Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: Secondary analyses by baseline pain intensity and use of rescue medication of a phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs). METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of rescue medications up to 4 and 48 h post-study drug dose, stratified by baseline pain intensity (moderate/severe), and on the incidence of TEAEs, stratified by rescue medication use. RESULTS: A significantly lower proportion of patients received any rescue medication within 4 h post-study dose with CTC (49.5%) versus tramadol (61.7%, p = 0.0178), celecoxib (65.2%, p = 0.0024), and placebo (75.3%, p = 0.0001); this was also seen for oxycodone use. Fewer patients in the CTC group received ≥3 doses of rescue medication compared with the other groups, irrespective of baseline pain intensity. In patients who did not receive opioid rescue medication, CTC was associated with a lower incidence of nausea and vomiting TEAEs versus tramadol alone. In patients who received rescue oxycodone, the incidence of nausea was similar in the CTC and tramadol groups, and higher versus celecoxib and placebo. CONCLUSION: Celecoxib-tramadol co-crystal was associated with reduced rescue medication use and an acceptable tolerability profile compared with tramadol or celecoxib alone in adults with acute, moderate-to-severe, postoperative pain.

Celecoxib-tramadol co-crystal in patients with moderate-to-severe pain following bunionectomy with osteotomy: A phase 3, randomized, double-blind, factorial, active- and placebo-controlled trial.

BACKGROUND: Celecoxib-tramadol co-crystal (CTC) is a first-in-class analgesic co-crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co-crystal structure, compared with its active constituents administered alone/concomitantly. AIM: We evaluated CTC in moderate-to-severe acute postoperative pain. MATERIALS AND METHODS: This randomized, double-blind, factorial, active- and placebo-controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate-to-severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac-tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0-48 h sum of pain intensity differences (SPID0-48) in all randomized patients. Pain intensity was assessed on a 0-10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals. RESULTS: In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0-48 (least-squares mean: -139.1 [95% confidence interval: -151.8, -126.5]) than tramadol (-109.1 [-121.7, -96.4]; p < 0.001), celecoxib (-103.7 [-116.4, -91.0]; p < 0.001), or placebo (-74.6 [-92.5, -56.6]; p < 0.001). Total treatment-emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug-related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths. CONCLUSION: CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States.

R&D efficiency of leading pharmaceutical companies - A 20-year analysis.

Comparative analysis of the R&D efficiency of 14 leading pharmaceutical companies for the years 1999-2018 shows that there is a close positive correlation between R&D spending and the two investigated R&D output parameters, approved NMEs and the cumulative impact factor of their publications. In other words, higher R&D investments (input) were associated with higher R&D output. Second, our analyses indicate that there are 'economies of scale' (size) in pharmaceutical R&D.

Big Techs and startups in pharmaceutical R&D - A 2020 perspective on artificial intelligence.

We investigated what kind of artificial intelligence (AI) technologies are utilized in pharmaceutical research and development (R&D) and which sources of AI-related competencies can be leveraged by pharmaceutical companies. First, we found that machine learning (ML) is the dominating AI technology currently used in pharmaceutical R&D. Second, both Big Techs and AI startups are competent knowledge bases for AI applications. Big Techs have long-lasting experience in the digital field and offer more general IT solutions to support pharmaceutical companies in cloud computing, health monitoring, diagnostics or clinical trial management, whereas startups can provide more specific AI services to address special issues in the drug-discovery space.

The upside of being a digital pharma player.

We investigated the state of artificial intelligence (AI) in pharmaceutical research and development (R&D) and outline here a risk and reward perspective regarding digital R&D. Given the novelty of the research area, a combined qualitative and quantitative research method was chosen, including the analysis of annual company reports, investor relations information, patent applications, and scientific publications of 21 pharmaceutical companies for the years 2014 to 2019. As a result, we can confirm that the industry is in an 'early mature' phase of using AI in R&D. Furthermore, we can demonstrate that, despite the efforts that need to be managed, recent developments in the industry indicate that it is worthwhile to invest to become a 'digital pharma player'.

