The clinical effects and biomechanical mechanisms of Peony and licorice decoction fumigation in the treatment of poststroke cavovarus foot: study protocol for a randomized controlled pilot trial

23 Background: As the most common functional disability in stroke patients with 24 hemiplegia, poststroke cavovarus foot (PCF) seriously affects the life quality of 25 patients and causes mental and emotional disorders. Some studies have suggested that 26 the traditional Chinese medicine fumigation therapy could be an effective intervention 27 method for PCF patients. This study aims to investigate the biomechanical effect of 28 the classic prescription Peony and licorice decoction (PLD) fumigation in the 29 treatment of PCF. 30 Methods/Design: This study is a multi-center, randomized, placebo-controlled, 31 double blind trial. A total of 190 patients with PCF according to the inclusion criteria 32 will be recruited in three centers and randomized and distributed to either the 33 intervention group or the control group at a 1:1 ratio. All patients will receive 34 standardized modern rehabilitation treatment according to the “Chinese Guidelines for 35 Stroke Rehabilitation” (2011 version). Patients will stick to the treatments they used 36 to take, and will be given present general treatment when acute exacerbation of stroke 37 occurs during the trial. The intervention group will receive PLD fumigation treatment, 38 while the control group will receive placebo fumigation treatment. The primary 39 outcome measure is medial plantar area (M1 ＋ M 2 ＋ H M) generating from the 40 RSSCAN gait system. The secondary outcome measures contain the scores of clinical 41 scales including Berg Balance Scale, Fugl-Meyer Assessment, Modified Ashworth 42 Scale, Barthel Index, and Stroke-Specific Quality of Life Scale. All assessments will 43 be implemented at baseline, 4 weeks after intervention and at the end of 3 month’ follow-up. Intention-to-treat analysis and per-protocol analysis will be applied in this 45 trial. 46 Discussion: The results of this study are expected to provide detailed interpretations 47 of clinical effects and biomechanical mechanisms of PLD fumigation in the treatment 48 of PCF. If PLD fumigation treatment is confirmed as an effective option, this study 49 may additionally set up the new treatment method for patients with PCF and provide 50 foundations for further clinical studies on a larger scale.

