Effectiveness of Topical Chinese Medicine Ointment Therapy (TCMO) (Ng's Prescription) Eccentric Exercise for Tennis Elbow as Control: a Randomized Controlled Trial.

B. Introduction Tennis elbow, medically termed lateral epicondylitis (LE), is a prevalent musculoskeletal disorder characterized by pain and tenderness over the lateral epicondyle of the humerus. Excessive mechanical stress on the elbow tendons, often caused by repetitive movements or manual labor, contributes to microtrauma and cumulative strain of the forearm and elbow musculature. Clinically, the site of maximal tenderness is situated just anterior and distal to the lateral epicondyle itself. Moreover, studies have demonstrated that pain intensity and grip strength are closely associated with manual test outcomes in chronic tennis elbow, further supporting the functional relevance of these diagnostic measures. Although historically associated with racquet sports, contemporary evidence indicates that the condition is more frequently linked to occupational and daily activities such as typing, carpentry, and healthcare work.Epidemiological studies estimate an annual prevalence of approximately 1.3% and an incidence of 3.4 per 1,000 individuals, making it one of the most common causes of elbow pain in adults aged 30-60 years.

The disorder exerts a considerable impact on modern life. Participants often experience reduced grip strength and functional limitations that interfere with essential tasks such as lifting, writing, or using tools. This functional impairment contributes to work productivity loss and increased healthcare utilization, resulting in substantial economic burden. Moreover, lifestyle factors such as smoking and repetitive manual work has been shown to negatively influence prognosis, with a subset of participants requiring surgical intervention after six months of unsuccessful conservative treatment. Collectively, these findings underscore that tennis elbow is not merely a sports-related injury but a significant occupational health issue, affecting individual well-being and societal efficiency in today's workforce.

A pilot randomize controlled cross-over trial of TCMO (Ng's prescription) in 2024 has significant efficacy on LE and can effectively improve the pain symptoms of participants (95%CI: -22.4 to -5.28, p: 0.0032). Modern drug treatments for tennis elbow mainly focus on reducing pain and inflammation. While this can provide short-term relief and help participants tolerate daily activities or rehabilitation, it often does not address the underlying tendon degeneration and impaired healing.

C. Trial Objective

1. Primary objective:

   To evaluate the efficacy of TCMO (Ng's prescription) in reducing pain intensity of LE through randomized controlled trial (RCT).

2. Secondary objective:

To evaluate safety of TCMO (Ng's prescription) of LE through randomized controlled trial (RCT). To assess functional improvement of TCMO (Ng's prescription) (PRTEE). D. Method

1. Study design Parallel-group, single-blinded superiority randomized controlled trial, allocation ratio 1:1 (Group A: Group B).

2. Participants and Recruitment Participants will be recruited at the Lui Seng Chun, one of the outpatient clinics at Hong Kong Baptist University. Prior to obtaining written informed consent from each participant, the principal investigation (PI) or research assistant (RA) will explain the purpose, procedures, nature and potential adverse reactions of the study involving Topical Chinese Medicine Ointment and physical therapy. Participants will also be informed that the study can be withdrawm at any time.

3. Diagnostic Criteria The PI verified each participant's diagnosis through face-to-face screening. To be considered eligible, participant was required to meet all of the following criteria for a diagnosis of LE: I. Tenderness to palpation of the lateral epicondyle; II. Tenderness within 2-3 centimeters distal to the epicondyle; III. Pain localized to the lateral elbow during resisted extension of wrist or middle finger; IV. V. VI. VII. VIII. IX. Pain at the lateral elbow when performing a forceful grasp; Reduced pain-free grip strength (PFGS) Preserved elbow range of motion (normal mobility); Diffuse lateral elbow pain elicited by repeated wrist dorsiflexion; No neurological symptoms (absence of tingling or numbness); No cervical involvement (absence of neck pain or stiffness).

4. Inclusion Criteria

   Participants will be included if all the following criteria is met:

   I. Men and women aged 18 to 60 who are able to give written informed consent; II. Meet the diagnostic criteria of the LE; III. Lateral elbow pain duration more than 3 weeks; IV. No history of allergic reactions to Chinese medicine ointment; V. No history of acupuncture treatment within the past month; VI. No other serious medical conditions; VII. No participation in other clinical trials during the same period. VIII. No history of medical treatment, physical therapy for pain in LE, or upper limb surgery within the past six months;

5. Exclusion Criteria Participants with any of the following conditions will not be permitted to participate in this clinical trial: I. Absolute contraindications exist for the use of traditional Chinese Medicine ointment; II. Use of non-steroidal anti-inflammatory drugs during the previous weeks; III. Participants are in pregnancy or lactation; IV. Participants with severe comorbidities, such as poorly controlled diabetes mellitus, thyroid enlargement, coagulation disorder, hepatic or renal failure, chronic obstructive pulmonary disease (COPD), cardiovascular disease, neurological disorder, psychiatric illness, acute or chronic infections, or malignant tumors; V. Brachioradial bursitis; VI. Receipt of corticosteroid injection within the past two months; VII. Local skin changes around the lateral epicondyle of the humerus, including erythema, warmth, pain, infections, or ulceration; VIII. Receipt of acupuncture treatment for LE within the two weeks prior to intervention.

