Adjusted Mean Treatment Difference Research Articles

Recombinant von Willebrand factor and tranexamic acid for heavy menstrual bleeding in patients with mild and moderate von Willebrand disease in the USA (VWDMin): a phase 3, open-label, randomised, crossover trial

Heavy menstrual bleeding occurs in 80% of women with von Willebrand disease and is associated with iron deficiency and poor response to current therapies. International guidelines indicate low certainty regarding effectiveness of hormonal therapy and tranexamic acid. Although von Willebrand factor (VWF) concentrate is approved for bleeds, no prospective trials guide its use in heavy menstrual bleeding. We aimed to compare recombinant VWF with tranexamic acid for reducing heavy menstrual bleeding in patients with von Willebrand disease. VWDMin, a phase 3, open-label, randomised crossover trial, was done in 13 haemophilia treatment centres in the USA. Female patients aged 13-45 years with mild or moderate von Willebrand disease, defined as VWF ristocetin cofactor less than 0·50 IU/mL, and heavy menstrual bleeding, defined as a pictorial blood assessment chart (PBAC) score more than 100 in one of the past two cycles were eligible for enrolment. Participants were randomly assigned (1:1) to two consecutive cycles each of intravenous recombinant VWF, 40 IU/kg over 5-10 min on day 1, and oral tranexamic acid 1300 mg three times daily on days 1-5, the order determined by randomisation. The primary outcome was a 40-point reduction in PBAC score by day 5 after two cycles of treatment. Efficacy and safety were analysed in all patients with any post-baseline PBAC scores. The trial was stopped early due to slow recruitment on Feb 15, 2022, by a data safety monitoring board request, and was registered at ClinicalTrials.gov, NCT02606045. Between Feb 12, 2019, and Nov 16, 2021, 39 patients were enrolled, 36 of whom completed the trial (17 received recombinant VWF then tranexamic acid and 19 received tranexamic acid then recombinant VWF). At the time of this unplanned interim analysis (data cutoff Jan 27, 2022), median follow-up was 23·97 weeks (IQR 21·81-28·14). The primary endpoint was not met, neither treatment corrected PBAC score to the normal range. Median PBAC score was significantly lower after two cycles with tranexamic acid than with recombinant VWF (146 [95% CI 117-199] vs 213 [152-298]; adjusted mean treatment difference 46 [95% CI 2-90]; p=0·039). There were no serious adverse events or treatment-related deaths and no grade 3-4 adverse events. The most common grade 1-2 adverse events were mucosal bleeding (four [6%] patients during tranexamic acid treatment vs zero during recombinant VWF treatment) and other bleeding (four [6%] vs two [3%]). These interim data suggest that recombinant VWF is not superior to tranexamic acid in reducing heavy menstrual bleeding in patients with mild or moderate von Willebrand disease. These findings support discussion of treatment options for heavy menstrual bleeding with patients based on their preferences and lived experience. National Heart Lung Blood Institute (National Institutes of Health).

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients

Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported. To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients. This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete. Randomized 1:1 to daprodustat or darbepoetin alfa. The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability. A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa. This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population. ClinicalTrials.gov Identifier: NCT03029208.

Safety and efficacy of erythropoietin for the treatment of patients with optic neuritis (TONE): a randomised, double-blind, multicentre, placebo-controlled study

