A Prospective Cohort Study of Exercise Rehabilitation in the Treatment of Parkinson's Disease
Phase: NA
Conditions: Parkinson Disease
Sponsor: Ruijin Hospital

PROTOCOL 
The components in this Supplementary Material document are as follows: 
Part I: Research Plan 
Part II: Modifications 
 
 
Title: A Prospective Cohort Study of Exercise Rehabilitation in the Treatment of 
Parkinson's Disease 
Place: Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine 
Document Date: Jan. 1st, 2015 
Modification Date: Modification 1 (Jan. 1st, 2016); Change 2: (Aug. 22nd, 2020) 
 

Part I: Research Plan 
Overview 
We proposed to conduct a cohort study to observe whether Tai Chi intervention could 
delay the disease progression of Parkinson’s disease (PD). 
PD patients were enrolled into 5 Tai Chi classes which began at different timepoints 
from Jan. 2016 to Jan. 2019. Each participant was assessed before they joined the Tai 
Chi class. After the recruitment, they accepted continuous Tai Chi training in the classes 
till the last follow-up. We performed three times of follow-up in Nov. – Dec. 2019, Oct. 
- Nov. 2020 and Jun. – July 2021. Using propensity score matching, we matched PD 
patients who did not receive Tai Chi training as control group in gender, disease 
duration, age, and Hoehn – Yahr staging. The aim is to observe the effect of Tai Chi on 
delaying the disease progression of PD. This original study is registered at Chinese 
Clinical Trial Registry (Registration No.: ChiCTR2000036306; Registration date: 
August 22, 2020). 
 
1. Participants 
We recruited PD patients aged 50-80 years with Hoehn -Yahr stage 1-2.5. The 
medication was stable at least 3 months before recruiting and not changed during 
follow-up unless increasing antiparkinsonian drugs or the need of deep brain 
stimulation (DBS) is required according to the disease severity. PD was diagnosed by 
senior movement disorder specialists (SDC, YYT) based on diagnostic criteria brought 
up by United Kingdom Brain Bank diagnostic criteria and MDS diagnostic criteria of 
PD in 2015 1,2. Patients who fitted any following item were excluded: 
1) Secondary causes, such as inflammatory, drug-induced, vascular and toxin-induced 
parkinsonism.  
2) Parkinsonism with other neurodegenerative diseases, such as progressive 
supranuclear palsy, multiple system atrophy, cortical basal ganglia degeneration, 
Wilson's disease. 
3) Other neurological diseases, such as stroke. 
4) Patients who were receiving any other clinical trials or regular exercise protocols. 

5) Patients who had fall incidents in the 6 months before recruiting due to safety 
considerations. 
6) Patients whose Mini-Mental State Examination (MMSE) scores were less than 24. 
7) Patients who had medical history that did not fit to exercise, such as orthopedics 
diseases or cardiopulmonary dysfunction. 
8) Patients who received education less than 6 years. 
9) Patients who could not walk and live independently. 
10) Patients who received brain surgery (e.g. deep brain stimulation); 
11) Patients whose exercise length longer than 50 minutes per week. 
All participants were fully informed and signed written consent forms. This study was 
approved by the ethic committee of Ruijin Hospital affiliated to Shanghai Jiao Tong 
University School of Medicine. 
 
2. Randomization, Blinding and Follow-Up 
There was no randomization adopted. Assessments were done at baseline and the 
three follow-ups (Nov. – Dec. 2019, Oct. - Nov. 2020 and Jun. – July 2021). We also 
monitored the frequency and lengths of Tai Chi exercise for each patient. Patients 
whose training were less than 60 minutes per time or less than twice per week were 
regarded as giving up training. The flow chart of recruitment and follow up was 
shown in Part II.  
 PD patients who did not receive Tai Chi training were matched to Tai Chi training 
PD patients with similar age, sex, disease duration and initial Hoehn - Yahr staging by 
propensity score matching methods. They also received evaluation at baseline and 
three follow-ups (Nov. – Dec. 2019, Oct. - Nov. 2020 and Jun. – July 2021). 
Since this is an interventional study of movement, we cannot perform the blinding on 
patients. Thus, the assessors and the statisticians were blinded to study design. The 
ethic committee monitored the whole process of blinding. Patients were demanded 
not to tell their group assignments to the assessors. 
 