A randomized, phase 2 study investigating TRV130, a biased ligand of the µ-opioid receptor, for the intravenous treatment of acute pain.

Efficacy of conventional opioids can be limited by adverse events (AEs). TRV130 is a structurally novel biased ligand of the µ-opioid receptor that activates G protein signaling with little ß-arrestin recruitment. In this phase 2, randomized, placebo- and active-controlled study, we investigated the efficacy and tolerability of TRV130 in acute pain after bunionectomy. We used an adaptive study design in which 144 patients experiencing moderate-to-severe acute pain after bunionectomy were randomized to receive double-blind TRV130, placebo, or morphine in a pilot phase. After pilot phase analysis, 195 patients were randomized to receive double-dummy TRV130 0.5, 1, 2, or 3 mg every 3 hours (q3h); placebo; or morphine 4 mg q4h intravenously. The primary end point was the time-weighted average change in numeric rating scale pain intensity over the 48-hour treatment period. Secondary end points included stopwatch and categorical assessments of pain relief. Safety and tolerability were also assessed. TRV130 2 and 3 mg q3h, and morphine 4 mg q4h produced statistically greater mean reductions in pain intensity than placebo over 48 hours (P < 0.005). TRV130 at 2 and 3 mg produced significantly greater categorical pain relief than morphine (P < 0.005) after the first dose, with meaningful pain relief occurring in under 5 minutes. TRV130 produced no serious AEs, with tolerability similar to morphine. These results demonstrate that TRV130 rapidly produces profound analgesia in moderate-to-severe acute pain, suggesting that G-protein-biased µ-opioid receptor activation is a promising target for development of novel analgesics.

A feasibility study to investigate the use of a bupivacaine-collagen implant (XaraColl) for postoperative analgesia following laparoscopic surgery.

BACKGROUND: XaraColl, a collagen-based implant that delivers bupivacaine to sites of surgical trauma, has been shown to reduce postoperative pain and use of opioid analgesia in patients undergoing open surgery. We therefore designed and conducted a preliminary feasibility study to investigate its application and ease of use for laparoscopic surgery. METHODS: We implanted four XaraColl implants each containing 50 mg of bupivacaine hydrochloride (200 mg total dose) in ten men undergoing laparoscopic inguinal or umbilical hernioplasty. Postoperative pain intensity and use of opioid analgesia were recorded through 72 hours for comparison with previously reported data from efficacy studies performed in men undergoing open inguinal hernioplasty. Safety was assessed for 30 days. RESULTS: XaraColl was easily and safely implanted via a laparoscope. The summed pain intensity and total use of opioid analgesia through the first 24 hours were similar to the values observed in previously reported studies for XaraColl-treated patients after open surgery, but were lower through 48 and 72 hours. CONCLUSION: XaraColl is suitable for use in laparoscopic surgery and may provide postoperative analgesia in laparoscopic patients who often experience considerable postoperative pain in the first 24-48 hours following hospital discharge. Randomized controlled trials specifically to evaluate its efficacy in this application are warranted.

A randomized, multicenter, pilot study comparing the efficacy and safety of a bupivacaine-collagen implant (XaraColl(®)) with the ON-Q PainBuster(®) Post-op Pain Relief System following open gynecological surgery.