The human cytokine erythropoietin conveys neuroprotection in animal models but has shown ambiguous results in phase 2 clinical trials in patients with optic neuritis. We assessed the safety and efficacy of erythropoietin in patients with optic neuritis as a clinically isolated syndrome in a multicentre, prospective, randomised clinical trial. This randomised, placebo-controlled, double-blind phase 3 trial, conducted at 12 tertiary referral centres in Germany, included participants aged 18-50 years, within 10 days of onset of unilateral optic neuritis, with visual acuity of 0·5 or less, and without a previous diagnosis of multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33 000 IU erythropoietin or placebo intravenously for 3 days as an adjunct to high-dose intravenous methylprednisolone (1000 mg per day). Block randomisation was performed by the trial statistician using an SAS code that generated randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked to treatment assignment, except the trial pharmacist. The first primary outcome was atrophy of the peripapillary retinal nerve fibre layer (pRNFL), measured by optic coherence tomography (OCT) as the difference in pRNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast letter acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in the full analysis set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. This trial is registered at ClinicalTrials.gov, NCT01962571. 108 participants were enrolled between Nov 25, 2014, and Oct 9, 2017, of whom 55 were assigned to erythropoietin and 53 to placebo. Five patients were excluded from the primary analysis due to not receiving the allocated medication, withdrawn consent, revised diagnosis, or loss to follow-up, yielding a full analysis set of 52 patients in the erythropoietin group and 51 in the placebo group. Mean pRNFL atrophy was 15·93 μm (SD 14·91) in the erythropoietin group and 14·65 μm (15·60) in the placebo group (adjusted mean treatment difference 1·02 μm; 95% CI -5·51 to 7·55; p=0·76). Mean low contrast letter acuity scores were 49·60 (21·31) in the erythropoietin group and 49·06 (21·93) in the placebo group (adjusted mean treatment difference -4·03; -13·06 to 5·01). Adverse events occurred in 43 (81%) participants in the erythropoietin group and in 42 (81%) in the placebo group. The most common adverse event was headache, occuring in 15 (28%) patients in the erythropoietin group and 13 (25%) patients in the placebo group. Serious adverse events occurred in eight (15%) participants in the erythropoietin and in four (8%) in the placebo group. One patient (2%) in the erythropoietin group developed a venous sinus thrombosis, which was treated with anticoagulants and resolved without sequelae. Erythropoietin as an adjunct to corticosteroids conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Future research could focus on modified erythropoietin administration, assess its efficacy independent of corticosteroids, and investigate whether it affects the conversion of optic neuritis to multiple sclerosis. German Federal Ministry of Education and Research (BMBF).

Empagliflozin and uric acid metabolism in diabetes: A post hoc analysis of the EMPA-REG OUTCOME trial.

AimTo evaluate the effect of empagliflozin on uric acid (UA) levels, antigout medication and gout episodes in the EMPA‐REG OUTCOME trial (NCT01131676).Materials and methodsA total of 7020 patients with type 2 diabetes (T2D) were randomized to either empagliflozin (10 or 25 mg) or placebo. The effects of empagliflozin versus placebo on UA concentration were assessed using mixed linear models. A composite outcome of new prescription of antigout medication or gout episode was studied with Cox proportional hazards models.ResultsEmpagliflozin reduced serum UA levels versus placebo: week 52 adjusted mean treatment difference = −0.37 (95% confidence interval [CI] −0.42, −0.31) mg/dL; this was more pronounced in patients with baseline UA ≥ 7.0 mg/dL versus <7.0 mg/dL: week 52 adjusted mean treatment difference = −0.56 (95% CI −0.68, −0.43) and −0.30 (95% CI −0.37, −0.24) mg/dL, respectively. Among 6607 patients not taking antigout medications at baseline, 5.2% had a gout episode or initiated antigout treatment versus 3.6% in the placebo and empagliflozin groups, respectively: hazard ratio 0.67 (95% CI 0.53, 0.85; P = 0.001). Both components of the composite outcome contributed to the reduction with empagliflozin in the composite. Risk reduction was similar with both empagliflozin doses.ConclusionsEmpagliflozin reduced UA levels and the composite of gout episodes or prescription of antigout medication. These clinically important findings expand the utility of empagliflozin as a potential antigout treatment in patients with T2D, beyond its well‐established cardio‐renal benefits.

Bradykinin 1 Receptor Antagonist BI1026706 Does Not Reduce Central Retinal Thickness in Center-Involved Diabetic Macular Edema.

PurposeThe bradykinin 1 receptor may be important in inflammatory retinal vascular leakage in diabetic macular edema. BI 1026706 is an antagonist of bradykinin 1 receptor that has demonstrated efficacy in preclinical studies. Boehringer Ingelheim trial 1320.22 (NCT02732951) was a randomized, double-blind, placebo-controlled study. The pharmacodynamics, safety, and tolerability of oral BI 1026706 for 12 weeks were evaluated in patients with type 1 or type 2 diabetes mellitus and mild visual impairment owing to center-involved diabetic macular edema.MethodsPatients (n = 105) were randomized to receive either oral BI 1026706 100 mg twice daily (morning and evening) or placebo for 12 weeks. The primary end point of the study was week 12 change from baseline in central subfield foveal thickness (CSFT) by spectral domain optical coherence tomography. Additional end points included absolute CSFT values, safety, and pharmacokinetics.ResultsAfter 12 weeks of treatment, there was no meaningful change from baseline in the adjusted mean CSFT in either treatment group (BI 1026706, 10.3 µm; placebo, –6.2 µm; adjusted mean treatment difference, 16.5 µm [95% confidence interval, –16.2 to 49.1]). There were also no differences in best-corrected visual acuity outcomes between treatment groups. Most reported adverse events were of mild or moderate intensity, and were balanced between treatment groups.ConclusionsBI 1026706 was not superior to placebo in CSFT week-12 change from baseline. Therefore, BI 1026706 does not reduce CSFT, a morphologic sign of diabetic macular edema.Translational RelevanceKinin-kallikrein inhibition effects may not be apparent over 12 weeks for bradykinin 1 receptor inhibition alone.

