Patient Disposition and Demographics
In total, 757 patients were screened and 746 patients were randomized from 18 centers within two different countries (14 in Germany and four in Russia) between May 2016 and July 2017, when the last patient completed the study. All 746 randomized patients were treated with study medication (Fig. 1). A total of 19 patients (2.5%) prematurely discontinued study medication, and the frequencies were comparable across the four treatment groups. The most frequent reasons for discontinuation were AEs [n = 11 (1.5%)], lack of efficacy [n = 3 (0.4%)], lost to follow-up [n = 2 (0.3%)], and refusal to continue taking trial medication [n = 2 (0.3%)]. AEs leading to discontinuation of study medication were reported for patients on active treatment only [capsaicin: n = 6 (2.7%), diclofenac: n = 2 (0.9%), diclofenac + capsaicin: n = 3 (1.3%)].
Analgesic concomitant therapies including dispensed rescue medication, during the treatment period, were reported for 65 patients (8.7%). The frequencies across treatment groups ranged from 17 patients (7.6%) in the diclofenac + capsaicin group to eight patients (10.7%) in the placebo group.
The demographic data were well balanced across the four treatment groups and are shown in Table 1. The overall mean duration of exposure was 5.2 days (SD 1.38; median 5 days) and exposure was well balanced across the four treatment groups.
Baseline disease characteristics were well balanced across the four treatment groups. In total, at baseline, mean PA was 15.65 (SD 5.372) N/cm2, mean pain intensity at rest was 6.0 (SD 1.62) on a numerical rating scale (NRS), mean average pain intensity (pain over the last 24 h) on an NRS was 6.4 (SD 1.48), and mean highest pain on movement score (VAS) was 7.26 cm (SD 1.198).
Pain on Movement Endpoints
The analysis of change in POMWP between baseline and day 2 evening, 1 h after drug application was based on the full analysis set (FAS), which slightly deviated from the treated set in that one patient from the capsaicin group and one patient from the diclofenac group was not included due to no recorded post-baseline POMWP value. From baseline to day 2 evening, 1 h after drug application, POMWP was most effectively lowered by capsaicin alone (− 3.26 cm), followed by the combination therapy diclofenac + capsaicin (− 3.05 cm), placebo (− 2.45 cm), and diclofenac alone (− 2.33 cm). Diclofenac + capsaicin was superior to placebo and to diclofenac alone, but superiority of diclofenac + capsaicin versus capsaicin alone could not be demonstrated (Table 2). The change over time from baseline to 1 h after drug application on the evening of day 2 is illustrated by treatment group in Fig. 2. Sensitivity analyses of the primary endpoint using the per-protocol set, and after adjusting for the use of rescue medication, supported the results of the primary analyses.
Exploratory analyses of key secondary parameters POMWP AUC(0–72h) and POMWP AUC(0–120h) supported the results of the POMWP from baseline to day 2 evening: the effect sizes of the combination therapy diclofenac + capsaicin and capsaicin alone in POMWP AUC(0–72h) (Table 2) and in POMWP AUC(0–120h) (Table 3) were similar. The effect sizes of diclofenac alone and placebo were also similar (Fig. 2).
Post-hoc analysis with the same data set and model, using capsaicin as a reference, revealed a distinct treatment effect for capsaicin, when change from baseline at day 2 evening, 1 h after drug application for POMwp was compared with placebo (P = 0.0035).
The highest percentage of patients with a decrease in POMWP of at least 30% and 50% from baseline until day 2 evening, 1 h after drug application was achieved with capsaicin alone, with 150 (67.3%) and 95 (42.6%) patients, respectively. The combination achieved a higher percentage of patients with at least a 30% and 50% POMWP decrease than diclofenac alone and placebo, with 134 (59.6%) and 85 (37.8%) patients, respectively (Table 5). By the morning of day 6, 190 (84.4%) and 159 (70.7%) patients in the diclofenac + capsaicin group experienced at least a 30% or 50% reduction in pain, respectively. This is higher than diclofenac alone and only slightly lower than the capsaicin group, in which 189 (84.8%) and 167 (74.9%) patients achieved a reduction in pain of at least 30% or 50%, respectively.
Consistent with the primary endpoint (change in POMWP between baseline and day 2 evening) and key exploratory secondary endpoints [POMWP AUC(0–72h) and AUC(0–120h)], the change from baseline in POMWP at day 6 in the morning showed no relevant difference between the combination therapy diclofenac + capsaicin and capsaicin alone [adjusted mean difference: 0.20, 95% confidence interval (CI) − 0.24, 0.64]. However, diclofenac + capsaicin was better than diclofenac alone (adjusted mean difference: − 1.12; 95% CI − 1.56, − 0.68) and placebo (adjusted mean difference: − 1.05; 95% CI − 1.67, − 0.44).
