluation time points are shown in detail in Figure 2. 20 21 22 Safety assessment 23 24 All patients will report any adverse event (AE, described as unfavourable symptoms 25 26 or diseases during the trial related to treatment of PD, emergency treatment for 27 constipation, and acupuncture) to the acupuncturists to avoid the data collectors 28 29 becoming aware of the patient's group allocation. Common AEs related to 30 31 acupuncture include fainting, local ecchymoses, continuous pain, acupoint location 32 33 infection and dizziness, while AEs related to PD treatment include nausea, vomiting, 34 hypotension, dry mouth, and oedema. Common AEs related to emergency treatment 35 36 for constipation include flatulence, abdominal pain, and diarrhoea. The relationships
37 http://bmjopen.bmj.com/ 38 between AEs and intervention methods will be assessed using the Standardized Case 39 40 Causality Assessment. We ask patients in both groups to call acupuncturists to report 41 any discomfort during the trial, and the acupuncturists need to ask in detail and 42 43 determine their relevance to treatment. When AEs are identified as being associated 44 with the intervention, it will be divided into general AEs or the other AEs. The other
45 on September 27, 2021 by guest. Protected copyright. 46 AEs may lead to stopping the intervention, such as fainting, acupoint location 47 48 infection, vomiting, hypotension and diarrhoea occur. Acupuncturists should evaluate 49 50 the patient's condition to decide whether the treatment can be continued if they 51 52 happen. The results of AEs will be described as the number and proportion (%) of 53 AEs. 54 55 Any severe adverse event (SAE) will be determined in accordance with the 56 24 57 International Conference on Harmonization’s harmonised tripartite guidelines and 58 must be reported to the Independent Data and Safety Monitoring Board (DSMB). 59 60
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1 2 3 Data collection BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 Each centre will have one data collector. Except for the stool diary, which will be 6 7 completed by the patients, all efficacy indicators will be completed by the data 8 collectors. All data collectors will receive training on how to administer the UPDRS 9 10 and other scales. 11 12 13 14 Data management 15 Data entry procedure 16 17 The electronic data capture (EDC) system will be used for data entry and data 18 For peer review only 19 management. Data entry will be carried out by one data collector who will be 20 21 allocated to each centre. After clinical raw data collection has been completed, the 22 data collectors will forward the data to the supervisor of the project for review. Error 23 24 correction and data export will be conducted by the supervisor. After verification, the 25 26 database will be locked and undergo statistical analysis. Participant information will 27 be stored in the EDC system, which researchers can access using a password. The 28 29 ethical review boards and DSMB shall have the right to consult the relevant records 30 31 when necessary. 32 33 34 Data interrogation procedure 35 36 If the authenticity of the data is questioned, the data collector will be notified by the
37 http://bmjopen.bmj.com/ 38 supervisor in the form of a data question form. The data collector’s response will be 39 40 entered into the data question form and returned to the statistician by the supervisor. 41 42 43 Missing data procedure 44 Missing data on the primary outcome will be imputed using multiple imputation
45 on September 27, 2021 by guest. Protected copyright. 46 according to the missing-at-random assumption. A control-based model will be used 47 48 to evaluate the sensitivity to missing data departure from the assumption. The 49 50 regression-based multiple imputation with baseline of mean weekly spontaneous 51 52 bowel movements as fixed effect will be used. Multiple imputation will be used to 53 impute missing data in full analysis set and per-protocol set. 54 55 56 57 Data monitoring 58 This study established an independent Data and Safety Monitoring Board (DSMB), 59 60 which is independent of the sponsor, consisting of an acupuncturist, a rehabilitation
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1 2 3 specialist, and a statistician. The DSMB will supervises whether the trial follows the BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 study design and standard guidelines, will monitor the progress of the trial, and will 6 7 observe whether AEs and aetiologies are adequately recorded. Acupuncturists will 8 need to assess, manage, and classify AEs. In the event of a SAE, it must be reported 9 10 to the main researchers, ethics committees, and the DSMB within 24 hours of the 11 12 occurrence. The DSMB and the main researchers will discuss the issue. The ethics 13 14 committees and the DSMB have the right to terminate the trial. 15 16 17 Sample size 18 For peer review only 19 We conducted a pilot trial to observe the effects of EA on PD patients with 20 21 constipation in Yueyang Hospital of Integrated Traditional Chinese and Western 22 Medicine and Shanghai Municipal Hospital of Traditional Chinese Medicine. The 23 24 results show that: an increase in mean weekly spontaneous bowel movements (SBMs) 25 26 from baseline to week 8 and 9 was 0.925, with a standard deviation (SD) of 1.873 in 27 the intervention group; an increase in mean weekly SBMs from baseline to week 8 28 29 and 9 was -0.323, with a SD of 1.127 in the waitlist control group (see online 30 31 supplementary file 2). The normality of the primary outcome in two groups were 32 33 validated by Shapiro-Wilk test. We used two-sample t-test by power analysis and 34 sample size (PASS) software with a power of 90% and a two-tailed significance level 35 36 of 0.05 to determine the required sample size. For a more conservative estimate, we
37 http://bmjopen.bmj.com/ 38 set the SD in both groups at 1.87. Assuming a 20% dropout rate, the sample size will 39 40 need to be to 62 per group, resulting in a total of 124 participants required for the 41 study. 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 Data sets included in the statistical analysis 47 48 Full analysis set (FAS) with modified intention-to-treat 49 50 Patients in the intervention group will receive at least one treatment and have one 51 52 therapeutic evaluation following treatment. Patients in the waitlist control group will 53 receive at least two evaluations. 54 55 56 57 Per protocol set (PPS) 58 Patients in this data set must meet the following criteria: (1) patients in both groups 59 60 must complete the efficacy evaluation in week 12; (2) patients in the intervention