Inhaled Methoxyflurane versus Intravenous Morphine for Severe Trauma Pain in the Emergency Setting: Subgroup Analysis of MEDITA, a Multicenter, Randomized, Controlled, Open-Label Trial.

PurposeOpioid analgesics remain the cornerstone of treatment for severe trauma pain in the emergency setting, but there are barriers to their use. This post hoc analysis of a previously reported trial (MEDITA) investigated the efficacy and safety of low-dose methoxyflurane versus intravenous (IV) morphine for severe trauma pain.Patients and MethodsMEDITA was a Phase IIIb, randomized, active-controlled, parallel-group, open-label study in Italian pre-hospital units and emergency departments (EudraCT: 2017-001565-25; NCT03585374). Adult patients (N=272) with moderate-to-severe trauma pain (score ≥4 on the Numerical Rating Scale [NRS]) were randomized 1:1 to inhaled methoxyflurane (3 mL) or standard analgesic treatment (SAT; IV paracetamol 1g or ketoprofen 100mg for moderate pain [NRS 4–6] and IV morphine 0.1mg/kg for severe pain [NRS ≥7]). Analyses were performed for the severe pain subgroup. The primary efficacy variable was the overall change from baseline in visual analog scale (VAS) pain intensity at 3, 5 and 10min post-randomization. Non-inferiority of methoxyflurane versus morphine was concluded if the upper 95% confidence interval (CI) for the treatment difference was <1; superiority was concluded if the upper 95% CI was <0.ResultsNinety-three patients (methoxyflurane: 49; SAT: 44) were included in the severe pain intention-to-treat population. The reduction in VAS pain intensity over the first 10min was superior for methoxyflurane versus morphine (adjusted mean treatment difference: −5.54mm; 95% CI: −10.49, −0.59mm; p=0.029). Median time to onset of pain relief was 9min for methoxyflurane and 15min for morphine. Patients rated treatment efficacy and physicians rated treatment practicality “Excellent” or “Very good” for more methoxyflurane-treated patients (42.8% and 67.3%) than morphine-treated patients (18.1% and 22.8%). Adverse events, all non-serious, were reported in 20.4% of methoxyflurane-treated patients and in 4.8% of morphine-treated patients.ConclusionMethoxyflurane provided superior short-term pain relief to IV morphine in patients with severe trauma pain and offers an effective non-narcotic treatment option.

Treatment of Optic Neuritis With Erythropoietin (TONE): A Randomized, Double-Blind, Placebo-Controlled Study

