TRAUMED - a randomized clinical trial evaluating the efficacy and safety of Traumed® gel in patients with acute ankle sprain.

Lateral ankle sprains are the most prevalent musculoskeletal injuries in physically active populations. They also have a high prevalence in the general population and pose a substantial healthcare burden. The injury mechanism is characterized by a high velocity inversion and internal rotation of the ankle/foot complex. The treatment for acute lateral ankle sprain is quite variable, with many patients returning to activity in a short period of time; however, half of the affected population may never seek initial care. Inadequate treatment of ankle sprains can lead to chronic problems such as decreased range of motion, pain, and joint instability.

Controlled trials of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in patients with ankle sprain showed that compared with placebo, NSAIDs were associated with improved pain control and function, decreased swelling, and more rapid return to activity. Diclofenac is meanwhile considered to be the gold standard in the treatment of joint sprains and other conditions. Topical diclofenac is well tolerated and is associated with fewer side-effects than other topical NSAIDs, mostly mild, easily resolved local skin irritation.

The current trial is designed to demonstrate the superior efficacy of Traumed® gel versus placebo and to assess the non-inferiority of Traumed® gel compared to diclofenac gel. After evaluation of entry criteria patients will be randomized to investigational treatment, which will be Traumed® gel or diclofenac gel or matching placebo gel, administered locally on the area of the injury, 3 times daily for 7 days. After end of the 7-day treatment phase patients will be followed up for another 7 days. Consequently the entire duration of the trial for each patient will be 14 days.

Patients will receive paracetamol (acetaminophen) 500 mg/tablets as rescue medication to be taken for pain relief when necessary.

All patients will receive soft support (elastic bandage). Grade 2 patients will receive a semi-rigid removable brace on Day 7.

Primary and secondary outcomes are listed separately as required. All statistical tests will be two-sided with a significance level of alpha =0.05, unless specified otherwise.

Confirmatory analyses

1. Area Under the Curve (AUC) for pain on passive movement in Visual Analog Scale (VAS) from Baseline to Day 4 (test for superiority, Traumed® gel versus placebo), Full Analysis Set (FAS).
2. AUC for pain on passive movement in VAS from Baseline to Day 4 (test for non-inferiority, Traumed® gel versus diclofenac gel), Per-Protocol (PP) analysis set.

If the first a priori ordered test (superiority) shows statistical significance, the subsequent hypothesis (non-inferiority) can then be tested individually in a confirmatory manner according to the principle of a priori ordered hypotheses.

Clinical safety will be addressed by assessing Adverse Events (AEs), physical examinations, vital signs and as needed laboratory assessments in a descriptive manner.

Estimation of sample size is based on the primary efficacy variable, AUC for pain on passive movement as measured by VAS from Baseline to Day 4. A two-sided test of equality of the investigational drug (Traumed® gel) and the comparator (placebo) at level 0.05 based on an expected raw scale treatment difference of AUC 25 [mm x days] and a common standard deviation of AUC 75 [mm x days] for the response variables (re-expressed for nonparametric evaluation in terms of the Mann-Whitney (MW) statistic as MW = 0.6, achieves a power of at least 90% for parametric first line analysis as well as for second line nonparametric analysis if the sample size is set to 291 patients for the Traumed® gel group and to 146 patients for the placebo group.

Due to an additional safety requirement that AEs with incidence level of 1% for Traumed® gel are found during the trial with probability 95%, 299 patients for the Traumed® gel group are required. Assuming a drop-out rate from the Safety Analysis Set of about 4% an amount of 312 randomized patients in the Traumed® gel group is needed. With an allocation ratio of 2:1:1 (Traumed® gel : diclofenac gel : placebo gel) 156 patients are obtained in the diclofenac gel and placebo group each, that is, a total of 624 patients with acute unilateral Grade 1 or Grade 2 sprain of the lateral ankle.

During the recruitment phase site inspections by the German Local Authorities in 2019 (Gesundheitsamt Düsseldorf of German Federal State North Rhine Westphalia, NRW) it was recognized that there could have been a possible violation of the predefined 'blinding firewall' described in the protocol at some locations.

All sites were checked rigorously to detect any risk of unintentional deblinding, which, in the end, was not found. To exclude any risk of including these patients, the German regulatory authority (Federal Institute for Drugs and Medical Devices) recommended including only those cases in the final analysis where blinding could be 100% confirmed.

In order to ensure the pre-defined power of the trial for the trial objectives including the confirmatory test for non-inferiority (Traumed® gel compared to diclofenac gel), which is based on the Per-Protocol Analysis Set (PP), a sample size enhancement is introduced for compensation of cases for whom maintenance of blinding procedures may have been compromised and, thus, are representing a major protocol violation (exclusion from PP analysis).

For compensation, the final sample size will be enhanced to 202 patients for the diclofenac and Placebo group each, and to 404 patients for the Traumed® gel group resulting in a new total of 808 patients .

Analyses will be based on the Safety Analysis, Full Analysis, and the Per-Protocol analysis sets. The definitions of the analysis sets follow those given in the ICH E9 guideline (CMP/ICH/363/96).

Inclusion Criteria:

• Acute unilateral Grade 1 or Grade 2 sprain of the lateral ankle.
• >/=18 years of age.
• Legally competent male or female outpatient.
• Injury occurred within previous 24 hours before first treatment expected.
• Signed Informed Consent.
• After 5 minutes of rest, pain on passive movement by investigator measured by Visual Analog Scale (VAS) >50 mm.
• Not pregnant or breast-feeding.

Exclusion Criteria:

• Similar injury affecting the same joint within the past 6 months.
• Bilateral ankle injury.
• Grade 3 ankle sprain.
• Fracture of the ankle (It should be excluded by using e.g., the Ottawa Ankle Rules. In case of any doubt the exclusion of fracture by x-ray should be considered as per standard of care).
• Chronic joint disorders such as clinically relevant osteoarthritis or aseptic arthritis
• Disorders that may lead to joint oedema for other reasons than ankle sprain (such as heart failure, thrombosis, lymphedema and others).
• Diagnosis requiring bed rest, hospitalization, surgery, or use of any cast during the planned treatment period.
• Debilitating acute or chronic illness.
• Use of systemic and /or topical corticosteroids in the previous 8 weeks, any analgesics (e.g., paracetamol / acetaminophen) in the previous 24 hours before Screening Visit, or 48 hours in the case of long-acting NSAID, cyclooxygenase type 2 (COX-2) specific inhibitors, or tramadol and other opioids. Low dose acetylsalicylic acid (70 - 100 mg per day) for anti-thrombotic therapy is permitted if doses are stable for the month prior to Screening Visit and planned to be stable during the entire study.
• History of sensitivity to any component of the study drugs (including e.g. paracetamol / acetaminophen intolerance; patients in whom asthma attacks, skin rash or acute rhinitis are triggered by acetylsalicylic acid or non-steroidal anti-inflammatory drugs (NSAIDs).
• Unwilling or unable to comply with all the requirements of the study protocol.
• Concurrent injury to proximal structures in ipsilateral lower extremity (i.e., concurrent shin, knee, thigh, or hip injury).
• History of ligament avulsion, fracture or surgery to the affected lower extremity.
• Presence of infections and/or skin diseases in the area of the study treatment site (including psoriasis).
• Any previous treatments of the injured ankle, whether topical or systemic, are prohibited except RICE (simultaneous combination of all 4 elements; Rest, Ice, Compression and Elevation; which is restricted to be used until starting treatment with the investigational drug).

CRO (including CRAs)