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1 2 3 group must reach a certain level of compliance, that is, patients must complete at least BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 80% of the 30 EA treatment sessions (i.e. ≤6 EA sessions may be missed). 6 7 8 Safety set (SS) 9 10 All patients will undergo at least one safety assessment. 11 12 13 14 Statistical analysis 15 The statistical analysis will be performed using Statistical Analysis System (SAS) 9.4 16 17 software with a two-tailed P value of less than 0.05 considered statistically 18 For peer review only 19 significant. Continuous data will be described in means and standard deviations or 20 21 median and interquartile ranges. Discrete data will be reported as a frequency and 22 corresponding percentage. 23 24 The primary outcome is the change from baseline in mean weekly spontaneous 25 26 bowel movements (SBMs) during weeks 8-9. The number of SBMs during weeks 8-9 27 and weeks -2-0 will be divided by two respectively to get the mean weekly number of 28 29 SBMs. Then, the mean weekly of SBMs at weeks -2-0 will be subtracted from the 30 31 mean weekly of SBMs at weeks 8-9. Analysis of the FAS and PPS will be conducted 32 33 simultaneously. We will assess the primary outcome by generalized linear model, 34 including group, baseline SBMs and site as fixed effects and age, visit number, rescue 35 36 medicine and other defecation as possible covariates. The result will be presented by
37 http://bmjopen.bmj.com/ 38 P value and 95% confidence interval. 39 40 Analysis of the secondary outcomes will be based on data from the FAS. The 41 outcomes include (1) the changes from baseline in mean weekly BMs, mean weekly 42 43 stool consistency (according to the Bristol Stool Form Scale score), and mean weekly 44 straining score; (2) mean weekly frequency and mean dosage of emergency
45 on September 27, 2021 by guest. Protected copyright. 46 defecation drugs; (3) VAS score on subjective improvements in stool symptoms; (4) 47 48 sections II and III of the UPDRS; and (5) the time and number of steps required to 49 50 walk 20 metres (including step speed and average step distance). The same statistical 51 52 methods used for the primary outcome will be used to analyse mean weekly bowel 53 movements, mean weekly stool consistency, mean weekly straining score, step speed 54 55 and average step distance, and UPDRS scores. In addition, the weekly mean dosage of 56 57 emergency defecation drugs used will be compared between the two groups using an 58 independent samples t-test or Wilcoxon rank-sum test, and their mean frequencies 59 60 will be compared using a Chi-square test or Fisher’s exact test. VAS for stool
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1 2 3 symptoms will be compared between the two groups using Wilcoxon rank-sum test. BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 The results will be presented by P value and 95% confidence interval. 6 7 The safety evaluation will use data from the SS group. Adverse events (AEs) and 8 serious adverse events (SAEs) will be compared between the two groups using a 9 10 Chi-square test or Fisher’s exact test. 11 12 13 Patient and public involvement 14 15 The patients and the general public were not involved in the design of this research. 16 17 18 Ethics and disseminationFor peer review only 19 20 This study protocol has been approved by four local ethics committees including 21 22 those at: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine 23 (Approval No. 2018-121), Longhua Hospital (Approval No. 2019LCSY034), 24 25 Shanghai Municipal Hospital of Traditional Chinese Medicine (Approval No. 26 27 2019SHL-KY-07-02), and Shuguang Hospital (Approval No. 2019-676-31-01). This 28 study conforms to the Declaration of Helsinki principles. Written informed consent 29 30 will be obtained from all participants who agree to take part in this study. Any major 31 32 modification of the protocol will be approved by the Ethical Review Board and the 33 34 DSMB and will be documented on the Chinese Clinical Trials Registry. 35 During data collection, the data will be stored in a password-protected database. 36
37 We plan to have the results of this study published in a peer-reviewed journal on time http://bmjopen.bmj.com/ 38 39 and disseminated through national and international conferences. 40 41 42 DISCUSSION 43 44 Non-motor symptoms (NMSs) in PD are receiving increased attention from
45 on September 27, 2021 by guest. Protected copyright. 25-28 46 physicians and researchers. The efficacy of acupuncture in the treatment of NMSs 47 in PD, such as sleep disorders and depression, has been supported by research.18 29 48 49 However, there is still insufficient clinical research regarding use of acupuncture to 50 51 treat constipation in PD. The efficacy of electroacupuncture (EA) in the treatment of 52 19 53 functional constipation has global value. Meanwhile, previous studies have shown 54 that using acupuncture as an auxiliary therapy for PD can reduce toxicity and lead to 55 56 increasing the efficacy of medication29-31 Therefore, we hypothesised that EA therapy 57 58 can ameliorate constipation in PD, although this hypothesis has not yet been 59 supported by high-quality research. We designed this RCT to provide better evidence 60
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1 2 3 of the efficacy of EA for constipation in PD. BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 At present, treatments for constipation in PD mostly include oral medications, 6 7 which can alleviate the clinical symptoms of functional constipation, but do not 8 benefit PD itself.32-34 This study examined constipation and motor symptoms 9 10 simultaneously because constipation in PD patients is distinct from simple functional 11 12 constipation owing to the interaction between parkinsonian motor symptoms and 13 14 constipation. The aggravation of motor symptoms leads to a decrease in patients' daily 15 activities and an increase in drug dosage, both of which may exacerbate constipation. 16 17 Clinical studies have confirmed that severe constipation in PD patients is caused by 18 For peer review only 19 the loss of dopaminergic neurons in the intestinal muscles.35 We believe that 20 21 treatment of PD may assist in reducing the loss of dopaminergic neurons in the body 22 to a certain extent, which will be helpful in treating constipation. Meanwhile, 23 24 constipation is also a risk factor for the development of PD.8-10 Chronic constipation 25 26 leads to weakening gastrointestinal function, which may reduce the absorption of 27 28 drugs and is consequently detrimental to the improvement of motor symptoms. If 29 patients' motor symptoms worsen, they may need to increase the dosage of drugs, but 30 31 some drugs can worsen the symptoms of constipation, which in turn creates a vicious 32 33 cycle. To some extent, treating motor symptoms also helps to improve the symptoms 34 of constipation. 35 36 Clinical trials of previous acupuncture treatments for PD have shown positive17
