Study Population
The study population included male and female patients, aged 18 years and over, suffering from acute back pain or neck pain for at least 24 h, but less than 21 days, diagnosed as pain on movement (POM) ≥ 5.0 cm [on a Visual Analog Scale (VAS) ranging from 0–10 cm] for at least one POM procedure out of five standardized procedures [5]. The POM measurement with the highest pain response determined if the patient had back or neck pain. Patients must also have had an algometric pressure trigger point with a pain pressure threshold of ≤ 25 N/centimeter2 (N/cm2).
Patients were excluded if they had experienced three or more episodes of back or neck pain in the last 6 months, had surgery due to back or neck pain in the previous 12 months, if the pain was attributable to an organic disease (e.g. prolapsed disc, inflammatory arthritis, neurological diseases, etc.) or experienced trauma or strains of the back or neck muscles. Concomitant use of anti-inflammatory drugs, heparinoids, muscle relaxants, analgesics or non-pharmacological treatment, (e.g. heat treatment) 3 days before visit 1, or meeting any other criteria defined in the study protocol (such as known intolerance or hypersensitivity to the active ingredients or any excipients) were also grounds for exclusion.
Study Design and Treatments
This was a prospective, randomized, double-blind, parallel-group, phase 3 study conducted in two countries.
To obtain a minimum total of 700 evaluable patients, 746 patients received one of the following four topical gels, of which 2 g was applied twice daily, with patients allowing for 12 ± 4 h between applications: diclofenac + capsaicin gel: 2% diclofenac and 0.075% capsaicin, diclofenac gel (2%), capsaicin gel (0.075%) and placebo gel.
Patients were randomized to the treatment groups diclofenac + capsaicin, diclofenac, capsaicin, and placebo in a 3:3:3:1 ratio in order to achieve 700 patients eligible for the assessment of the primary endpoint. Randomization was stratified according to application site (back or neck) and country. Patients were blinded to their treatment and all participants were instructed to wear disposable gloves when applying the trial medication.
After a screening evaluation (visit 1), eligible patients were randomized on the same day into the double-blind treatment period of the trial. After administration of the first treatment, patients administered the second application of the trial medication in the evening at home on day 1. They returned to the trial site for four more visits (visits 2–5) during the treatment period as follows: in the morning and in the evening of the following day (day 2) and in the morning of days 3 and 4. At scheduled visits, patients were dosed while at the site. Evening applications on day 3 and day 4 were administered by the patients at home. Thereafter, the treatment was administered at home for one more day (day 5). The patients then returned to the trial site for final assessments (visit 6) in the morning of day 6. Depending on the severity of a patient’s condition and on a patient’s availability, the treatment period at home (day 5) could be skipped or treatment could be extended for 1 or 2 days. Visit 6 was then to be performed on the day immediately following the shortened or extended treatment period. Trial participation was concluded with a telephone call (visit 7 T) for follow-up on adverse events (AEs).
The interval between the two daily applications of the trial medication was approximately 12 h, which could be shortened or extended by 4 h as long as no more and no less than two applications were administered on each treatment day. Treatments were always to be applied by the patient (if possible).
If required, rescue medication (paracetamol, 500 mg tablets) was provided by the sponsor using locally sourced, commercially available products.
One global protocol amendment led to a global protocol revision, which was implemented in June 2016, shortly after the first patient entered the study. These amendments included the trigger point for algometric pressure being revised from ≤ 2.5 to ≤ 25 N/cm2. An analysis of the primary endpoint, including an additional variable for analgesic use was also added.
Endpoints
The primary endpoint was the change in POM for the worst procedure (the movement with maximum pain when assessed at baseline; POMWP) between baseline and day 2 evening, 1 h after drug application. POM was assessed by patients assisted by adequately trained personnel, on performance of standardized, muscle-group-specific movements measured using a VAS (0–10 cm) ranging from 0 = no pain to 10 = worst pain possible. The change in POM was calculated as POM at a given time point subtracted by the POM at baseline.
Key secondary variables were area under the curve (AUC) of POMWP calculated until day 4 morning, i.e. 72 h after start of treatment (POMWP AUC72), and POMWP AUC120 (AUC of POMWP calculated until day 6 morning, i.e. 120 h after start of treatment). Other POM-related endpoints were: the number of patients with a decrease in POMWP of at least 30% and 50% from baseline on day 2 evening, 1 h after drug application, and the change in POMWP between baseline and the morning of day 6.