Methods/Design: This study is a multi-center, randomized, placebo-controlled, 31 double blind trial. A total of 190 patients with PCF according to the inclusion criteria 32 will be recruited in three centers and randomized and distributed to either the 33 intervention group or the control group at a 1:1 ratio. All patients will receive 34 standardized modern rehabilitation treatment according to the "Chinese Guidelines for 35 Stroke Rehabilitation" (2011 version). Patients will stick to the treatments they used 36 to take, and will be given present general treatment when acute exacerbation of stroke 37 occurs during the trial. The intervention group will receive PLD fumigation treatment, 38 while the control group will receive placebo fumigation treatment. The primary Strokes are a type of cerebrovascular disease characterized by high incidence, high 58 disability and high mortality. An authoritative survey in 2014 showed that strokes had 59 become the leading cause of disability and the second leading cause of death in the 60 world [1] . Epidemiological studies showed that the annual incidence of strokes in 61 China was as high as 116-219 / 100000, and is rising year by year [2] . With the 62 continuous improvement of modern medical technology, most patients with strokes 63 can be treated in time, so the fatality rate of strokes can be controlled to a certain 64 extent, but the disability rate keeps increasing. Poststroke cavovarus foot (PCF) is one 65 of the most common functional disabilities in stroke patients with hemiplegia [3] . 66 Studies showed that the incidence of PCF ranges from 17% to 38% in the population 67 of patients with strokes, and 4% to 9% of stroke survivors were being disabled [4] . The 68 life quality of stroke patients is seriously affected by the abnormal gait [5] , balance 69 disorder [6] , life restriction and the consequent abnormal mental mood [7][8][9] caused by 70 PCF. 71 Modern rehabilitation techniques such as foot support fixation, plantar inhibition 72 and other good limb placement methods are used in the acute phase of stroke to 73 prevent the occurrence of PCF [10] . To some extent, these methods reduce the 74 incidence of PCF in stroke patients. However, because of the relatively serious 75 condition of patients in the acute stage, most treatment schemes focus on the 76 intervention of vital signs. However, the intervention of early rehabilitation treatment 77 is often neglected. As a result, most patients begin rehabilitation only when their vital 78 signs are relatively stable [11] . For the spasmodic cavovarus foo forming during the 79 recovery period, modern rehabilitation medicine mostly adopts rehabilitation 80 techniques such as passive joint activity training, weight loss gait training and so on. 81 For the refractory cavovarus foot, Botox injection and surgery are used to inhibit the 82 excessive flexion spasm of the medial muscles [12,13] . However, the outcome of the 83 above therapies are not satisfactory. Such situations drive us to seek a more effective 84 method for the treatment of PCF. 85 The traditional Chinese medicine fumigation therapy uses the gas generated by the 86 boiling of drugs and water to fumigate the patient's diseased area to achieve the 87 treatment effect. Absorption through the skin plays a role in avoiding the stimulation 88 of drugs to the gastrointestinal tract, reducing the burden for the liver and kidney, 89 making the incidence of adverse drug reactions being significantly reduced, and for 90 the patients who are not suitable for oral administration of drugs, it is undoubtedly a 91 good way to administer drugs [14] . From Zhang Zhongjing's Treatise on Febrile 92 Diseases, the classic prescription Peony and Licorice Decoction (PLD), known as 93 "traditional Chinese medicine morphine", is primarily used to treat visceral pain, 94 painful muscle spasms, menstrual pain and so on [15,16] . Modern research confirmed 95 that total paeoniflorin in white peony and total glycyrrhizin in licorice have strong 96 anti-inflammatory and analgesic effects, so that it has a strong relaxing effect for the 97 smooth muscle [17] . The oral treatment of them can significantly improve limb motor 98 function and activities of daily living for patients with spastic hemiplegia after a 99 stroke [18] . But for the treatment of PCF, the clinical application of PLD is carried out  [19] . Patients will stick to the treatment they previously have had, and will be 121 given present general treatment when acute exacerbation of stroke occurs during the 122 trial. The intervention group will receive PLD fumigation treatment, while the control 123 group will receive placebo fumigation treatment. The treatments will be taken once a 124 day lasting 30 minutes, 5 days per week. An objective biomechanical parameter, the 125 medial plantar area (M1＋M2＋HM) from the RSSCAN gait system, will be used to 126 assess the outcome as the primary measure. Scores of Berg Balance Scale (BBS), 127 Fugl-Meyer Assessment (FMA), Modified Ashworth Scale (MAS), Barthel Index (BI) 128 and Stroke-Specific Quality of Life Scale (SSQOL) will be used to assess the 129 outcome as the secondary measure. All assessments will be conducted at baseline, a  Table 1 [20] .  Ethical issues 142 We will fully explain the details of this study to participants and their families before 143 the patients take part in this research, including probable risks, potential benefits, as Considering a 20% dropout rate during the study, 95 patients will be enrolled in 198 each group and the total sample size will be 190.

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Randomization and allocation concealment 200 The block randomization method will be applied in this trial. An independent 201 statistician will generate the randomization sequence using SPSS 25. 0 (IBM, USA). 202 All participants who meet the inclusion criteria will be randomly assigned to a 203 intervention group or control group (95 cases each) at a 1:1 ratio by the 204 computer-generated random sequences. In accordance with best practice 205 recommendations for randomized controlled trials, allocation concealment will be 206 employed. A physician who will be trained before the study and will not participate in 207 treatment will seal assignments in opaque envelopes. The assignment will be 208 concealed to the outcome assessors and data statistical analysts. Moreover, the 209 allocation of eligible participants will also be concealed from their caregivers and 210 therapist. The therapists will only take charge of the allocated treatments for patients. 211 Three clinical research coordinators of the trial sites will be responsible for enrolling 212 patients, acquiring informed consent and requesting randomization.

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Blinding 214 In this study, the double-blind method will be implemented. A "third party" staff that 215 is trained and does not participate in the experiment will manage and supervise the 216 performance of the blinding method. Firstly, the random computer-generated 217 assignments will be sealed in opaque envelopes. The participants will only be told that 218 they will be randomly allocated to either intervention group or control group, and both 219 be treated with regular rehabilitation therapies. And the researchers including 220 therapists, assessors, statisticians, and data analysts will be blinded to the group 221 allocation. All of them will work independently and separately. Secondly, the placebo 222 used in control group will be made of 5% PLD and 95% dextrin to ensure it mimics 223 the appearance and smell of PLD.