37 http://bmjopen.bmj.com/ 38 36 37 and negative18 38 39 results. Upon evaluation of the related articles, we suggest that 39 40 the negative results may be related to the long intervals between acupuncture 41 treatment and the short treatment period, which may have resulted in an insufficient 42 43 dosage of acupuncture stimulation. Different amounts of stimulation may affect the 44 efficacy of acupuncture,40 which may account for this inconsistency.41 Therefore, in
45 on September 27, 2021 by guest. Protected copyright. 46 47 order to obtain a more accurate result, the intervention group receiving three EA 48 treatment sessions per week from weeks 1 to 8. Maintenance treatments will be 49 50 administered in the form of two sessions per week during weeks 9 and 10, and one 51 52 session per week during weeks 11 and 12. Maintenance treatments serve two 53 purposes. First, to observe whether reducing the treatment frequency can maintain the 54 55 therapeutic effect after acupuncture has achieved a certain therapeutic threshold. This 56 57 will prevent excessive treatment caused by increasing the number of patients' visits. 58 59 Second, maintenance treatments are more economical. If a reduced frequency of 60
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1 2 3 acupuncture sessions remains effective as a maintenance treatment, the economic BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 burden upon patients can be reduced. The maintenance treatments are widely used in 6 7 current researches related to acupuncture.14 42 8 9 This study will not use a sham acupuncture group as a control group. The main 10 reasons for this are as follows: (1) the primary outcome is the number of spontaneous 11 12 bowel movements (SBMs), which is objective and less susceptible to the placebo 13 14 effect; (2) in the pilot study, we used a sham acupuncture treatment. The result 15 indicates that patients in the sham acupuncture group struggled to attend the three 16 17 treatment sessions per week, due to motor limitations and unconspicuous 18 For peer review only 19 improvements in constipation symptoms. Therefore, the drop-out rate is high. 20 21 Due to the high frequency of visits and long-term treatment course in this study, 22 patients will receive free EA treatment and emergency treatment for constipation 23 24 throughout the trial to improve patient compliance. When they finish the relevant 25 26 evaluation, they will receive a transport subsidy for each visit. Upon completing each 27 28 evaluation over the 24-week trial, patients in the waitlist control group can also 29 receive 24 true acupuncture sessions as a reward. 30 31 32 33 TRIAL STATUS 34 Patient recruitment will begin in August 2019 and is expected to finish at the end of 35 36 2022.
37 http://bmjopen.bmj.com/ 38 39 40 Acknowledgements We thank all participants and researchers at each sub-centre for 41 their contribution throughout all stages of this research. 42 43 44 Author Contributions KSL and ZQW are joint first authors. KSL participated in the
45 on September 27, 2021 by guest. Protected copyright. 46 47 design of this study and drafted the manuscript. LYW, CHB, and YH revised and 48 edited this manuscript. WZ was responsible for the statistical plan and design. YYC 49 50 and ZQL participated in the implementation of the project. ZQW, LRS, YWW, and 51 52 CXY will help recruit participants. SFX contributed to the design of this study and 53 critical revisions of the manuscript. HGW conceived this research and is the research 54 55 manager. All authors have read and approved this final manuscript. 56 57 58 59 Funding This work was supported by the Shanghai Science and Technology 60
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1 2 3 Committee (grant number: 18401970700), the National Key Basic Research Program BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 of China (grant number: 2015CB554501) and the Shanghai Municipal Commission of 6 7 Health and Family Planning (grant number: 2018Y0143). The funding agencies have 8 no role in designing the research or the decision to publish research results. 9 10 11 12 Competing interests The authors declare that they have no competing interests. 13 14 15 Ethical approval This study protocol has been approved by four local ethics 16 17 committees including those at: Yueyang Hospital of Integrated Traditional Chinese 18 For peer review only 19 and Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of 20 21 Traditional Chinese Medicine, and Shuguang Hospital. 22 23 24 Data sharing statement We plan to share the results of the study within six months 25 26 after publication of the research results. The dataset will be available from the 27 ResMan repository, http://www.medresman.org/login.aspx. Participants’ basic 28 29 information will not be accessible by the public except for the number of participants, 30 31 gender, inclusion time, inclusion location. 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 2 3 REFERENCES BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 1. Zaichick SV, McGrath KM, Caraveo G. The role of Ca2+ signaling in Parkinson's disease. Dis 7 Model Mech 2017;10(5):519-35. 8 9 2. de Rijk MC, Launer LJ, Berger K, et al. Prevalence of Parkinson's disease in Europe: A 10 collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research 11 12 Group. Neurology 2000;54(11 Suppl 5):S21-3. 13 3. Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features 14 15 and risk factors for Parkinson disease. Ann Neurol 2012;72(6):893-901. 16 17 4. Barichella M, Cereda E, Pezzoli G. Major nutritional issues in the management of Parkinson's 18 disease. Mov DisordFor 2009;24(13):1881-92. peer review only 19 20 5. Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson's disease. 21 Lancet Neurol 2015;14(6):625-39. 22 23 6. Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson's disease. 24 Mov Disord 2015;30(12):1600-11. 25 26 7. Chen Y, Yu M, Liu X, et al. Clinical characteristics and peripheral T cell subsets in Parkinson's 27 disease patients with constipation. Int J Clin Exp Pathol 2015;8(3):2495-504. 28 29 8. Abbott RD, Petrovitch H, White LR, et al. Frequency of bowel movements and the future risk 30 of Parkinson's disease. Neurology 2001;57(3):456-62. 31 32 9. Gao X, Chen H, Schwarzschild MA, et al. A prospective study of bowel movement frequency 33 and risk of Parkinson's disease. Am J Epidemiol 2011;174(5):546-51. 34 35 10. Adams-Carr KL, Bestwick JP, Shribman S, et al. Constipation preceding Parkinson's disease: 36 a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2016;87(7):710-6.