BACKGROUND: XaraColl(®), a collagen-based intraoperative implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. We compared the efficacy and safety of XaraColl for the prevention of postsurgical pain versus a slow postoperative perfusion of bupivacaine to the wound environment via the ON-Q PainBuster(®) Post-op Pain Relief System (ON-Q). METHODS: We randomized 27 women undergoing open gynecological surgery to receive either three XaraColl implants (each containing 50 mg bupivacaine hydrochloride) or ON-Q (900 mg bupivacaine hydrochloride perfused over 72 hours) in a 1:1 ratio. Following surgery, patients had access to intravenous morphine via a patient-controlled analgesia pump as rescue analgesia for the first 24 hours and to oral opioid medication thereafter. Total use of opioid analgesia was compared through 24, 48, 72, and 96 hours after surgery. Patients also evaluated overall pain control over the 96-hour period using a five-point numeric rating scale. Safety was assessed for 30 days after surgery. RESULTS: XaraColl was non-inferior to ON-Q in total use of opioid analgesia for the first 24, 48, 72, and 96 hours after surgery, with a statistical trend towards reduced opioid use in favor of XaraColl over 24, 48, and 72 hours (P = 0.067, 0.100, and 0.089, respectively). The time to first use of opioid analgesia was also significantly delayed in patients treated with XaraColl (P = 0.024). There was no significant difference between groups in patients' evaluation of pain control or their satisfaction with the treatment in general. Both treatments were considered safe and well tolerated. CONCLUSION: Despite using only 17% of the ON-Q dose, XaraColl is as effective as ON-Q in providing postoperative analgesia for 4 days after open gynecological surgery. These preliminary findings suggest that XaraColl offers great potential for the management of postoperative pain and warrants further definitive studies.

Clinical evaluation of XaraColl(®), a bupivacaine-collagen implant, for postoperative analgesia in two multicenter, randomized, double-blind, placebo-controlled pilot studies.

BACKGROUND: XaraColl(®), a collagen-based implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. Because of differing patient attitudes to postoperative pain control and the inability to assess baseline pain, standard clinical methods for evaluating analgesic efficacy are compromised and justify application of novel integrated approaches. METHODS: We conducted two independent, multicenter, double-blind, placebo-controlled studies in men undergoing unilateral inguinal hernioplasty by open laparotomy to evaluate the safety and efficacy of XaraColl at different doses (100 mg and 200 mg of bupivacaine hydrochloride; study 1 and 2, respectively). Enrolled patients (50 in study 1 and 53 in study 2) were randomized to receive active or placebo implants in a 1:1 ratio. Postoperative pain intensity and use of supplementary opioid medication were recorded through 72 hours. Safety was assessed through 30 days. The principal efficacy variables were the summed pain intensity (SPI), total use of opioid analgesia (TOpA), and an integrated endpoint (I-SPI-TOpA). Each variable was analyzed at 24, 48, and 72 hours after implantation. A pooled analysis of both studies was also performed retrospectively. RESULTS: Through 24 and 48 hours, XaraColl-treated patients experienced significantly less pain in study 1 (P < 0.001 and P = 0.012, respectively) whereas they took significantly less opioid analgesia in study 2 (P = 0.004 and P = 0.042, respectively). Over the same time intervals in the pooled analysis, treated patients experienced both significantly less pain (P < 0.001 and P = 0.006, respectively) and took significantly less opioid analgesia (P = 0.001 and P = 0.024, respectively). The I-SPI-TOpA endpoint that combined both SPI and TOpA demonstrated a significant treatment effect through 72 hours in the pooled analysis (P = 0.021). CONCLUSION: XaraColl offers great potential for improving the management of postoperative pain and warrants further investigation in definitive clinical trials.

Topical application of a gentamicin-collagen sponge combined with systemic antibiotic therapy for the treatment of diabetic foot infections of moderate severity: a randomized, controlled, multicenter clinical trial.