3. Exercise Interventions and Quality Control 

3.1 Tai Chi 
As for Tai Chi training, standardized Tai Chi was taught by professional Tai Chi 
coaches from Sino Taiji of Fuxing International in classes: Qishi (“Starting Posture”), 
Shangsanbu (“Twist Step”), Yema Fenzong(“Part the Wild Horse's Mane on Both 
Side”), Jingang Daozhui (“Buddha’s warrior attendant pounds mortar”), Shoushi 
(“Closing Posture”). Patients participated in this class were trained, twice a week, 60 
min per time. PD patients whose attendance rate less than 75% were excluded. 
The detailed Tai Chi protocols are referenced as our previous work 3. 
 
3.2 Control 
We did not give any exercise interventions to the control group. They continued to use 
anti-parkinsonism therapy and keep daily activities as usual. They did not exercise 
regularly as we additionally required. 
 
4. Evaluation: Motor and non-motor symptom assessment by rating scales 
The following rating scales were used to assess the status of patients at “on” periods at 
movement disorders clinic.  
(1) Overall assessment of PD: Unified Parkinson's Disease Rating Scale (UPDRS) and 
Hoehn -Yahr stage; 
(2) Non-motor symptoms:  
1) overall assessment: Non-Motor Symptoms Questionnaire (NMS-Quest); 
2) autonomic function: Scales for Outcomes in Parkinson's Disease-Autonomic 
questionnaire (SCOPA-AUT); 
3) mood disorders: Hamilton anxiety rating scale (HAMA) and Hamilton depression 
rating scale (HAMD);  
4) sleep: Parkinson’s disease sleep scale (PDSS), Epworth Sleepiness Scale (ESS), 
Rapid eye movement sleep behavior disorder questionnaire-Hong Kong version (RBD-
HK) were used.  
5) cognitive function: MMSE – simplified Chinese version and Parkinson’s disease 
cognitive rating scale (PDCRS); 

(3) Quality of life: 39-item Parkinson's Disease Questionnaire (PDQ-39). 
All patients were assessed by experienced doctors (PH, YCH, GL, SSC), who all passed 
the tests for proving the inter-rater reliability.  
 
5. Outcomes 
5.1 Primary Outcome 
The primary outcome was the annual change of UPDRS total score measured in “ON” 
state at three follow-ups. 
5.2 Secondary Outcomes 
The secondary outcomes were annual change of the following indicators except the 
need of increasing antiparkinsonian therapies which were analyzed by survival analysis: 
(1) the change of LEDD4 
(2) the need of increasing antiparkinsonian therapies, including both the need of 
increasing antiparkinsonian drugs and the need of surgery, such as DBS or lesion 
surgery. 
(3) Motor evaluations: UPDRS part III as overall motor evaluations; TUG and BBS. 
(4) Other non-motor symptoms, including autonomic function, mood, sleep and 
cognition, assessed by rating scales. 
(5) Quality of life: PDQ-39; 
(6) the difference of prevalence of complications (dyskinesia, on-off phenomenon, 
dystonia, PD-MCI, hallucinations, restless legs syndrome). 
 
NOTE: We consider the following aspects as the evidences for delaying disease 
progression: 
(1) the annual change of UPDRS total score; 
(2) the annual change of LEDD; 
(3) the need of increasing antiparkinsonian therapies. 
 