37 http://bmjopen.bmj.com/ 38 11. Pfeiffer RF. Gastrointestinal dysfunction in Parkinson’s disease. Semin Neurol 2011;17(1): 39 10-5. 40 41 12. Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment 42 Pharm Ther 2010;25(5):599-608. 43 44 13. Zheng H, Liu ZS, Zhang W, et al. Acupuncture for patients with chronic functional
45 on September 27, 2021 by guest. Protected copyright. constipation: A randomized controlled trial. Neurogastroenterol Motil 2018;30(7):e13307. 46 47 14. Liu Z, Yan S, Wu J, et al. Acupuncture for chronic severe functional constipation: a 48 randomized trial. Ann Intern Med 2016;165(11):761-69. 49 50 15. Lei H, Toosizadeh N, Schwenk M, et al. A pilot clinical trial to objectively assess the efficacy 51 of electroacupuncture on gait in patients with Parkinson's disease using body worn sensors. PLoS 52 53 One 2016;11(5):e0155613. 54 55 16. Doo KH, Lee JH, Cho SY, et al. A prospective open-label study of combined treatment for 56 idiopathic Parkinson's disease using acupuncture and bee venom acupuncture as an adjunctive 57 58 treatment. J Altern Complement Med 2015;21(10):598-603. 59 17. Fukuda S, Kuriyama N, Tsuru H, et al. Immediate effects of acupuncture on tongue pressure 60
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1 2 3 including swallowing reflex latency in Parkinson's disease. Acupunct Med 2016;34(1):59-61. BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 18. Zeng BY, Zhao K. Effect of acupuncture on the motor and nonmotor symptoms in Parkinson's 6 disease--a review of clinical studies. CNS Neurosci Ther 2016;22(5):333-41. 7 8 19. Wang F, Sun L, Zhang XZ, et al. Effect and potential mechanism of electroacupuncture 9 add-on treatment in patients with Parkinson's disease. Evid Based Complement Alternat Med 10 11 2015;2015:692795. 12 20. Shen LR, Wang QD, Shen LP, et al. Therapeutic observation of acupuncture-moxibustion plus 13 14 Ma Ren capsules for constipation in middle-late stage Parkinson disease. Shanghai Journal of 15 Acupuncture and Moxibustion 2018;37(12):1381-5. 16 17 21. Rajput DR. Accuracy of clinical diagnosis of idiopathic Parkinson's disease. J Neurol 18 Neurosurg PsychiatryFor 1993;56(8):938-9. peer review only 19 20 22. Rome Foundation. Rome Ⅳ diagnostic criteria for functional constipation. 2016. Accessed at 21 www.nature.com/nrgastro/journal/v13/n9/extref/nrgastro.2016.110-s1.pdf. 22 23 23. Tomlinson CL, Rebecca S, Smitaa P, et al. Systematic review of levodopa dose equivalency 24 reporting in Parkinson's disease. Mov Disord 2010;25(15):2649-53. 25 26 24. International Conference on Harmonisation of Techinical Requirements for Registration of 27 Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: safety pharmacology 28 29 studiesfor human pharmaceuticals S7A. http://www. ich. org/ fileadmin/Public_ Web_ Site/ ICH_ 30 31 Products/ Guidelines/ Safety/ S7A/ Step4/ S7A_Guideline. pdf. 32 25. Pfeiffer RF. Non-motor symptoms in Parkinson's disease. Parkinsonism Relat Disord 2016;22 33 34 Suppl 1:S119-22. 35 26. Song R, Grabowska W, Park M, et al. The impact of Tai Chi and Qigong mind-body exercises 36 on motor and non-motor function and quality of life in Parkinson's disease: A systematic review
37 http://bmjopen.bmj.com/ 38 and meta-analysis. Parkinsonism Relat Disord 2017;41. 39 40 27. O’Brien C, Clemson L, Canning CG. Multiple factors, including non-motor impairments, 41 influence decision making with regard to exercise participation in Parkinson’s disease: a 42 43 qualitative enquiry. Disabil Rehabil 2016;38(5):472-81. 44 28. Fox SH, Regina K, Shen-Yang L, et al. The Movement Disorder Society Evidence-Based
45 on September 27, 2021 by guest. Protected copyright. 46 Medicine Review Update: Treatments for the motor symptoms of Parkinson's disease. Mov 47 Disord 2011;26(S3):S2-S41. 48 49 29. Zhuang XL, Wang LL. Acupuncture treatment of Parkinson’s disease system-A report of 29 50 cases. J Tradit Chin Med 2000;20(4):265-7. 51 52 30. Chen FP, Chang CM, Shiu JH, et al. A clinical study of integrating acupuncture and western 53 medicine in treating patients with Parkinson's disease. Am J Chin Med 2015;43(03):407-23. 54 55 31. Lee SH, Lim S. Clinical effectiveness of acupuncture on Parkinson disease: A 56 PRISMA-compliant systematic review and meta-analysis. Medicine 2017;96(3):e5836. 57 58 32. Parkinson Study Group. A randomized trial of relamorelin for constipation in Parkinson's 59 disease (MOVE-PD): Trial results and lessons learned. Parkinsonism Relat Disord 2017;37:101-5. 60
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1 2 3 33. Barichella M, Pacchetti C, Bolliri C, et al. Probiotics and prebiotic fiber for constipation BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 associated with Parkinson disease: An RCT. Neurology 2016;87(12):1274. 6 34. Ondo WG, Kenney C, Sullivan K, et al. Placebo-controlled trial of lubiprostone for 7 8 constipation associated with Parkinson disease. Neurology 2012;78(21):1650-4. 9 35. C Singaram M, Gaumnitz, E. A, C Torbey M, et al. Dopaminergic defect of enteric nervous 10 11 system in Parkinson's disease patients with chronic constipation. Lancet 1995;346(8979):861. 12 36. Doo KH, Lee JH, Cho SY, et al. A prospective open-label study of combined treatment for 13 14 idiopathic Parkinson's disease using acupuncture and bee venom acupuncture as an adjunctive 15 treatment. J Altern Complement Med 2015;21(10):598. 16 17 37. Seung-Yeon C, So-Ra S, Hak Young R, et al. Effectiveness of acupuncture and bee venom 18 acupuncture in idiopathicFor Parkinson's peer disease. review Parkinsonism Relat only Disord 2013;333(8):e115-e15. 19 20 38. Cristian A, Katz ME, Walker RH. Evaluation of acupuncture in the treatment of Parkinson's 21 disease: a double-blind pilot study. Mov Disord 2010;20(9):1185-8. 22 23 39. Kluger BM, Rakowski D, Christian M, et al. Randomized, Controlled Trial of Acupuncture 24 for Fatigue in Parkinson's Disease. Mov Disord 2016;31(7):1027-32. 25 26 40. SjöLund BH. Acupuncture or acupuncture? Pain 2005;114(3):311-2. 27 41. Meng ZH. The quantity-effect relationship of acupuncture. World Chinese Medicine 28 29 2014;(12):1581-5. 30 42. Hershman D L , Unger J M , Heather G , et al. Effect of Acupuncture vs Sham Acupuncture or 31 32 Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage 33 Breast Cancer. JAMA, 2018;320(2):167-76. 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 Figure legends 41 42 43 Figure 1 Flow chart 44