BACKGROUND: The aim of this pilot study was to determine the safety and potential benefit of adding a topical gentamicin-collagen sponge to standard of care (systemic antibiotic therapy plus standard diabetic wound management) for treating diabetic foot infections of moderate severity. METHODS: We randomized 56 patients with moderately infected diabetic foot ulcers in a 2:1 ratio to receive standard of care plus the gentamicin-collagen sponge (treatment group, n = 38) or standard of care only (control group, n = 18) for up to 28 days of treatment. Investigators performed clinical, microbiological, and safety assessments at regularly scheduled intervals and collected pharmacokinetic samples from patients treated with the gentamicin-collagen sponge. Test of cure was clinically assessed 14 days after all antibiotic therapy was stopped. RESULTS: On treatment day 7, we noted clinical cure in no treatment patients and three control patients (P = .017). However, for evaluable patients at the test-of-cure visit, the treatment group had a significantly higher proportion of patients with clinical cure than did the control group (22 of 22 [100.0%] versus 7 of 10 [70.0%]; P =.024). Patients in the treatment group also had a higher rate of eradication of baseline pathogens at all visits (P ≤ .038) and a reduced time to pathogen eradication (P < .001). Safety data were similar for both groups. CONCLUSIONS: Topical application of the gentamicin-collagen sponge seems safe and may improve clinical and microbiological outcomes of diabetic foot infections of moderate severity when combined with standard of care. These pilot data suggest that a larger trial of this treatment is warranted.

Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery.

BACKGROUND: This study tested the hypothesis that an injectable cyclooxygenase (COX)-2-specific inhibitor will be at least as effective and well tolerated as a COX-nonspecific conventional nonsteroidal antiinflammatory drug (NSAID) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium, an injectable prodrug of the novel COX-2-specific inhibitor, valdecoxib, with ketorolac and placebo in postoperative laparotomy surgery patients. Intravenous morphine, 4 mg, was studied as a positive analgesic control. METHODS: In this multicenter, double-blinded, placebo-controlled study, women experiencing moderate-to-severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium, 20 or 40 mg, ketorolac, 30 mg, morphine, 4 mg, or placebo. Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients, whose pain was not adequately controlled, opted to receive rescue analgesia. RESULTS: Two hundred two patients were enrolled. All treatment groups had comparable demographics and baseline pain status. All active treatments had an equally rapid time to onset of analgesia (10-23 min). Overall, each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points, including a significantly longer (two- to threefold) time to rescue analgesia (P

Upper GI mucosal effects of parecoxib sodium in healthy elderly subjects.

OBJECTIVE: The aim of this study was to compare the upper GI mucosal effects of i.v. parecoxib sodium with i.v. ketorolac tromethamine and placebo in healthy elderly subjects. METHODS: This was a two-center, double-blind, randomized, placebo-controlled study. Healthy subjects aged 65-75 yr who were shown at baseline endoscopy to have no gastric or duodenal lesions received either parecoxib sodium 40 mg b.i.d. for 7 days, ketorolac 15 mg q.i.d. for 5 days, or placebo for 7 days. Endoscopy was repeated at the end of dosing. Measures of upper GI effects were: 1) ulceration, 2) incidence of an ulcer and/or any erosions, and 3) incidence of an ulcer and/or > or = 11 erosions in the stomach, duodenum, or both. RESULTS: No gastric or duodenal ulcers occurred in any subjects receiving parecoxib sodium (n = 29) or placebo (n = 32). In contrast, seven (23%) of the 31 ketorolac subjects had at least one ulcer; five (16%) had gastric ulcers, and two (6%) had duodenal ulcers (p < 0.05 vs parecoxib sodium and placebo for gastroduodenal ulcers and for gastric ulcers). A total of 28 (90%) ketorolac subjects had an ulcer or at least one erosion in the stomach, compared with incidences of four (14%) and two (6%) for parecoxib sodium and placebo, respectively. Incidences of duodenal ulcers/erosions were 45% (n = 14) for ketorolac, 10% (n = 3) for parecoxib sodium, and none for placebo. The differences between ketorolac and both other treatment groups were statistically significant for both stomach and duodenum. No parecoxib sodium or placebo subjects had an ulcer or > or = 11 erosions in the stomach, compared with eight (26%) ketorolac subjects (p < 0.05 vs both parecoxib sodium and placebo). No subject in any group had > or = 11 duodenal erosions. CONCLUSIONS: These results indicate that multiple dose administration of parecoxib sodium is safe and well tolerated in healthy elderly subjects, with a decreased risk of gastroduodenal mucosal injury compared with ketorolac.