Effectiveness of Selected Traditional Chinese Medicine Topical Agents on Long Distance Runner Versus Exercise Therapy as Control for Patellofemoral Pain Syndrome

1. Aim 1.1 To evaluate the efficacy and safety of the selected topical agents Used in Traditional Chinese Medicine on PFPS of long distance runner.To evaluate the efficacy of the selected topical agents Used in Traditional Chinese Medicine on the running performance of long distance runner with PFPS.

2. Method 2.1 This is a randomized, controlled, parallel-group, single-blinded trial. After screening, a total of 50 eligible patients will be allocated to Group A or B, with an allocation ratio of 1:1.

   2.2 Groups Group A: receive Topical Chinese Medicine ointment (TCMO) and exercise therapy Group B: receive exercise therapy

   2.3 Study setting In terms of recruiting, social media outreach and Posters at HKBU clinics will be used. Site of intervention will be at Lui Seng Chun, an outpatient clinic affiliated with Hong Kong Baptist University. Prior to obtaining written informed consent, the Principal Investigator (PI) or designated research assistant will clearly explain to each potential participant the purpose of the study, its procedures, the characteristics of the treatment, and the potential adverse reactions associated with the use of Chinese herbal topical agents and physical therapy. Participants will also be informed that their participation is entirely voluntary and that they may withdraw from the study at any time without penalty. All assessment would be done on-site.

3. Diagnostic criteria Diagnostic criteria would be designed according to Clinical Practice Guidelines Linked to the International Classification of Functioning, Disability and Health From the Academy of Orthopaedic Physical Therapy of the American Physical Therapy Association I. Presence of retropatellar or peripatellar pain II. Reproduction of reptropatellar with squatting, stair climbing, prolonged sitting, or other functional activities loading the patellofemoral joint in a flexed position III. Positive patellar tilt test with presence of limited mobility

4. Inclusion criteria

   Eligible participants must meet all the following criteria:

   I. Mean running distance > 20 km/week and 10 km/session. If kilometer per week conflicted with kilometers per session, for example, 40 km/week with a frequency of 5 times/week, it is classified according to kilometers per week.

   II. Meet established diagnostic criteria for patellofemoral pain syndrome (PFPS).

   III. Be between 18 and 60 years of age and able to provide written informed consent.

   IV. Have experienced knee pain for more than four weeks. V. Have no history of external medical interventions, physical therapy, or lower limb surgery for PFPS within the past six weeks, and no acupuncture treatment on knee within the past month.

5. Exclusion criteria:

   Patients will be excluded if they meet any of the following criteria:

   I. Presence of absolute contraindications for Chinese herbal medicated plasters; II. Pregnancy or lactation; III. Oral or topical use of nonsteroidal anti-inflammatory drugs within the past two weeks; IV. Steroid injections within the past two months; V. Clinical, radiographic, or MRI evidence of meniscal or other intra-articular lesions, cruciate ligament or collateral ligament injury or laxity; VI. Concurrent conditions including diabetes, goiter, coagulation disorders, hepatic or renal failure, chronic obstructive pulmonary disease, cardiac disease, neurological disorders, psychiatric disorders, acute or chronic infections, or malignancies; VII. Presence of redness, swelling, burning sensation, pain, infection, or ulceration around the patellar; VIII. History of knee surgery, patellar dislocation, fracture (local or at the hip joint), ankle or hip joint injury, meniscus or ligament injury; IX. Lower limb tendinitis, low back pain, sacroiliac joint pain, or any neurological or cardiovascular disease; X. Presence of rheumatic disease, septic arthritis, osteoarthritis, Osgood-Schlatter disease, or Chondro-Larsen-Johansson syndrome; or clinical assessment indicating significant knee effusion, pronounced hip or lumbar pain (potentially causing referred knee pain), or impairment in performing prescribed exercises; or recurrent patellar subluxation or dislocation; XI. Presence of patella folding syndrome or deep vein thrombosis; XII. Presence of joint fibrosis; XIII. Presence of tumors; Differential diagnosis for PFPS will be conducted by Dr. Chow Chi Ho, a registered Chinese medicine practitioner.