Background: The human cytokine erythropoietin (EPO) conveys neuroprotection in preclinical models and has shown ambiguous results in phase 2 clinical trials in optic neuritis. We assessed the efficacy and safety of EPO in optic neuritis as a clinically isolated syndrome in a sufficiently powered RCT. Methods: This randomized, placebo-controlled, double-blind phase 3 trial conducted at 12 German tertiary care centres included participants aged 18-50 years with an acute presentation of unilateral optic neuritis within 10 days, visual acuity ≤ 0·5 and without previously known multiple sclerosis. Participants were randomly assigned (1:1) to receive either 33.000 IU erythropoietin or placebo intravenously for three days as an adjunct to high-dose methylprednisolone (1000 mg/day). Block Randomisation was performed with randomly varying block sizes, stratified by study site and distributed using sealed envelopes. All trial participants and all study staff were masked from treatment assignment with the exception of the trial pharmacist. The first primary outcome was the amount of retinal nerve fibre layer (RNFL) atrophy, measured by optic coherence tomography (OCT) as the difference in RNFL thickness between the affected eye at week 26 and the unaffected eye at baseline. The second primary outcome was low contrast visual acuity at week 26, measured as the 2·5% Sloan chart score of the affected eye. Analysis was performed in a set of all randomised participants for whom treatment was started and at least one follow-up OCT measurement was available. Safety was analysed in all patients who received at least one dose of the trial medication. Findings: The study enrolled 108 participants between November 25 th , 2014 and October 9 th , 2017, 55 of which were assigned to EPO and 53 to placebo. Five patients were excluded from the primary analysis due to screening failure, revised diagnosis or loss to follow-up, yielding a full analysis set of 52 EPO and 51 placebo recipients. The adjusted mean treatment difference of EPO versus placebo was 1·02 µm of RNFL atrophy (95% CI -5·51 to 7·55; p=0·76; unadjusted 15·9 vs 14·7 µm) and -4·03 (-13·6 to 5·01; p=0·38) on the letter score for low contrast visual acuity (unadjusted 49·06 vs 49·60). One patient in the EPO group developed a sinus venous thrombosis which was treated with anticoagulants and resolved without sequelae. Interpretation: EPO conveyed neither functional nor structural neuroprotection in the visual pathways after optic neuritis. Trial Registration: This trial is registered with ClinicalTrials.gov (NCT01962571). Funding Statement: German Ministry of Health and Science (BMBF), Clinical trials programme. Declaration of Interests: WL reports grants from the German Federal Ministry for Education and Research (BMBF) and the German Research Foundation (DFG). He received speakers’ honoraria from and worked on advisory boards for Alcon, Allergan, Santhera, Boehringer Ingelheim, and Merz Pharma. SK has received a doctoral fellowship with funding from the University of Freiburg, Faculty of Medicine and the Else Kroner-Fresenius foundation. GI has received funding from Novartis and Janssen Pharmaceutica. BG and FB have nothing to report. MV has worked on an advisory board for Roche Pharma. SH has received funding from the DFG, the German Federal Institute for Sport Science and the German Ophthalmological Society. PA reports reports grants, personal fees, and non-financial support from Allergan, Biogen, Celgene, Ipsen, Merck, Merz Pharmaceuticals, Novartis, Roche, and Teva outside the submitted work. JU has received a doctoral fellowship with funding from the Ministry of Science, Research and Arts Baden-Wuerttemberg as part of the HAW-Prom program. She received a speakers’ honorary from AMO Ireland (affiliated to Johnson & Johnson Vision) and is co-inventor of patents/patent applications with the numbers 10 2017 126 741, WO 2020/089284 A1 and 20 174 551.0. MW is a managing partner of Blickshift GmbH and coinventor of patent applications WO 2020/089284 A1 and 20 174 551.0. MH reports grants from Bristol-Myers Squibb and speaker’s honoraria from Amgen, Baxter Deutschland, CSL Behring, Biotest Pharma, Fresenius Kabi, Leo Pharma, Merck Serono, Novartis Pharma, Pfizer, Roche Pharma, and Sun Pharmaceuticals Industries. SW has served as a consultant for Bayer, Novartis, Chengdu Kanghong Biotech, Zeiss, and Roche and has received grant support from Zeiss and Heidelberg Engineering. RD was funded by the BMBF, the DFG, and the Hertie Foundation. Ethics Approval Statement: The study protocol was approved by the institutional review boards and ethics committees of each participating site under the conduct of the ethics committee of the University of Freiburg, Germany.

Analgesic Efficacy, Practicality and Safety of Inhaled Methoxyflurane Versus Standard Analgesic Treatment for Acute Trauma Pain in the Emergency Setting: A Randomised, Open-Label, Active-Controlled, Multicentre Trial in Italy (MEDITA).

IntroductionInhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The phase IIIb Methoxyflurane in Emergency Department in ITAly (MEDITA) trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain.MethodsThis was a randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥ 4 on numerical rating scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3 mL or SAT [intravenously administered (IV) morphine 0.1 mg/kg for severe pain (NRS ≥ 7); IV paracetamol 1 g or IV ketoprofen 100 mg for moderate pain (NRS 4–6)]. The primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10 min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the treatment comparison (methoxyflurane–SAT) was less than 1 and less than 0, respectively.ResultsBetween 8 February 2018 and 8 February 2019, 272 patients were randomised (136 per treatment group). A total of 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS 67 mm) were treated and analysed for efficacy and safety. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference − 5.94 mm; 95% CI − 8.83, − 3.06 mm), moderate pain (− 5.97 mm; 95% CI − 9.55, − 2.39 mm) and severe pain (− 5.54 mm; 95% CI − 10.49, − 0.59 mm). Median onset of pain relief was 9 min for methoxyflurane and 15 min for SAT. Practicality of methoxyflurane treatment was rated “Excellent”, “Very Good” or “Good” by 90% of clinicians vs. 64% for SAT. Adverse events (all non-serious) were reported by 17% of methoxyflurane-treated patients and 3% of SAT-treated patients.ConclusionMethoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option.Trial registrationTrial registered with EudraCT (2017-001565-25) on 2 March 2018 and ClinicalTrials.gov (NCT03585374) on 13 July 2018.FundingMundipharma Pharmaceuticals S.r.l.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01055-9) contains supplementary material, which is available to authorized users.

