A multi-center, double-blind, randomized, placebo-controlled trial protocol to assess Traumeel injection vs dexamethasone injection in rotator cuff syndrome: the TRAumeel in ROtator cuff syndrome (TRARO) study protocol

Male and female patients aged 40 to 65 years, inclusive, will be recruited if they have acute episodes of chronic rotator cuff syndrome and/or bursitis: tendinopathy of the supraspinatus tendon, bursitis, or partial degenerative tears of the supraspinatus and/or infraspinatus tendon (differentiation by ultrasonography). They must be willing and able to understand and sign an approved informed consent form. Female patients must not be pregnant (as proven by negative pregnancy test before first study drug administration) or breast-feeding. Females of childbearing potential (including those less than one year post-menopausal) must agree to maintain reliable birth control throughout the study, i.e. an established use of oral, injected or implanted hormonal contraception, female sterilization by hysterectomy, bilateral oophorectomy, or bilateral tubal exeresis, intrauterine device (IUD) or coil or barrier method (e.g. diaphragm, cervical/vault cap) plus spermicidal cream/gel.

Potential study patients will be excluded if one of the following exclusion criteria is present: calcifications in shoulder joint; complete rotator cuff tears; treatment with NSAIDs (previous treatment with NSAIDs is allowed, with a wash-out period of 1 week; paracetamol [acetaminophen] can be taken until 48 hours before baseline visit); corticosteroid therapy by mouth or by injection within the previous 3 months prior to screening; any contraindication for corticosteroid therapy; physical therapy, acupuncture, transcutaneous electrical nerve stimulation (TENS) and shock-wave therapy (within 30 days prior to screening); treatment with anticoagulants (except low-dose aspirin); diabetic patients including borderline cases (glycosylated fraction of hemoglobin [HbA_1c] >7.0% at screening); clinically significant shoulder joint deformities; major injury, including sports-related injury, to the shoulder within the past year; significant osteoarthritis of the shoulder; cervical spine disorder (that could confound the clinical assessment) that has been symptomatic and required active treatment within the past 3 months before screening; any active musculoskeletal disease that could confound the diagnosis/evaluation of the painful shoulder, any neurological etiology of the pain, or any acute infection of the shoulder joint; any major surgery, arthroplasty, or arthroscopy in the signal shoulder within 6 months of screening or planned surgery within the duration of the study; prior history of any malignancy (with the exception of basal cell carcinoma) treated less than 2 years ago; patients with rheumatic polymyalgia; known or suspected allergies against one or any particular ingredients of any of the study preparations; presence of serious gastrointestinal, renal, hepatic, pulmonary, cardiovascular, neurological disease or other known systemic disease (like leukemia, tuberculosis, immune mediated diseases, multiple sclerosis, Acquired Immuno Deficiency Syndrome, Human Immunodeficiency Virus-infections or other chronic virus infections) that might interfere with the outcome of the study or the patient’s ability to comply with study requirements; presence of infections and/or skin diseases in the area of the injection site (including psoriasis); clinically significant abnormal laboratory values (as judged of the investigator) at the screening visit; consumption of any investigational product within 1 month prior to the screening visit; and patients who are likely to be non-compliant or uncooperative during the study, as judged by the investigator.

The recruitment phase will be completed when 160 patients have been enrolled, and the duration of this recruitment period will be about 12 months. Patients will be recruited from the existent patient pools at the trial centers. They will be outpatients attending for a scheduled visit who would then be asked about their willingness to be included in a clinical trial.

All interventions will be provided in 2 ml vials, identical in appearance. Traumeel® injection solution (Biologische Heilmittel Heel GmbH) is officially classified as a homeopathic medicinal product [17]. Tr14 injection solution is a formulation of 12 botanical and 2 mineral substances. The quantities of each component are shown in Table 1. Dexamethasone 8 mg will be provided as Fortecortin® (Merck Pharma GmbH) and placebo will be saline solution in 2 ml vials.

Participants will receive 3 injections at weekly intervals on visits 2, 3 and 4. All investigators were trained in ultrasound-guided injection technique at an investigator’s meeting in Ghent, Belgium, to ensure consistency of administration. The patient is placed in a supine position to reduce any risk of syncope during the procedure. Ultrasound guidance using a sagittal view (7 till 14 MHz) obtained over the lateral edge of the shoulder is used to guide the injection into the subacromial bursa with the ultrasound probe used in a long-axis lateral view. A narrow gauge needle should be used (22–30 gauge). The needle is advanced until its tip penetrates the bursal cavity. Images are taken before and after injection, showing distension of the bursa following injection of the product. For the first 48 hours after injection, the patient is allowed to continue all routine activities of daily living, but is advised not to overuse the treated shoulder.