Change in pressure algometry (PA) between baseline and the morning of day 6 was also measured as a secondary endpoint. PA was determined by the investigator at baseline on day 1 and at defined time points between days 2 and 6 as the pressure value (N/cm2) at a defined trigger point located in the area of POMWP. The pain reaction was determined by increasing the pressure via an algometer on the most tender position (always done at the same position) within the painful area until the patient asked not to increase the pressure anymore. The corresponding pressure value was documented. The change in PA between baseline and day 2 evening (before drug application) and between baseline and the morning of day 6 was compared between treatment groups.
Exposure to rescue medication (days) was analyzed descriptively. Rescue medication was defined as study-dispensed paracetamol.
Safety endpoints included skin reactions using a numerical dermal response score (DRS; categorized as positive for scores ≥ 3 and negative for scores < 3), incidence and intensity of AEs, and changes in safety laboratory parameters, vital signs, and patient and investigator assessment of tolerability.
Statistical Analysis
The sample size for this study was based on an anticipated treatment difference of 1.2 cm on a 0–10 cm VAS and a common standard deviation (SD) of 3 cm, yielding a standardized treatment difference of 0.4 concerning the primary endpoint. The allocation ratio to the treatment groups diclofenac + capsaicin, diclofenac, capsaicin and placebo was planned to be 3:3:3:1.
A total sample size of 700 patients (210 patients each treated with diclofenac + capsaicin, diclofenac, and capsaicin, and 70 patients with placebo) was calculated to have 98% power to detect a difference of 1.2 cm on a 0–10 cm VAS for the primary endpoint between treatment effects of diclofenac + capsaicin versus diclofenac and capsaicin, respectively (3:3 allocation ratio) and 82% power to detect the same difference between diclofenac + capsaicin and placebo (3:1 allocation ratio). This assumes a common SD of 3 cm and uses a 0.05 two-sided significance level.
The primary endpoint was analyzed using a restricted maximum likelihood (REML)-based repeated measures approach using all available longitudinal POMWP observations at the assessment times up to day 2 evening, 1 h after drug application. The statistical model, applied to the analysis of change from baseline in POMWP, included the fixed categorical effects of treatment, country, application site (back/neck), time and treatment-by-time interaction, as well as the continuous fixed covariates of baseline POMWP and baseline-by-time interaction.
The key secondary endpoints POMWP AUC72 and POMWP AUC120 were analyzed using analysis of covariance (ANCOVA) including treatment, country, and application site (back/neck) as fixed effects and baseline POMWP as a continuous covariate. The key secondary endpoints were analyzed hierarchically (POMWP AUC72 first) in a confirmatory way, only if statistical significance was achieved for the primary endpoint. Therefore, no alpha-adjustment for multiple endpoint testing was applied.
All other secondary endpoints were considered as supportive only. The change in PA between baseline and day 2 evening before drug application, and the morning of day 6, respectively, were analyzed using an REML approach analogous to the primary analysis. The numbers of patients with a decrease in POMWP of at least 30% or 50%, respectively, from baseline until day 2 evening, 1 h after drug application, were analyzed by a logistic regression model, including the factor of treatment and the categorical stratification factors of country and application site (back/neck). No interim analysis was planned or performed.
Compliance with Ethics Guidelines
The clinical study (ClinicalTrials.gov identifier: NCT02700815) was conducted in compliance with the clinical trial protocol, the principles laid down in the Declaration of Helsinki, in accordance with ICH-GCP, and was based on the Guideline on Clinical Development of Fixed Combination Medicinal Products of the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) current at trial initiation [33]. The study was done to support the registration of a new product so the respective guidelines had to be followed in addition to the specific requests from the German Federal Institute for Drugs and Medical Devices. The study protocol (EudraCT number 2015-000404-25), protocol amendment and associated documents were reviewed by the Independent Ethics Committees and/or Institutional Review Boards (IECs/IRBs) of the participating centers; the master ethics committee is Ethik-Kommission der Bayrischen Landesärztekammer, München, Germany (Ethic Committee 16004) and further details of local committees can be found in Supplementary Table S1. Informed consent was obtained from each patient in writing before randomization and the rights of patients were protected.