Modified Ashworth Scale (MAS)
The MAS is a simple grading system that scores 313 from 0 (normal) to 4 (severe), which will be used to evaluate the level of muscular 314 tension of the patients briefly.

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Barthel Index (BI) The BI contains ten basic daily activities and its total score is 100. 316 We will use the BI to assess the daily living ability of patients by the score. and has no competing interests. All the researchers involved in data management will 333 be trained. Firstly, 3 assessors will be responsible for acquisition and assessment of 334 patients' information during the study. After assessors finish the case report forms 335 (CRF) completely, 2 data collectors will validate the completeness and consistency of 336 the data, and then convert the credible paper data to electronic data. All paper and 337 electronic data related to the study will be safely kept in the Clinical Research Center 338 of Beijing Dongzhimen Hospital. Only the independent statisticians will have access 339 to the final complete data, others who have any questions will be required written 340 requests to the DSMC to get permission. 341 The DSMC is also in charge of monitoring. Members of the committee will 342 monitor the overall quality and completeness of the data, interview assessors, examine 343 original documents, and make sure that the study is implemented with the principles 344 of this protocol. In case of any changes to the study protocol, the DSMC will submit 345 the written application to the REC to obtain permission. In addition, the monitors will 346 verify that all adverse events will be recorded in the correct format. The DSMC will 347 audit the study through regular interviews and the periodic review will be done every 348 2 months.

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Statistical analysis 350 Statisticians who are independent from the trial will be responsible for the statistical 351 analysis. The SPSS 25.0 (IBM, USA) for Windows (Chicago, IL, USA) will be used. 352 Categorical variables will be presented with frequencies or percentages and 353 continuous variables will be presented as the mean and standard deviation. The 354 analysis will mainly compare efficacy between the intervention group and the control 355 group, including primary and secondary outcomes. Changes in all outcome 356 measurements of before and after the treatment and of the between group will be 357 analyzed. The demographic and clinical characteristics of the two groups will be 358 compared at baseline applying unpaired two-sample t-tests (continuous data) and 359 Chi-square analysis (categorical data). Rank sum test will be used when the normal 360 distribution hypothesis is not met. Considering some participants may fail follow-up, 361 we will conduct both intention-to-treat analysis and per-protocol analysis. The 362 intention-to-treat analysis will include all the participants. The missing data will be 363 treated by multiple imputations. The per protocol analysis will incorporate the 364 participants who follow all the time points outcome measurement and fully comply 365 with the treatment schedule in the intervention group. The statistical significance 366 threshold will be set at 0.05 (2-sided), with 95% confidence intervals (CIs).

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Although PCF seriously affects the life quality of stroke patients during the recovery 369 periods, there is a lack of effective treatment in clinics. At present, numerous domestic 370 and foreign scholars think that exercise therapy is the basic treatment for PCF, 371 however, the actual effect is less than expected. Oral or intrathecal injection of 372 baclofen is also a common clinical method [22,23] . Its effect is relatively significant, but 373 it will also have an impact on normal muscle strength, which is not conducive to 374 rehabilitation training. Therefore, seeking an effective treatment with few side effects 375 appears to be particularly important. 376 In China, traditional Chinese medicine fumigation therapy is widely used in clinics 377 because of its characteristics of external treatment and direct action to the disease 378 location. Previous studies have shown that the application of traditional Chinese 379 medicine fumigation therapy in the rehabilitation of PCF has a good theoretical basis 380 and certain therapeutic advantages [24] . However, there are few current studies on the 381 application of PLD fumigation in the treatment of PCF, and there is no evidence of 382 curative effect supported by clinical trials. Thus, it is necessary to conduct this study 383 to determine its real efficacy. 384 In order to achieve the best performance in the field, the RSSCAN gait system used 385 to be designed for providing accurate and objective biomechanical parameters to 386 formulate and improve athletes' gait [25] . And research reveals it is also useful in 387 clinical studies of diabetes, multiple sclerosis and knee osteoarthritis to provide 388 quantitative assessments and achieved satisfactory results [26] . Based on it, we hope to