6. Statistical Analysis 
R (version 3.5.1) and RStudio (version 1.1463) were used to perform statistical analysis. 

Packages stats (version 3.5.1), base (version 3.5.1), spinds (version 2.2.0), lars (version 
1.2), nlme (version 3.1-145), plyr (version 1.8.5), PGEE (version 1.5), ggplot2 (version 
3.2.1), survival (version 2.43-3) and survminer (version 0.4.3) were introduced into 
statistical analysis. Figures were plotted in Prism 9 (version 9.3.1, San Diego, CA). 
All analysis about primary and secondary outcomes were conducted on an intention-
to-treat basis. Analysis of variance (ANOVA) were used in comparing at numerical 
demographic information. Pearson Chisq-Square test or Fisher test were used in 
analysis at categorical demographic information. Shapiro-Wilk normality test was used 
to assess the normality of variables. Independent-sample t-tests (with 95% confidence 
intervals) were used to compare group means. Data were presented in the way of 
between-group differences. The longitudinal effects of self-changes were calculated 
using repeated measures ANOVA. 
We built a cohort which started enrollment since 2016, then more patients were enrolled 
gradually into another 4 classes (2nd Class: start from Nov. 2016; 3rd Class: start from 
Mar. 2017; 4th Class: start from Sept. 2017; 5th Class: start from Jan. 2018). All the 
patients in those 5 classes were trained continually and has been received assessment 
in the follow-up of 2019, the follow-up of 2020 and the follow-up of 2021. 
We set the rate of UPDRS total score change (per year) as the primary outcome. As for 
the secondary outcomes, UPDRS part III, other motor evaluations (TUG and BBS), 
evaluations of non-motor symptoms (autonomic function, mood, sleep, and cognition, 
assessed by rating scales), quality of life evaluated by PDQ-39, the change of LEDD, 
and the difference of prevalence of complications (dyskinesia, on-off phenomenon, 
dystonia, PD-MCI, hallucinations, restless legs syndrome). We also observed the need 
for increasing antiparkinsonian therapy, including increasing antiparkinsonian drugs, 
and deep brain stimulation (DBS). LEDD of patients who received DBS were not taken 
into account.  
We make the comparisons between the patients who received Tai Chi training and 
patients who did not receive Tai Chi training as controls. Analyses of the adjusted means 
of change from baseline to each follow-up in rating scales were done with logarithmic 
linear model of covariance that included the following fixed effects: treatment group 

(Tai Chi = 1, control group = 0), months in this trial, the changed amount of LEDD and 
baseline Hoehn-Yahr score. Years of education were also included when analyzing 
PDCRS. We calculated the p value with the bootstrap method for resampling 1000 
times. To demonstrate the results, mean change with its 95% confidential intervals (CIs) 
was introduced. Kaplan Meier plot with table of number at risk was introduced. 
Bonferroni correction was introduced. 
 
7. Safety Reporting: Adverse events (AEs) and serious adverse events (SAEs) 
7.1 Adverse events (AEs) 
We defined AE as undesirable experience of patients during the study. All AEs were 
reported by the patients or observed by the research team. Each AE will be recorded. 
 
7.2 Serious adverse events (SAEs) 
SAEs were defined as the following: 
1. Life threatening or resulted in death; 
2. Required hospitalization or prolonged the time of hospitalization; 
3. Resulted in disability or incapacity; 
4.  Other medical conditions considered as serious adverse experiences based on the 
medical judgement of all research team members. 
 
7.3 Safety committee 
The safety committee was composed as our research team. AEs and SAEs were 
judged by the meetings of safety committee. 
 
References 
1. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 
1992;55(3):181-4. (In eng). DOI: 10.1136/jnnp.55.3.181. 
2. 
Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. 
Mov Disord 2015;30(12):1591-601. (In eng). DOI: 10.1002/mds.26424. 
3. 
Li G, Huang P, Cui SS, et al. Mechanisms of motor symptom improvement by long-term Tai 
Chi training in Parkinson's disease patients. Transl Neurodegener 2022;11(1):6. (In eng). DOI: 

10.1186/s40035-022-00280-7. 
4. 
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa 
dose equivalency reporting in Parkinson's disease. Mov Disord 2010;25(15):2649-53. (In eng). 
DOI: 10.1002/mds.23429. 
 

Part II: Modifications 
Basically, there were no significant changes made in the original research protocol as 
we reported. The following changes were done. All modifications were approved by 
the ethics committee and the meeting of authors. 
 
Change 1: (Jan. 1st, 2016) 
Patients were met both UK brain bank diagnostic criteria and MDS diagnostic criteria. 
The MDS diagnostic criteria were not published when we got the approval from Ruijin 
Hospital Ethic Committee, Shanghai Jiao Tong University School of Medicine at 
December 04, 2014. However, when we put the protocol into effect, the MDS 
diagnostic criteria of PD were published at 2015 year. Thus, we enrolled PD patients 
both met UK brain bank diagnostic criteria and MDS diagnostic criteria from 2016 year. 
 
Change 2: (Aug. 22nd, 2020) 
We noticed the inappropriate information were submitted due to inappropriate 
operation in 2016 (register number: ChiCTR-OPC-16008074). We mis-clicked 
“interventional” as “observational” when we registered at the Chinese Clinical Trial 
website. We found this incorrect information in 2020. So we re-registered a new project 
called “A prospective cohort study of exercise rehabilitation in the treatment of 
Parkinson's disease and its mechanism” after the approval of our ethic committee 
(register number: ChiCTR2000036306).