45 Figure 2 Outcome evaluation time point on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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1 Participants 2 recruitment 3 4 5 Screening and informed 6 7 consent 8 Excluded not meeting 9 inclusion criteria 10 11 12 Baseline assessment and stratified 13 ranomisation (n=124) 14 For peer review only 15 16 17 18 19 20 Intervention group(n=62) Waitlist control group(n=62) 21 Received EA+PD basic therapy + Received PD basic therapy + 22 emergency defecation medicine emergency defecation medicine 23 24 for 12 weeks for 12 weeks 25 http://bmjopen.bmj.com/ 26 27 28 29 30 31 Assessment during intervention period 32 (at week 4, week 8, and week 12) 33 on September 27, 2021 by guest. Protected copyright. 34 35 36 37 Assessment during follow-up period 38 (at week 16 and week 24) 39 40 41 42 43 statistical analysis 44 45 46 47 48 49 50 Figure 1 Flow chart 51 52 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ UPDRS-Ⅱ and UPDRS-Ⅲ 1 VAS 2 Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS Gait Speed (20 meter walk) Gait Speed (20 meter walk) VAS VAS VAS VAS 3 4 5 6 -1-2 0 point 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 (week) 7 8 stool stool stool stool stool stool 9 diary diary diary diary diary diary 10 11 12 Figure 2 Outcome evaluation time point 13 14 15 16 17 For peer review only 18 19 20 21 22 23 24 http://bmjopen.bmj.com/ 25 26 27 28 29 30 31 32 on September 27, 2021 by guest. Protected copyright. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 26 of 45
1 2
3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Informed Consent Form-Information Page 5 6 7 Dear participant: 8 9 Your doctor has diagnosed you with constipation in Parkinson's disease. 10 11 You are invited to participate in a study titled “Efficacy of acupuncture for the 12 treatment of constipation in Parkinson's disease：a multi-centre randomised controlled 13 14 trial”. 15 16 Please read the following information as carefully as possible before you decide 17 whether to participate in this study. It can help you understand why this study is being 18 For peer review only 19 done, the procedures and duration of the study, the benefits, the risks you may face, 20 and the discomfort you may experience if you participate in the study. You can 21 22 discuss it with your relatives, friends, or ask your doctor for an explanation to help 23 you make a decision. 24 25 Study background and objectives 26 27 Parkinson's disease (PD) is a kind of progressive neurodegenerative disease 28 29 commonly in people over 50 years old. With the increase in the percentage of ageing 30 people in the global population, the incidence of PD is also increasing. In recent years, 31 32 PD related non-motor symptoms have attracted more attention than ever. Constipation 33 is the most common and earliest non-motion symptom of PD which seriously affects 34 35 the quality of patients’ life . Meanwhile, studies indicate that constipation may be one 36 of the risk factors for the occurrence and development of PD. Furthermore, common
37 drugs used to treat PD, such as dopamine agonists, anticholinergics and http://bmjopen.bmj.com/ 38 39 catechol-oxyl-methyltransferase inhibitors, can aggravate constipation. 40 41 Acupuncture, as a green treatment method, has gained global popularity in recent 42 43 decades. In addition, acupuncture can delay the progression of PD to some extent. It 44 can play an important role in reducing adverse reactions to medicine and improving
45 on September 27, 2021 by guest. Protected copyright. 46 non-motor symptoms. Electroacupuncture is often used to treat constipation and PD. 47 48 Nevertheless, a high-quality randomised controlled trial (RCT) study on acupuncture 49 treatment for constipation in PD patients has been found. Therefore, this study will 50 51 investigate the efficacy of EA for treating constipation in PD through a multi-centre 52 53 randomised controlled trial. 54 55 This study will be conducted at Yueyang Hospital of Integrated Traditional 56 Chinese and Western Medicine, Longhua Hospital, Shanghai Municipal Hospital of 57 58 Traditional Chinese Medicine, and Shuguang Hospital, which are all affiliated to 59 Shanghai University of Traditional Chinese Medicine. 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 If you agree to take part in the study, you will need to do the following: 5 6 1. Before you are enrolled in the study, you will undergo some examinations to 7 determine whether you can participate in the study. The doctor will ask about your 8 medical history. A general physical examination will be conducted as well. 9 10 11 2. If you meet the inclusion criteria, you will be assigned to the waitlist control 12 group or the intervention group for treatment according to the randomisation. Patients 13 in the study have a 50 percent chance of being assigned to either group. 14 15 16 Waitlist Control group: Administration of conventional medications will be done 17 for the treatment of PD. If the patients are without bowel movements for three or 18 more consecutiveFor days, peer they will bereview allowed to take only oral lactulose solutions or 19 20 glycerine enema by rectal injection depending on their conditions. Patients need be 21 assessed before treatment, at week 4, week 8, week 12, week16 and week24. 22 23 Intervention group: Based on the same manner as in the waitlist control group, 24 25 electroacupuncture will be performed: three times per week from week 1 to 8, two 26 times per week for weeks 9 and 10, and one time per week for weeks 11 and 12. 27 28 Patients need be assessed before treatment, at week 4, week 8, week 12, week16 and 29 week24. 30 31 3. Possible benefits of participating in the study 32 33 You and society probably benefit from this research. Your condition and quality 34 35 of life may improve. This study may have a good guiding effect on clinical treatment. 36 However, it is not excluded that this trial may not improve your condition.
