The study design of DANTE is shown in Fig. 1. A total of 544 patients with acute LBP were screened, of whom 538 were randomized to the treatment groups as follows: DKP/TRAM (n = 211); TRAM (n = 207); placebo-DKP/TRAM (n = 59); placebo-TRAM (n = 61). Baseline characteristics are shown in Table 1. The mean (± standard deviation [SD]) age of the entire cohort was 42.9 ± 12.5 years and the proportion of males and females was 52.6% and 47.4%, respectively. Overall, about one-half of patients had radiculopathy, and more than one-third of them had radiation to a distal or proximal extremity. The mean NSR-PI score was 7.0 ± 1.3 for all groups, and one-third of patients had severe pain. Of the 538 patients enrolled, 468 (87.0%) completed the study treatment, and the remaining 70 (13.0%) discontinued the study after the first dose. The main reason for discontinuation was AEs (n = 55, 78.6%), which are described in detail below.

The primary endpoint of the study was not met. Specifically, although the proportion of patients with NRS-PI score < 4 or pain intensity reduction ≥ 30% was numerically higher in the DKP/TRAM arm compared with the placebo arm (46.1% vs. 42.6%, respectively), the HR was 1.11 and not statistically significant [95% confidence interval (CI) 0.775, 1.595; p = 0.566] using a CPH model with treatment, baseline pain intensity categories, and baseline radiculopathy categories as factors. In relation to the secondary endpoints, the mean time to reach an NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake up to 8 h after the first dose was 105 (range 15–480) min in the DKP/TRAM group compared to 120 (range 15–360) min in the placebo groups (ESM Table 2).

Changes in TOTPAR at 4, 6, and 8 h are shown in Fig. 2. During the single-dose phase, DKP/TRAM achieved superiority over TRAM in TOTPAR at 4, 6, and 8 h in the modified ITT population (4h: LS mean difference 0.78; 95% CI 0.163, 1.402; p = 0.013; 6h: LS mean difference 1.33; 95% CI 0.380, 2.280; p = 0.006; 8h: LS mean difference 1.59; 95% CI 0.336, 2.840; p = 0.013). The DKP/TRAM combination also achieved superiority over placebo in TOTPAR at 6 and 8 h (6h: LS mean difference 1.28; 95% CI 0.118, 2.450; p = 0.031; 8h: LS mean difference 1.73; 95% CI 0.194, 3.270; p = 0.027). The LS mean %max TOTPAR at 4, 6, and 8 h was significantly higher with DKP/TRAM compared to TRAM [per protocol (PP) population at 4 h: 30.10 vs. 24.55; p = 0.005; at 6 h: 32.16 vs. 25.61; p = 0.001; at 8 h: 33.32 vs. 27.15; p = 0.002]. There was a significantly higher percentage of patients achieving at least 50% of maximum TOTPAR at 4, 6, and 8 h after the first dose in the DKP/TRAM arm compared with the TRAM arm (modified ITT population, at 4 h: 20.6% vs 8.8%; p < 0,001; at 6 h: 22.5% vs 9.8%; p < 0,001; at 8h 23.5% vs 11.3% p = 0.001) (Fig. 3). The percentage of achieving changes in SPID in the PP population are shown in Fig. 4; significantly lower values were seen at 4, 6, and 8 h versus placebo. Changes in SPID are shown in Fig. 2b. In the single-dose phase, SPID values were significantly lower at 4, 6, and 8 h in the DKP/TRAM group compared with the TRAM group. The LS mean of SPID was significantly lower in the DKP/TRAM compared with TRAM arm at 4, 6, and 8 h after dosing in the PP population (t4h: LS mean difference − 1.55; 95% CI − 2.637, − 0.454; p = 0.003; t6h: LS mean difference − 2.41; 95% CI − 4.156, − 0.671; p = 0.003; t8h: LS mean difference − 2.95; 95% CI − 5.247, − 0.653; p = 0.006).