6. Sample Size Calculation Given a pilot randomized controlled cross-over trial study about TCMO (Ng's prescription) for lateral epicondylitis in 2024, the treatment leads of the TCMO has given a 95% CI: -22.4 to -5.28, and the difference is -13.8. Based on the d=0.844, α=0.05, power=0.817, the total sample size should be 48 participants (24 per group).

   I. Group A: receive Topical Chinese Medicine Ointment (TCMO)（Ng's prescription）and eccentric exercise II. Group B: receive eccentric exercise only

7. Randomization and allocation concealment To minimize research bias, 48 participants will be assigned to two treatment groups and a control group in a 1:1 ratio. Block randomization via Sealed Envelope tool, with gender as the stratification criterion. Sealed opaque envelopes and password-protected file. RA generates sequence; Research Assistant II (RAII) blinded. To further minimize potential bias, evaluators and data analysts involved in the study will be blinded to treatment assignments. RAII will manage and analyze collected data. The PI will assess participant outcomes and oversee the entire study process.

8. Intervention I. Topical Chinese Medicine Ointment (TCMO)（Ng's prescription） Table 1. (Ingredients of Prof Ng's TCMO prescription) Latin Pharmaceutical Name, English Name, Ratio(%) Gram (g) per cylinder container(corr. to 3 sig. fig.) Rhei Radix et Rhizoma Rhubarb Tangute Rhubarb 0.01 0.0142 Eupolyphaga Steleophaga Ground Beetle 0.004 0.00567 Aralia chinensis Root of Spine Aralia 0.01 0.0142 Croton crassifolius Croton Root 0.018 0.0255 Ardisia crenata Sims Cinnabarroot 0.01 0.0142 Ardisia punctata Lindl Hance's Ardisia 0.01 0.0142 Phryma leptostachya L. Lopseed 0.01 0.0142 Notoginseng Radix et Rhizoma Sanchi 0.01 0.0142 Chuanxiong Rhizoma Szechwan Lovage Rhizome 0.003 0.00425 Angelicae Sinensis Radix Chinese Angelica 0.006 0.00850 Herba Artemisiae Anomalae Diverse Wormwood Herb 0.01 0.0142 Sappan Lignum Sappan Wood 0.01 0.0142 Saposhnikoviae Radix Saposhnikovia 0.006 0.00850 Teucrium viscidum Teucrium 0.01 0.0142 Olibanum Frankincense 0.006 0.00850 Myrrha Myrrh 0.006 0.00850 Paeoniae Radix Rubra Paeoniae Trichocarpae 0.006 0.00850 Scutellariae Radix Baikal Skullcap Root 0.006 0.00850 Gardeniae Fructus Common Gardenia Fruit 0.006 0.00850 Carthamus tinctorius Safflower 0.01 0.0142 Persicae Semen Peach Seed 0.006 0.00850 Pyritum Pyrite 0.022 0.0312 Talcum Talc 41.2 5.84 Bletillae Rhizoma Common Bletilla Tuber 4.1 0.581 Glycerol (as medium) Glycerol 54.5 7.83 II. Preparation of TCMO The dry powder of the selected herbs was prepared and mixed according to the ratios specified in Table 1, after which the formulation was processed into an ointment and stored in 0.5-oz (14.2g) cylinder containers at room temperature, with an instruction sheet enclosed in each package. A total of four containers (one per week) was allocated to each participant for the entire treatment period, and the dosage administered was determined by calculating the difference between the initial mass of the container and its mass following treatment. III. Supervision and administration of TCMO The administration procedure will be taught and supervised by the researcher at the time of each participant's initial receipt of TCMO. A written document specifying the ingredients and dosage of TCMO will be provided, and detailed instructions regarding application procedures, safety considerations, and important notes will be communicated both verbally and in written form. Participants will be required to attend Lui Seng Chun once per week to obtain a new TCMO container, and during each weekly visit throughout the treatment period, the researcher will reiterate and reinforce the administration procedure. When applying the TCMO on their own, participants should first bend their elbow to locate the lateral epicondyle of the humerus. Apply the ointment within a 1-cm radius around the most prominent point of the lateral epicondyle.

9. ii. iii. During the first week (week 1), group A participants were instructed to apply the TCMO to the lateral epicondyle region and surrounding area twice daily (morning and evening) for four consecutive weeks, with each administration recorded in a provided journal. But group B participants were not received any TCMO. On the same time all the participants will receive an eccentric exercise, participant need to follow the schedule and finish the group of exercise daily. During the following three week (week 2-4), group A participants will get the new TCMO when the participants came to weekly visit. Group B participants will not receive any treatment but will have the observation and record. For the applicants of group B who receive exercise only, 4 TCMO will give to the participants after the last assessment of the research study.

i. Control exercises Group A and B participants need to do the 2 types of control exercises with the stretching exercise first follow by the loading exercise. This can minimize the risk of injury during the loading exercise.