37 http://bmjopen.bmj.com/ 38 4. Possible adverse events, risks, discomfort, and inconvenience of participating 39 40 in the study 41 42 If you experience any discomfort during the study period, changes in your 43 condition, or any unexpected circumstances, whether it related to treatment or not, 44 you should inform your doctor immediately. The doctor will make a judgment and
45 on September 27, 2021 by guest. Protected copyright. 46 initiate medical treatment as needed. During acupuncture clinical trials, some adverse 47 48 events may occur, such as fainting (during the acupuncture process, patients may 49 suffer from palpitation, sweating, nausea, vomiting or even fainting), stagnation of 50 needles (difficulty in needle extraction, and pain in patients) and so on. When fainting 51 52 occurs, the needle will be removed immediately. The participant will be asked to lie 53 flat with his/her head slightly lower than their body. The participant will be given 54 55 warm boiled water or sugar water. In general, the participants will recover after lying 56 for a while. When the hysteresis needle occurs, skin near the needle will be gently 57 58 tapped to relieve the tense skin and muscles, moxibustion will be applied on the hilt 59 of the needle or another needle will be used to puncture the skin near the needle. If the 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 unidirectional twist is too large, the needle will be twisted in the opposite direction. 5 6 During the study period, you need to come to our outpatient on time for 7 treatment and follow-up, and do some physical or chemical tests. These may cause 8 trouble or inconvenience to you. 9 10 11 5. Is personal information confidential? 12 13 Your medical records (CRF, physical and chemical examination reports, etc.) 14 will be kept in the hospital. Researchers, sponsor representatives, and ethics 15 16 committees will be allowed access to your medical records. Any public report on this 17 study will not disclose your personal identity. We will make every effort to protect the 18 privacy of yourFor personal peer medical data review within the scope only permitted by law. 19 20 21 6. You are voluntarily choose to participate in the study or drop out of the study. 22 Participation in the study depends entirely on your willingness. You may refuse to 23 participate in the study or withdraw from the study at any time during the study 24 25 without affecting your relationship with your doctor, loss of your medical treatment or 26 other benefits. 27 28 Your doctor or researcher may discontinue your participation in this study at any 29 time for your best interest. 30 31 If you withdraw from the study for any reason, you may be asked about the 32 33 treatment you are taking in the study. You may also be asked to perform physical 34 examinations if your doctor thinks it is needed. 35 36 If you do not participate in this study, or withdraw from the study, there are many
37 http://bmjopen.bmj.com/ 38 other alternatives, such as exercise therapy, surgery, and so on. You do not have to 39 choose to participate in this study in order to treat your illness. 40 41 If you choose to participate in this study, we hope that you will be able to 42 43 complete the entire study process. 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Informed Consent Form-Signature Page 5 6 7 Clinical study project name: Efficacy of acupuncture for the treatment of 8 constipation in Parkinson's disease：a multi-centre randomised controlled trial 9 10 Research unit: Yueyang Hospital of Integrated Traditional Chinese and Western 11 12 Medicine, Shanghai University of Traditional Chinese Medicine 13 14 Longhua Hospital, Shanghai University of Traditional Chinese 15 Medicine 16 17 Shanghai Municipal Hospital of Traditional Chinese Medicine, 18 For peer review only 19 Shanghai University of Traditional Chinese Medicine 20 21 Shuguang Hospital, Shanghai University of Traditional Chinese 22 Medicine 23 24 25 Approval number : 2018-121 26 27 2019LCSY034 28 29 2019SHL-KY-07-02 30 31 2019-676-31-01 32 33 Fill in the corresponding Research unit and Approval number according to 34 different centres. 35 36 Voluntary Subject Statement:
37 http://bmjopen.bmj.com/ 38 39 I have read the above introduction to this study and had the opportunity to 40 discuss and ask questions about this study with my doctor. All my questions were 41 satisfactorily answered. 42 43 44 I am aware of the risks and benefits of participating in this study. I understand
45 that participation in the study is voluntary. I confirm that there is sufficient time to on September 27, 2021 by guest. Protected copyright. 46 consider this and I understand that: 47 48 49 I can always ask my doctor for more information. 50 51 I can withdraw from the study at any time without being discriminated against or 52 penalised and my medical rights and treatment will not be affected. 53 54 I am also aware that if I drop out of the study, especially I drop out of the study 55 56 due to treatment reasons, it will be very beneficial to me and the study if I tell the 57 doctor about the change in my condition and complete the required physical 58 examination. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 If I need to take any other treatment due to the change in my condition, I will 5 consult my doctor in advance or inform him/her afterwards. 6 7 I grant access to my research materials to the ethics committee or the sponsor's 8 representative. 9 10 11 I will receive a signed and dated copy of the informed consent. In the end, I 12 agree to participate in the study and will try to follow my doctor's advice. 13 14 15 16 Subject’s signature: Date: 17 18 For peer review only 19 20 Subject contact number: 21 22 23 24 25 Signature of subject’s guardian: Date: 26 27 28 29 Guardian’s contact number: 30 31 32 33 Subject’s guardian is required to sign the informed consent if necessary. 34 35 36
37 Doctor's declaration http://bmjopen.bmj.com/ 38 39 I have fully explained this study in detail to the above participant, including 40 41 his/her rights and possible benefits and risks, and I have answered all his/her 42 questions. To the best of my knowledge, the participant has been informed adequately 43 44 and has consented to the trial.