Changes in total pain relief (TOTPAR) at 4, 6, and 8 h after the first dose (T4h, T6h, T8h) in the modified intent-to-treat population. Asterisk (*) indicates significant difference at p < 0.05 vs. placebo; obelisk (†) indicates significant difference at p < 0.05 vs. TRAM. DKP/TRAM Dexketoprofen/tramadol fixed-dose combination, TRAM tramadol

Percentage of patients achieving at least 50% of maximum total pain relief (TOTPAR) in the modified intent-to-treat population. Asterisk (*) indicates significant difference at p < 0.05 vs. placebo at all timepoints; obelisk (†) indicates significant difference at p < 0.05 vs. TRAM at all timepoints. DKP/TRAM Dexketoprofen/tramadol fixed-dose combination, TRAM tramadol, T4h, T6h, T8h 4, 6, and 8 h after the first dose

Changes in summed pain intensity difference (SPID) at 4, 6, and 8 h after the first dose(T4h, T6h, T8h) per protocol population. Obelisk (†) indicates significant difference at p < 0.05 vs. TRAM. DKP/TRAM Dexketoprofen/tramadol, TRAM Tramadol

The time to first achieve an NRS-PI score < 4 or pain intensity reduction ≥ 30% from drug intake until 8 h after the first dose is shown in ESM Tables 3 and 4, respectively. The related HR for DKP/TRAM versus placebo was 1.10 (p = 0.576) in the ITT population and 1.17 (p = 0.397) in the PP population. A significantly greater reduction in NRS-PI was seen with DKP/TRAM versus placebo starting from 1 h, which remained numerically lower, but not statistically significant, throughout 8 h (Fig. 5). The analysis of the PGE in the single-dose phase is presented in ESM Table 5.

Summary of Numerical Rating Scale-Pain Intensity (NRS-PI) score by timepoints (single-dose phase) in the modified intent-to-treat population. There were no statistically significant differences between groups at any timepoint. DKP/TRAM Dexketoprofen/tramadol

All 510 patients in the single-dose phase continued to the multiple-dose phase, and none were lost. During the multiple-dose phase, DKP/TRAM achieved superiority over TRAM in TOTPAR at 24, 48, and 72 h in the modified ITT population (24 h: LS mean difference 3.62; 95% CI 0.083, 7.165; p = 0.045; 48 h: LS mean difference 7.62; 95% CI 0.263, 14.973; p = 0.042; 72 h: LS mean difference 11.99; 95% CI 0.721, 23.257; p = 0.037). The LS mean %max TOTPAR at 24, 48, 72, and 96 h was significantly higher in the DKP/TRAM arm than in the TRAM arm in the PP population (at 24 h: 47.75 vs. 42.97; p = 0.007; at 48 h: 52.61 vs. 47.68; p = 0.007; at 72 h: 56.28 vs. 51.17; p = 0.007; at 96 h: 59.36 vs. 54.42; p = 0.010) (Fig. 6). The percentage of patients achieving at least 50% of maximum TOTPAR at 24, 48, 72, and 96 h after the first dose was higher in the DKP/TRAM arm compared with the TRAM group; it was also significantly higher in the DKP/TRAM arm versus the TRAM arm at 48 and 72 h in the PP population (at 24 h: 46.4% vs. 42.6%; p = 0.170; at 48 h: 60% vs. 46.5%; p = 0.001; at 72 h: 62.6% vs. 53.5%; p = 0.019; at 96 h: 65.1% vs. 60.4%; p = 0.146).

Percentage of maximum total pain relief (TOTPAR) at 24, 48, 72, and 96 h of the multiple-dose phase (T24h, T48h, T72h, T96h) estimated from the analysis of covariance arm in the per protocol population. Asterisk (*) indicates a signficant difference at p < 0.05 vs. TRAM at all timepoints. DKP/TRAM Dexketoprofen/tramadol, TRAM Tramadol

There was no significant difference in the LS means of SPID between the DKP/TRAM and the TRAM arms at any timepoint during the multiple-dose phase (24, 48, 72, and 96 h).