6. Randomization and allocation concealment To minimize bias, Research Assistant (RA) I will generate a block-randomized list to assign participants to the intervention and control groups in a 1:1 ratio. The allocation list will be securely stored-a hard copy sealed in an envelope and a digital copy password-protected. Access to the allocation list will be restricted to the RA. To further prevent bias, outcome assessors and data analysts will remain blinded to group assignments. RA I will manage and analyse collected data, while the RA II will evaluate participant outcomes and provide overall study oversight.
7. Intervention i. Topical Chinese medicine ointment (TCMO) Prof. Ng's Traditional Chinese Medicine ointment (TCMO) formula is composed of a wide range of Chinese medicinal herbs and mineral ingredients blended into a topical base. The herbal components include Rhei Radix et Rhizom, Rhubarb Tangute Rhubar, Aralia spinosa, Root of Spine Aralia, Eupolyphaga Steleophaga, Ground Beetle, Radix Crotonis Crassifolii, Croton Root, Ardisia crenata Sims, Cinnabarroot, Ardisia punctata Lindl, Hance's Ardisia, Phryma leptostachya L. var. Asiatica, Lopseed, Notoginseng Radix et Rhizoma, Sanchi, Chuanxiong Rhizoma, Szechwan Lovage Rhizome, Angelicae Sinensis Radix, Chinese Angelica, Artemisia anomala S. Moore, Diverse Wormwood Herb, Sappan Lignum, Sappan Wood, Saposhnikoviae Radix, Saposhnikovia, Teucrium viscidum, Teucrium, Olibanum, Frankincense, Myrrha, Myrrh, Paeoniae Radix Rubra, Paeoniae Trichocarpae, Scutellariae Radix, Baikal Skullcap Root, Gardeniae Fructus, Common Gardenia Fruit, Carthamus tinctorius, Safflower, and Persicae Semen, Peach Seed.

In addition to these herbs, the formula incorporates mineral and supportive agents such as Pyritum, Pyrite, Talcum, Talc, and Bletillae Rhizoma, Common Bletilla Tuber. Glycerol is used as the medium, serving as the ointment base.

ii. Preparation of TCMO The prepared herbal powders were blended according to the ratios specified in Tables 1 to form a topical ointment. The finished formulation was stored in 0.5-ounce cylindrical containers at room temperature, with instructions included in each package. During the study period, each participant will receive four jars of TCM ointment, equivalent to one jar per week. Since each jar contains 0.5 ounces (14.17 grams) of ointment, the actual amount used will be determined by calculating the difference between the initial weight of the container and its weight at the end of the treatment period.

iii. Supervision and administration of TCMO For non-training days, participants will be instructed to self-apply the topical medication to the patellar region and surrounding areas once daily in evening before sleeping for four consecutive weeks. For training days, topical medication would be applied before training and sleeping respectively. As knee pain of PFPS patients are triggered by flexion of knee namely prolonged running, applying the topical medication could give a prevention effect. Applying the ointment before sleep would aim on recovering the knee joint.

Each patient will receive a logbook to record application frequency. To ensure adequate coverage, patients must apply the ointment approximately 2 mm beyond the affected area, forming a thin layer about 2-3 mm thick, and spread it evenly as directed. Upon initial collection of the Chinese herbal topical agent, researchers will demonstrate and supervise the application procedure. Written documentation detailing the formulation's ingredients and dosage will be provided, along with verbal and written explanations of administration steps, safety precautions, and usage guidelines. Participants must personally collect new doses weekly at Lui Seng Chun, where researchers will reinforce the correct application procedure.

iv. Safety of intervention The intervention measures in this study are considered safe as they do not involve invasive procedures or tissue punctures. Individuals with severe illnesses, pregnant or lactating women, and those with contraindications to topical therapies will be excluded from participation. During the trial, participants are advised to continuously monitor their health status and immediately inform the Chinese medicine practitioner if any discomfort or symptoms of illness arise.

v. Control group Exercise therapy is used as control due to its proven effectiveness on pain relieving in multiple studies, it is chosen as the control group in this protocol.