1. Stretching exercise This exercise is designed to stretch the extensor muscles of the forearm, wrist, and fingers. To perform this exercise, extend the affected arm straight out in front of the participants, keeping the elbow fully extended (locked) and avoiding any bending. Keep their palm facing down (back of the hand facing up). Next, grasp the back of the affected hand with another hand and gently press to move the palm inward and downward, thereby increasing the stretch in the forearm. Start with a sitting position, participants should feel a distinct stretch in the outer area of the forearm (typically near the lateral epicondyle and the associated extensor tendons/muscles). Perform three sets daily, with 15-30 seconds per set. Avoid causing pain- the goal is to achieve a tolerable tightness or stretching sensation.
2. Loading exercise This eccentric exercise, participants demonstrated meaningful reductions in pain and improvements in muscle strength compared with baseline (HR 0.78, 95% CI 0.63-0.96, p < 0.02), highlighting that eccentric exercise not only produced faster initial improvement but also sustained superior pain reduction and strength recovery over time. The loading device consists of a plastic water tank equipped with a handle. Initial resistance is standardized at 1 kg (equivalent to 1 liter of water) for female participants and 2kg for male participants. Participants sit with their forearms resting on chair armrests or a nearby tabletop. Both group of subjects must grip the container handle with a pronated fist, allowing the container to hang freely in front of the chair or beneath the table.

The training protocol for the centrifugal movement group requires:

first flexing the wrist of the affected side to lower the weight, then using the unaffected arm to lift the weight back to its original position. Perform three sets daily, with 15 repetitions per set, totaling 45 wrist lowering movement. j. Safety of intervention The administration procedure will be taught and supervised by the PI at the time of each participant's initial receipt of TCMO. A written document specifying the ingredients and dosage of the TCMO will be provided, and detailed instructions regarding application procedures, safety considerations, and important notes will be communicated both verbally and in written form. Participants will be required to attend Lui Seng Chun once per week to obtain a new TCMO container, and during each weekly visit throughout the treatment period, the PI will reiterate and reinforce the administration procedure E. Outcome Measurements I. Primary Outcome The Patient-Reported Tennis Elbow Evaluation Questionnaire (PRTEE) provides a concise, efficient, and reliable tool for assessing arm pain and functional status in patients with lateral collateral ligament inflammation. To facilitate communication with Chinese-speaking participants, this study will use the English version of the PRTEE as a template for translation. Participants will complete the questionnaire independently with assistance from research assistants. II. Secondary Outcome A. Visual Analog Scale (VAS) has been used as the measurement of the pain intensity. Pain intensity was measured using the Visual Analogue Scale (VAS), with 0 defined as no pain and 10 defined as the worst imaginable pain. During assessment, no verbal prompts or guidance were given by nurses or physicians, and the scores were recorded solely based on patient self-report. B. In addition to pain metrics, wrist and elbow range of motion will be utilized as a reference data point in this study. Given that lateral epicondylitis can significantly affect wrist and elbow mobility, the flexion and extension angles for each participant will be measured using a universal goniometer both prior to and following the treatment intervention. C. A weak handgrip strength (HGS) is a significant predictor of mortality in patients with established coronary artery disease (CAD), with weaker individuals facing nearly double the risk of death. Therefore, includes HGS as one of the outcomes to provide participants with a health reference. HGS will test by a handgrip dynamometer and take the average of three times griping. Participants should be seated with the shoulder adducted and neutrally rotated, the elbow extended and the forearm and wrist keep in neutral position. Both affected and normal side will be asked to grip the handgrip dynamometer and recorded in week 0 and the assessment will repeat every weeks. III. IV. Plan of Reporting and Evaluating the adverse events Adverse events (AEs) will be systematically monitored and documented once participants have applied the investigational ointment at least once. Participants will be instructed to maintain a daily record of any adverse effects experienced following ointment use and to notify the research team promptly.

Expected AEs include:

1. Itching and burning sensations;
2. Flaking of skin/desquamation;
3. Rash development;
4. Dryness. Measure to Handle Withdrawal and Dropout Prior to participant enrollment, a comprehensive explanation of the study's purpose, procedures, potential benefits, and risks will be provided. Each participant will receive an information sheet and must sign a written informed consent form in accordance with ethical guidelines. To minimize withdrawal and discontinuation rates, the research team will implement the following measures:

To minimize withdrawal and dropout, the study team will:

1. Maintain regular communication with participants;
2. Provide a dedicated telephone hotline and email contact for inquiries;
3. Actively engage with participants throughout the trial to enhance compliance and retention rates. V. Termination Criteria

Participants will be withdrawn from the trial if any of the following occur:

1. Allergic reaction or intolerable pain following topical treatment;
2. Pregnancy during the study;
3. Diagnosis of a serious disease listed in the exclusion criteria;
4. Development of a life-threatening illness during the study;
5. Undergoing surgical treatment during trial participation.