At 96 h of the multiple-dose phase, there was a reduction in mean RMQ total scores from 64.1 at baseline to 29.6 at 104 h in the DKP/TRAM arm and from 65.2 at baseline to 35.2 at 104 h in the TRAM arm. The mean percentage change in RMQ score from baseline to t104 h was − 53.5% and − 46.1% in the DKP/TRAM and TRAM arms, respectively. There was no significant difference in LS mean score at 104 h between the DKP/TRAM and the TRAM arms (p = 0.067). Data on PGE at 96 h of the multiple-dose phase and RMQ total score are presented in ESM Tables 6 and 7, respectively.

Time to rescue medication ranged from 79 to 450 min in the DKP/TRAM arm and from 91 to 365 min in the TRAM arm. No significant difference in the time to first use of rescue medication was reported between the DKP/TRAM and TRAM arms. In the single-dose phase, 11 (5.2%) patients in the DKP/TRAM arm, 14 (6.8%) in the TRAM arm, and nine (7.5%) in the placebo arm received rescue medication. Of these, nine (4.3%) patients in DKP/TRAM arm, 11 (5.3%) in the TRAM arm, and five (4.2%) in the placebo arm took rescue medication once. The frequency of taking rescue medication twice or ≥ 3 times was < 2% in all treatment arms.

Overall, the DKP/TRAM fixed-dose combination was well tolerated in patients with moderate to severe acute LBP after a single-dose (first 8 h) and during the multiple-dose phase (from 8 h up to day 5). No clinically significant hematological abnormalities were reported in the study and there were no major changes in vital signs.

In the single-dose phase (Table 2), a total of 70 (13.0%) patients had at least one treatment-emergent adverse event (TEAE), with a rate of 13.3%, 15%, and 9.2% in the DKP/TRAM, TRAM, and placebo groups, respectively. There were no statistically significant differences in TEAEs between the DKP/TRAM and TRAM groups in either the single- or multiple-dose phases, or between DKP/TRAM and placebo in the single-dose phase. The majority of TEAEs were mild or moderate in intensity. One severe TEAE (urinary calculus) was reported in the DKP/TRAM arm and was considered to be serious and unrelated to treatment. Treatment-related TEAEs were reported in 63 (11.7%) patients, with an incidence of 11.8%, 13.0%, 9.2% in the DKP/TRAM, TRAM, and placebo arms, respectively. In the single-dose phase, > 1% of the patients in the DKP/TRAM, TRAM, and placebo arms had the following TEAEs: dizziness (5.7%, 5.8%, and 1.7%, respectively) and nausea (3.8%, 2.9%, and 4.2%, respectively). In the multiple-dose phase, > 1% of the patients in the DKP/TRAM and in the TRAM arms had the following TEAEs: nausea (6.7%, 9.3%, respectively), dizziness (6.3%, 6%, respectively), vomiting (4.8%, 8.2%, respectively), somnolence (4.4%, 2.6%, respectively), headache (3%, 1.9%, respectively), and constipation (1.9%, 1.1%, respectively).

TEAEs leading to discontinuation in the single-dose phase are shown in Table 2. Treatment discontinuations due to TEAEs were reported in 17 (3.2%) patients, with a comparable incidence between groups. In the multiple-dose phase, 141 (26.2%) patients reported TEAEs, with a comparable incidence between the DKP/TRAM (25.2%) and TRAM (27.2%) arms (Table 2). The majority of the TEAEs were mild to moderate in intensity. Three (0.6%) patients had severe TEAEs. Treatment-related TEAEs were reported in 127 (23.6%) patients, with a comparable incidence between the DKP/TRAM and the TRAM arms (22.6% and 24.6%, respectively). Treatment discontinuations due to TEAEs were reported in 38 (7.1%) patients with an incidence of 7.5% versus 6.7% in the TRAM and DKP/TRAM groups, respectively (ESM Table 8).