According to Hamada et al. (2017), for the group with 4 weeks of hip exercise first and followed by 4 weeks of quadriceps exercise (Group A), the Kujala score increases from 69.8 ± ± 9.8 to 84.1±7.7 after the first 4 weeks, and to 94.7±5.2 after 8 weeks. While for the group with 4 weeks of quadriceps exercise first and followed by 4 weeks of hip exercise (Group B), the Kujala score increases from 68.1±13.8 to 82.4±10.5 after 4 weeks, and to 86.4±10.5 after 8 weeks. It shows the effectiveness of both exercise respectively.

In this trial, both hip exercise and quadriceps exercise would be done, but for 4 weeks in total, each exercise with 2 weeks respectively. Reducing intervention week from 8 weeks to 4 weeks is due to the consideration of reducing the number of drop out. Longer intervention period would lead to lower compliance of participants.

Group A show a higher increase in percentage at Kujala score than Group B, thus pattern of group A would be used. Hip exercise would be done first 2 weeks and followed by quadriceps exercise.

Each patient in both groups received 12 sessions (3 sessions per week for 4 weeks) of hip strengthening and quadriceps strengthening exercises in group. Each strengthening exercise was performed for three sets of 10 repetitions with 3 seconds rest between repetitions and 1 minute rest after each set. Each patient was trained at 60% of 10 repetitions maximum which is the amount of weight that was lifted and lowered through available range of motion exactly 10 times. Determining the 10 repetition maximum, the investigator select a specific amount of resistance and document how many repetitions can be completed through the full range before the participant reported to fatigue. New 10 repetition maximum would be established at the end of each week of training.

Appendix 1: content of exercise therapy

Hip exercise:

Hip Training The patient lies on their unaffected side for strengthening exercises targeting the hip abductors and external rotators. During treatment, the unaffected knee is flexed while the affected leg remains extended, with the therapist stabilizing the pelvis. Secure a sandbag above the lateral malleolus and instruct the patient to elevate the affected limb into abduction. Hold for six seconds, then slowly lower back to the starting position over six seconds before relaxing.

For external rotation strengthening, the patient sits on the edge of the bed with hips and knees flexed at 90 degrees, supporting themselves with one hand behind them. While the therapist stabilizes the thigh, a sandbag is placed near the lateral malleolus. The patient internally rotates the leg toward the unaffected side, holds the position for six seconds, then gradually returns to the starting position over six seconds before relaxing.

Knee exercises program:

Knee Joint Training Program This program combines two key elements: muscle strengthening and stretching exercises.

Strengthening Exercises:

Straight Leg Raise: Patient lies supine with the affected knee fully extended and the unaffected leg flexed at 90° for stability. A sandbag is placed above the affected ankle. The patient contracts the quadriceps to raise the affected leg to the level of the opposite knee, holds for six seconds, then slowly lowers it over six seconds before relaxing.

End-Range Knee Extension: Patient lies supine with both knees extended. Place a rolled towel under the affected knee and secure a sandbag near the ankle joint. Using the towel for support, the patient extends the knee as fully as possible, holds for six seconds, then slowly returns to the starting position.

Stretching Exercises:

Hamstrings: Lie supine with knees extended. Place the affected leg on the therapist's arm or shoulder for support. Secure the opposite thigh with a strap. Hold each stretch for 30 seconds, repeating three times with 10-second rest intervals between each.

Quadriceps: Lie on your side with the unaffected limb down. The therapist grasps the bent knee from behind, stabilizes the pelvis, and gently pulls the limb backward. Hold each stretch for 30 seconds, repeat three times, with 10 seconds rest between each stretch.

IT Band: Maintain lateral recumbent position. Therapist stabilizes the pelvis and adducts the upper limb over the lower limb. Hold each stretch for 30 seconds, repeat three times, with 10 seconds rest between each.