Previous treatment with NSAIDs, analgesics, and COX type 2 (COX-2) inhibitors is allowed, with a washout period of 1 week before baseline; paracetamol can be taken until 48 hours before baseline visit. This also includes all kinds of applications, i.e. topical, oral or parenteral. Patients have to be instructed that for the duration of the study they must not take any pain relief medication other than paracetamol (which will be used as rescue medication and can be taken during the study except 48 hours before the study visits). No chondroprotective medication is allowed (e.g. among others, glucosamine, chondroitin sulfate, hyaluronic acid, diacerein, native collagen and so-called USA-300 preparation).

Treatment with anticoagulants is not permitted during the study. Low-dose (70–100 mg/d) aspirin for anti-thrombotic therapy is permitted if doses are stable for the month prior to screening and remain stable throughout the study period. Also, treatment with corticosteroid injections or intake of oral corticosteroids in the 3 months prior to the study or during the study is not permitted.

Physiotherapy is forbidden within 30 days prior to screening, but will be allowed as non-drug rescue treatment from Day 23 until Week 15. Acupuncture, TENS and shock-wave therapy are also forbidden within 30 days prior to screening and during the course of the study until week 15.

After screening, only paracetamol (500 mg when necessary) is permitted during the study as rescue medication for pain relief. At screening, after ensuring patient eligibility, paracetamol rescue medication and a patient diary will be provided to the patients. Patients will be instructed to document the paracetamol consumption every day and to bring the diary to the site at each visit, where paracetamol usage will be documented. Paracetamol consumption is limited to 2000 mg (4 tablets) per day. Patients are instructed that they must not take paracetamol within the 48 hours prior to a study visit.

Study completion or discontinuation will be documented with the reason for any discontinuation. Reasons for a patient discontinuing participation in the study include:

In case of an AE, the patient is to be followed up until resolution of the AE. Patients who discontinue prematurely from the study will not be replaced.

Protocol adherence will be documented and judged by patient reporting (diary) and attendance at clinic visits according to schedule.

The primary endpoint is change from baseline in abduction-rotation pain VAS (0–100 mm scale, 0 corresponds to no pain and 100 to extreme pain) at visit 5 (day 22) (Tr14 injection solution injections versus dexamethasone injections) for active external rotation. The abduction-rotation will be done with an internal rotation and external rotation and both actively and passively. However, the primary parameter is active rotation abduction with external rotation and only for this movement the VAS will be measured. During the shoulder examination, the active external abduction rotation must be the first movement during evaluation for pain VAS determination.

Secondary efficacy parameters include ROM, disability of arm, shoulder, hand (DASH) score and patient’s/investigator’s global assessment. For ROM the following movements will be analyzed [18,19]:

Safety parameters include local tolerability, laboratory monitoring, vital signs and AEs. AEs will be standardized for terminology and classification, using Medical Dictionary for Regulatory Activities (MedDRA) (the latest available version will be used). Concomitant medications will be classified by site of action and therapeutic and clinical characteristics using the World Health Organization (WHO) DRUG dictionary (the latest available version will be used).

A schedule of study procedures and events is provided in Table 2.

Clinical efficacy will be assessed as non-inferiority of Tr14 injection solution with respect to dexamethasone regarding the primary efficacy parameter. A one-sided test of non-inferiority of Tr14 injection solution with respect to dexamethasone at level 0.025 will be computed using an analysis of covariance (ANCOVA) model with treatment group and center as qualitative factors and the baseline value of the abduction rotation pain VAS for active external rotation as a covariate.

All continuous efficacy parameters will be analyzed by suitable analysis of ANCOVA models, whereas the dichotomous Jobe and painful arc test data will undergo suitable logistic regression model analyses. The ordered categorical responses of the patients’ and examiners’ global assessment will be evaluated by Cochran-Mantel-Haenszel (CMH) tests that account for stratification by center. Clinical safety will be addressed by assessing AEs, physical examinations, laboratory assessments, and vital signs results in a descriptive manner. All statistical analyses in this study will be exploratory in nature.

Analyses will be based on the safety analysis, full analysis, and the per-protocol sets. The summaries of the efficacy parameters, the statistical analyses of the primary efficacy variable, and the statistical analyses of the secondary efficacy variables will be performed on the per-protocol set. These summaries and analyses will be supported by corresponding summaries and exploratory statistical analyses performed on the full analysis set. Missing values for all efficacy parameters will be imputed by the last observation carried forward (LOCF) approach. All statistical tests will be supported by presenting estimates and 95% confidence intervals for the respective treatment effects and differences between the treatment groups. These estimates and confidence intervals will be based on the respective statistical models used for the analysis, shown in Table 3.