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 Doctor’s signature: Date: 49 50 51 52 Doctor contact number: 53 54 55 56 In the event of inconsistency or discrepancy between the Chinese version and the 57 58 English version, the Chinese language version shall prevail. 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Brief introduction to the pilot trial 5 6 From January 2019 to July 2019, a randomized controlled clinical trial was 7 8 conducted at Yueyang Hospital of Integrated Traditional Chinese and Western 9 10 Medicine and Shanghai Hospital of Traditional Chinese Medicine to observe the 11 12 efficacy of electroacupuncture for constipation in Parkinson's disease. So far, a total 13 14 of 45 patients (23 in the intervention group and 22 in the waitlist control group) have 15 16 been enrolled. There were 3 and 2 patients dropout in the intervention group and the 17 18 control group, respectively.For peer Finally, review 40 patients completed only the efficacy evaluation in 19 20 week 8. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 The brief raw data on primary outcome 5 6 Table 1 Brief raw data on primary outcome 7 8 The change in mean weekly spontaneous 9 bowel movements from baseline to 8-9weeks 10 11 Intervention Waitlist control 12 13 group(n=20) group(n=20) 14 15 -2.50 0.50 16 17 -2.00 -1.50 18 For peer review only 19 1.50 1.00 20 21 -1.00 0.00 22 23 -1.00 0.00 24 25 -1.00 0.00 26 27 0.00 -2.50 28 29 4.50 0.00 30 31 32 1.50 0.00 33 34 2.50 0.00 35 36 0.50 -0.50
37 http://bmjopen.bmj.com/ 38 1.00 -1.50 39 40 -1.50 0.00 41 42 0.00 -0.50 43 44 3.00 1.00
45 on September 27, 2021 by guest. Protected copyright. 46 0.00 -1.50 47 48 4.00 -0.50 49 50 51 2.00 2.00 52 53 0.00 0.00 54 55 0.50 -2.50 56 57 58 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Statistical analysis 5 6 Group Statistics 7 8 1=waitlist control group; N Mean Std. Deviation Std. Error Mean 9 2=intervention group 10 11 1 20 -.3250 1.12712 .25203 12 SBMs 13 2 20 .9250 1.87276 .41876 14 15 16 17 18 For peer reviewTests of Normality only 19 20 1=waitlist control group; 2=intervention group Shapiro-Wilka 21 22 Sig. 23 24 1 .110 25 SBMs 26 2 .586 27 28 29 30 31 Independent Samples Test 32 33 Levene's Test for Equality of t-test for Equality of 34 Variances Means 35 36 F Sig. t df
37 http://bmjopen.bmj.com/ 38 39 Equal variances assumed 7.589 .009 -2.558 38 40 SBMs 41 Equal variances not assumed -2.558 31.168 42 43 44
45 Independent Samples Test on September 27, 2021 by guest. Protected copyright. 46 47 t-test for Equality of Means 48 49 Sig. (2-tailed) Mean Difference Std. Error 95% Confidence 50 51 Difference Interval of the 52 Difference 53 54 Lower 55 56 Equal variances assumed .015 -1.25000 .48876 -2.23943 57 SBMs 58 59 Equal variances not assumed .016 -1.25000 .48876 -2.24661 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 5 6 Independent Samples Test 7 8 t-test for Equality of Means 9 10 95% Confidence Interval of the 11 Difference 12 13 Upper 14 15 16 Equal variances assumed -.26057 17 SBMs 18 ForEqual variances peer not assumed review only -.25339 19 20 21 22 SBMs, the change in mean weekly spontaneous bowel movements from baseline to weeks 8 and 9. 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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3 BMJ Open: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from 4 Sample size 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For peer review only 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
37 http://bmjopen.bmj.com/ 38 39 40 41 42 43 44
45 on September 27, 2021 by guest. Protected copyright. 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 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents* 20 21 22 23 Section/item Item Description Addressed on 24 No page number 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 Administrative information 29 30 31 Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ______2______32 33 34 Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry _____ 5______35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 2b All items from the World Health Organization Trial Registration Data Set _____ 5______6 7 8 Protocol version 3 Date and version identifier ______4______9 10 11 Funding 4 Sources and types of financial, material, and other support _____20-21 ____ 12 For peer review only 13 14 Roles and 5a Names, affiliations, and roles of protocol contributors _____2,20______15 16 responsibilities 17 http://bmjopen.bmj.com/ 5b Name and contact information for the trial sponsor ______2-3______18 19 20 5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and 21 22 interpretation of data; writing of the report; and the decision to submit the report for publication, including 23 _ __20-21_____ whether they will have ultimate authority over any of these activities 24 25 on September 27, 2021 by guest. Protected copyright. 26 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication ____15-16______27 28 committee, data management team, and other individuals or groups overseeing the trial, if applicable (see 29 Item 21a for data monitoring committee) 30 31 32 33 34 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 6 Introduction 7 8 9 Background and 6a Description of research question and justification for undertaking the trial, including summary of relevant _____7-8______10 rationale studies (published and unpublished) examining benefits and harms for each intervention 11 12 For peer review only 13 6b Explanation for choice of comparators ____12-13,20___ 14 15 16
Objectives 7 Specific objectives or hypotheses http://bmjopen.bmj.com/ ______8______17 18 19 Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), 20 21 allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 22 ______8______23 24 25 on September 27, 2021 by guest. Protected copyright. Methods: Participants, interventions, and outcomes 26 27 28 Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will _____10______29 30 be collected. Reference to where list of study sites can be obtained 31 32 33 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and ___ 10,12 ____ 34 individuals who will perform the interventions (eg, surgeons, psychotherapists) 35 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be _____11-13_____ 6 7 administered 8 9 10 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose ______14_____ 11 change in response to harms, participant request, or improving/worsening disease) 12 For peer review only 13 14 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence _____ 20 _____ 15 16 (eg, drug tablet return, laboratory tests) 17 http://bmjopen.bmj.com/ 18 19 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _____12______20 21 22 Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood 23 pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, 24 ____13-14______25 median, proportion), and time point for each outcome. Explanation of the clinical on September 27, 2021 by guest. Protected copyright. relevance of chosen 26 efficacy and harm outcomes is strongly recommended 27 28 29 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for ___9(table 1)____ 30 31 participants. A schematic diagram is highly recommended (see Figure) 32 33 34 Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including ______16_____ 35 clinical and statistical assumptions supporting any sample size calculations 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size ______9______6 7 8 9 Methods: Assignment of interventions (for controlled trials) 10 11 12 Allocation: For peer review only 13 14 15 Sequence 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any _____11______16 17 generation factors for stratification. To reduce predictability of a random sequence, details of anyhttp://bmjopen.bmj.com/ planned restriction (eg, 18 blocking) should be provided in a separate document that is unavailable to those who enrol participants or 19 20 assign interventions 21 22 23 Allocation 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, _____11______24 concealment sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 25 on September 27, 2021 by guest. Protected copyright. 26 mechanism 27 28 29 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to ____9,11____ 30 interventions 31 32 33 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome ______11______34 35 assessors, data analysts), and how 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s _Not applicable, 6 7 allocated intervention during the trial only data collectors 8 are blinded _____ 9 10 11 12 Methods: Data collection, management,For and analysis peer review only 13 14 15 Data collection 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related _____15_____ 16 17 methods processes to promote data quality (eg, duplicate measurements, training of assessors)http://bmjopen.bmj.com/ and a description of 18 study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. 19 20 Reference to where data collection forms can be found, if not in the protocol 21 22 23 18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be ____ 20______24 collected for participants who discontinue or deviate from intervention protocols 25 on September 27, 2021 by guest. Protected copyright. 26 27 Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality _____15______28 29 (eg, double data entry; range checks for data values). Reference to where details of data management 30 procedures can be found, if not in the protocol 31 32 33 Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the ____ 17 _____ 34 35 statistical analysis plan can be found, if not in the protocol 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ______18_____ 6 7 8 20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any 9 10 statistical methods to handle missing data (eg, multiple imputation) 11 ____15,16-17___ 12 For peer review only 13 14 Methods: Monitoring 15 16 17 http://bmjopen.bmj.com/ Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of ____15-16_____ 18 19 whether it is independent from the sponsor and competing interests; and reference to where further details 20 about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not 21 22 needed 23 24 25 21b Description of any interim analyses and stopping guidelines, including who will have on September 27, 2021 by guest. Protected copyright. access to these interim _____16______26 results and make the final decision to terminate the trial 27 28 29 30 Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse ____14______31 events and other unintended effects of trial interventions or trial conduct 32 33 34 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent _____16_____ 35 36 from investigators and the sponsor 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 6 Ethics and dissemination 7 8 9 Research ethics 24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ____18,21_____ 10 approval 11 12 For peer review only 13 Protocol 25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, ______18______14 15 amendments analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, 16
regulators) http://bmjopen.bmj.com/ 17 18 19 Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and ______9______20 21 how (see Item 32) 22 23 24 26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary _Not applicable__ 25 on September 27, 2021 by guest. Protected copyright. studies, if applicable 26 27 28 Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained ____18,21_____ 29 30 in order to protect confidentiality before, during, and after the trial 31 32 33 Declaration of 28 Financial and other competing interests for principal investigators for the overall trial and each study site _____21______34 35 interests 36 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that _____21____ _ 6 7 limit such access for investigators 8 9 10 Ancillary and 30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial _Not applicable__ 11 post-trial care participation 12 For peer review only 13 14 Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the _____18______15 16 public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing http://bmjopen.bmj.com/ 17 arrangements), including any publication restrictions 18 19 20 31b Authorship eligibility guidelines and any intended use of professional writers _ Not applicable__ 21 22 23 31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ______21______24 25 on September 27, 2021 by guest. Protected copyright. 26 27 Appendices 28 29 30 Informed consent 32 Model consent form and other related documentation given to participants and authorised surrogates 27 31 32 materials 33 34 35 Biological 33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular _Not applicable__ 36 specimens analysis in the current trial and for future use in ancillary studies, if applicable 37 38 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: first published as 10.1136/bmjopen-2019-029841 on 27 November 2019. Downloaded from
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1 2 3 4 5 *It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification 6 on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the 7 8 Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license. 9 10 11 12 For peer review only 13 14 15 16 17 http://bmjopen.bmj.com/ 18 19 20 21 22 23 24 25 on September 27, 2021 by guest. Protected copyright. 26 27 28 29 30 31 32 33 34 35 36 37 38 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