Gastrocnemius: Supine position. Therapist stabilizes the leg with one hand and applies traction by supporting the heel with the other hand. Hold the position for 30 seconds, repeat three times, with 10 seconds rest between each.

vi. Adherence Monitoring

1. Weekly Follow-Up Visits:

   Participants will personally visit the Lui Sheng Chun Clinic once per week for in-person follow-up visits. During each visit, researchers will review the participant's progress, reinforce proper application techniques for the topical ointment, and supervise exercise techniques. Any difficulties, missed applications, or exercise compliance issues will be discussed and documented.

2. Topical Medication Log:

   Each participant will receive a logbook to document daily application of the traditional Chinese medicated ointment (TCMO). Entries must include date, time of application, and any local reactions (e.g., warmth, itching, rash). Researchers will review logs weekly to verify compliance and cross-check with remaining ointment weight.

3. Exercise Therapy Log:

   Participants must maintain a separate exercise diary documenting each hip and quadriceps strengthening session. Entries must include exercise name, sets and repetitions, perceived exertion level, and any pain sensations. Therapists will review exercise logs weekly to ensure accuracy and adherence to the prescribed regimen.

4. Compliance Verification:

   Ointment usage adherence will be quantified by comparing the initial and final weights of each ointment container. Exercise adherence will be assessed based on class attendance records and participant logs. Participants achieving ≥80% adherence for both interventions will be considered compliant.

5. Feedback and Reinforcement Measures:

During weekly routine follow-ups, participants will receive verbal feedback and encouragement to maintain adherence. Corrective guidance will be provided if improper application or exercise technique is observed.

vii. Concomitant care No other physical therapy or medication included in exclusion criteria are allowed during trial.

viii. Outcome assessment i. Primary outcome

1. Kujala Scale Functional assessment through AKPS, also named as Kujala Scale would be used. It is a 13-item self-administered questionnaire designed to record patients' subjective responses to specific activities and symptoms associated with anterior knee pain syndrome. Scores range from 0 to 100, with lower values indicating more severe pain and functional impairment. Chinese version of the AKPS assessment will be used to facilitate the communication with Chinese-speaking participants. The assessment will be done at week 0 (before intervention), week 2 and week4.

2. Eccentric step down test The eccentric step down test will be used. It shows moderate specificity (0.82; 95% CI: 0.62, 0.93) and +LR (2.3; 95% CI: 1.9, 2.9), shows that probability of PFPS being present when there is a positive test is moderately increased. Reproduction of anterior knee pain during the test is considered a positive test result.

   Subjects will perform the test barefoot using a 15 cm step (or more precisely, equivalent to 50% of tibial length). Each subject will be instructed to stand on the step with hands on hips, step down as slowly and smoothly as possible while maintaining this posture throughout. The test will first be performed on one leg, then repeated on the other leg. Warm-up or practice trials are prohibited. If anterior knee pain (AKP) recurs during the test, it is recorded as a positive test result. The assessment will be done at week 0, week 2 and week4.

3. Fastest finishing time of recorded distance Finishing time would be used as measuring the running performance. Fastest finishing time of 5000m, 10000m, half marathon (21,097.5m) and marathon (42,195m) within a racing season (180 days preceding the marathon race) is measured. The shorter finishing time will imply the rising performance for the runner. The fastest record of 5000m, 10000m, half marathon or marathon before week 0 would be collected as the baseline. Collection of finish time of one of these four distance would be done at week 2 and week 4.

ii. Secondary outcome

1. Visual analogue scale (VAS):

   Participants will be instructed to indicate their pain level on a line ranging from 0 to 10, with 0 representing no pain and 10 indicating unbearable pain. It has be proven valid and reliable. The VAS will be applied at two moments: (1) pain in the last month (during the baseline assessment); and (2) before and after performing two functional activities: bilateral squatting at 90° (for 30 seconds) and step-up/down 26 cm (for 30 seconds). Squatting and stepping up and down are activities which exacerbates anterior knee pain for patient of PFPS. The assessment will be done at week 0, week 2 and week4. The higher the value of VAS, the more the pain.