Pressure Algometry Endpoints
At day 2 evening, the pressure on the trigger point in the area of the worst procedure site could be increased by at least 3 N/cm2 in all treatment groups. Change from baseline in PA at day 2 evening, before drug application, showed only small differences between all treatment arms; capsaicin alone (adjusted mean difference: 0.31 N/cm2, 95% CI − 0.87, 1.49), diclofenac alone (adjusted mean difference: 0.76 N/cm2, 95% CI − 0.42, 1.95) and placebo (adjusted mean difference: − 0.13 N/cm2, 95% CI − 1.78, 1.53), compared with diclofenac + capsaicin.
Similarly, change from baseline in PA at day 6 morning is shown in Table 6. Only small differences were reported between diclofenac + capsaicin and capsaicin alone (adjusted mean difference: 0.28 N/cm2, 95% CI − 1.58, 2.15); however, diclofenac + capsaicin was superior to diclofenac alone (adjusted mean difference: 2.02 N/cm2, 95% CI 0.15, 3.88). No difference was seen between diclofenac + capsaicin and placebo (adjusted mean difference: 1.65 N/cm2, 95% CI − 0.98, 4.27). The changes in PA (N/cm2) over time to day 6 morning are illustrated in Fig. 3.
Of the 746 treated patients, a total of 146 patients (19.6%) reported AEs (Table 7). The overall percentage of patients with AEs was 21.3% (n = 48) in the diclofenac + capsaicin group, 26.5% (n = 59) for capsaicin alone, 12.1% (n = 27) for diclofenac alone and 16.0% (n = 12) in the placebo treatment group. The type, incidence, and severity of AEs reported in patients in each of the treatment groups were consistent with known profiles for capsaicin and diclofenac. As per preferred term, the most frequent AEs for all patients were burning sensation [n = 29 (3.9%)], skin burning sensation [n = 21 (2.8%)], nasopharyngitis [n = 20 (2.7%)], headache [n = 20 (2.7%)], and application-site pain [n = 17 (2.3%)]. The incidences of AEs related to the application site (burning sensation, skin burning sensation and application-site pain) were more frequent in the diclofenac + capsaicin [n = 12 (5.3%), n = 12 (5.3%) and n = 7 (3.1), respectively] and capsaicin alone [n = 16 (7.2%), n = 7 (3.1%) and n = 10 (4.5%), respectively] treatment groups than the diclofenac alone [n = 1 (0.4%), n = 2 (0.9%) and n = 0 (0.0%), respectively] or placebo (n = 0, 0.0% for each AE) treatment groups.
The incidence of AEs leading to discontinuation of study medication was low in all active treatment groups [capsaicin alone: n = 5 (2.2%); diclofenac alone: n = 3 (1.3%); diclofenac + capsaicin: N = 3 (1.3%) and placebo: n = 0 (0.0%)]. Diarrhea and vomiting led to the discontinuation of two patients (0.9%) from the capsaicin-alone treatment group. Other causes for discontinuation were (skin) burning sensation [n = 2 (0.3%)], pruritus [n = 1 (0.1%)], gastroenteritis [n = 1 (0.1%)], nasopharyngitis [n = 1 (0.1%)], dizziness [n = 1 (0.1%)] and paresthesia [n = 1 (0.1%)].
Overall, the incidences of drug-related AEs were higher in the diclofenac + capsaicin [n = 39 (17.3%)] and capsaicin alone [n = 43 (19.3%)] treatment groups than in the diclofenac alone [n = 7 (3.1%)] and placebo [n = 2 (2.7%)] treatment groups. The incidences of drug-related AEs by system organ class (SOC) and preferred term followed the same pattern as for all AEs. There were no serious adverse events (SAEs) in any of the treatment groups; no relevant changes in safety laboratory parameters (hematology or biochemistry) or vital signs over time were observed in any treatment group.
The incidence of all skin irritations was reflected by the use of the dermal response score. The percentages of patients without skin irritation at 1 h after dosing on day 1 were higher for the diclofenac alone [n = 204 (91.5%)] and placebo [n = 65 (86.7%))] treatment groups than the diclofenac + capsaicin [n = 136 (60.4%)] and capsaicin alone [n = 113 (50.7%)] treatment groups. However, these skin irritations were confined to barely perceptible or readily visible erythema in almost all cases [diclofenac + capsaicin group (39.1%, one patient had minimal edema or papular response), capsaicin group (49.3%)]. Similar results were reported at evaluations on days 2–4. At day 6, the percentage of patients with no irritation from the diclofenac + capsaicin and capsaicin-alone treatment groups were comparable with the diclofenac alone and placebo treatment groups [diclofenac + capsaicin: n = 193 (87.3%); capsaicin alone: n = 198 (89.2%); diclofenac alone: n = 211 (95.5%); placebo: n = 72 (97.3%)].
Overall tolerability, as assessed by patients and investigators, was very good or good in the majority of patients in all treatment groups. In the diclofenac + capsaicin treatment group, overall tolerability was assessed as very good or good in 75.5% and 81.3% by patients and investigators, respectively (capsaicin alone: 77.1% and 81.6%, diclofenac alone: 91.9% and 92.8%, placebo: 94.7% and 96.0%, respectively).