2. Timed Up and Go (TUG) The Timed Up and Go (TUG) test is a standardized measurement tool for assessing functional mobility, balance, and gait. Participants begin seated, rise to a standing position as instructed, walk a fixed distance of 3 meters with safe steps, turn around, return to the chair, and sit down. The total time is recorded using a stopwatch, with the duration from standing up to resitting serving as the test result. Each participant must complete three trials, and the final analysis is based on the average of these three trials. The assessment will be done at week 0, week 2 and week4.
3. Treatment Expectation Questionnaire (TEX-Q) The Questionnaire could be used for evaluating the change of treatment expectation [23]. Chinese version of this questionnaire would be used in this trial [24]. It will be done at week 0 and week 4. Comparison of two data could be used to evaluate the extent of placebo effect.

ix. Data collection Tools: AKPS, VAS, finish time, TUG, step-down test, TEX-Q Retention Plan: weekly follow-ups and reminder calls

x. Plan of reporting and evaluating the adverse events Following the initial application of the ointment, any adverse reactions will be continuously monitored and documented. Participants must record any side effects experienced after use daily and immediately notify the research team. Adverse events to be observed include itching, burning sensation, skin scaling or peeling, rash formation, and dryness, with burning sensation and itching being the most common. Mild reactions (such as transient warmth and scaling within two hours of application) are common and typically resolve spontaneously within six hours. If symptoms persist beyond this timeframe, participants should discontinue the ointment for two days and promptly report to the research team. Experienced practitioner will then reassess the situation to determine if treatment can be resumed. Participants must immediately stop using the ointment if a severe allergic reaction or other major adverse event occurs at the application site.

Table 2. Treatment methods on different reported adverse events Adverse events in this study were categorized into three levels: normal, mild, and severe, with corresponding treatment methods for each. At the normal level, participants occasionally experienced mild hotness or scaling on the skin within two hours of application. If these symptoms diminished within six hours, therapy was continued without interruption. Mild adverse events included desquamation, itching, burning sensations, rash development, and dryness. In such cases, participants were instructed to discontinue the ointment for two days and report back to the researcher promptly. An experienced practitioner would then observe and reassess the condition to determine whether ointment use could be resumed. Severe adverse events involved significant skin allergies or other unfavorable reactions. In these situations, participants were required to stop using the ointment immediately and report to the researcher for further evaluation and management. This structured approach ensured that adverse events were carefully monitored and addressed according to their severity.

xi. Measures to handle withdrawal and dropout Prior to study initiation, participants will receive comprehensive explanations detailing the study objectives, procedures, and potential benefits and risks of participation to ensure full understanding of their responsibilities. Before enrolment, each participant will be provided with an information sheet and required to sign an informed consent form confirming agreement to comply with all study requirements and conditions. The research team will establish a dedicated telephone hotline and email contact channel for participants to consult questions at any time. To enhance compliance and reduce dropout rates, the team will maintain regular communication and interaction with participants. Should a participant consider withdrawing, the team will make every effort to contact them and address their concerns. Participants identified during screening as high-risk for non-compliance will be excluded at the screening stage. Once the participants dropout, "Modified Intention-To-Treat" will be used to manage the data.

xii. Termination criteria

Subjects must withdraw from the trial if any of the following occur:

I. Allergic reactions or severe pain following topical medication use II. Pregnancy during the study period III. Diagnosis of any serious disease meeting exclusion criteria during participation IV. Development of a life-threatening illness during participation V. Undergoing surgical treatment at any stage during the trial

xiii. Statistical analysis An independent samples t-test using the difference-in-scores method was performed to compare differences in demographic and clinical characteristics between Group A and Group B. To assess treatment efficacy, a linear mixed model was used to analyse trends in primary and secondary outcome scores from baseline and endpoints of intervention and control. Analysis will be carried out using IBM SPSS Statistics and RStudio IDE.

xiv. Ethics approval To be obtained from HKBU human clinical ethical committee

8. Purposes and potential for implementation of results This study is expected to promote the practice of TCM by efficiency and safety of TCM intreating PFPS on long-distance runners. If the results are encouraging, PFPS among runners could have alternative option of treatment to reduce level of pain or recurrence.