A multicenter randomized, double-blind, placebo-controlled pilot study to assess the efficacy and safety of riociguat in systemic sclerosis-associated digital ulcers

BackgroundTo determine the effect of riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc).MethodsParticipants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs).ResultsSeventeen participants (eight placebo, nine riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference − 0.24, 95% CI (− 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the riociguat-riociguat arm had complete healing of their DUs.ConclusionIn participants with SSc-DU, treatment with riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial.Trial registrationClinicalTrials.gov, NCT02915835. Registered on September 27, 2016.

Analgesic Efficacy, Practicality and Safety of Inhaled Methoxyflurane Versus Standard Analgesic Treatment for Acute Trauma Pain in the Emergency Setting: A Randomised, Open-Label, Active-Controlled, Multicentre Trial in Italy (MEDITA)

Background: Inhaled low-dose methoxyflurane is approved in Europe for emergency relief of moderate-to-severe trauma-related pain in adults, but data versus active comparators are sparse. The Phase IIIb MEDITA trial investigated the analgesic efficacy, practicality and safety of methoxyflurane versus standard analgesic treatment (SAT) for acute trauma pain. Methods: Randomised, active-controlled, parallel-group, open-label trial conducted in 15 Italian emergency units. Adults with limb trauma and pain score ≥4 on Numerical Rating Scale (NRS) were randomised 1:1 to inhaled methoxyflurane 3mL or SAT (intravenous [IV] morphine 0.1mg/kg for severe pain [NRS ≥7]; IV paracetamol 1g or IV ketoprofen 100mg for moderate pain [NRS 4-6]). Primary endpoint was overall change in visual analogue scale (VAS) pain intensity from baseline (time of randomisation) to 3, 5 and 10min. Non-inferiority and superiority of methoxyflurane versus SAT were concluded if the upper 95% confidence interval (CI) for the comparison was <1 and <0, respectively. Findings: Between February 8, 2018, and February 8, 2019, 272 patients were randomised (136 per group). 270 patients (mean age 51 years; 49% male; 34% with severe pain; mean baseline VAS: 67mm) were treated and analysed. Superiority of methoxyflurane was demonstrated for moderate-to-severe pain (adjusted mean treatment difference: -5·94mm; 95% CI: -8·83, -3·06mm), moderate pain ( 5·97mm; 95% CI: 9·55, -2·39mm) and severe pain (-5·54mm; 95% CI: -10·49, -0·59mm). Median onset of pain relief was 9min for methoxyflurane and 15min for SAT. Practicality of methoxyflurane treatment was rated Excellent, Very or Good by 90% of clinicians vs. 64% for SAT. 17% of methoxyflurane-treated patients and 3% of SAT-treated patients reported adverse events (all non-serious). Interpretation: Methoxyflurane provided superior pain relief to SAT in patients with moderate-to-severe trauma pain and may offer a simple, fast, effective non-opioid treatment option. Trial Registration: This trial is registered with EudraCT (2017- 001565-25) and ClinicalTrials.gov (NCT03585374). Funding Statement: The study was funded by Mundipharma Pharmaceuticals srl. Costs for article processing and Open Access were funded by Mundipharma Pharmaceuticals srl. Declaration of Interests: Sebastiano Mercadante, Antonio Voza, Sossio Serra, Germana Ruggiano, Giseppe Carpinteri, Gianfilippo Gangitano, Fabio Intelligente and Andrea Fabbri have nothing to disclose. Elisabetta Bonafede is an employee of the clinical research organisation that conducted the study. Antonella Sblendido, Amedeo Soldi and Alberto Farina are employees of Mundipharma Pharmaceuticals srl. Ethics Approval Statement: The study was approved by the Italian Medicines Agency (AIFA). The trial was conducted in accordance with the principles established in the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice. All trial documents and procedures were approved by the appropriate ethics committees at each site, and written informed consent (or verbal witnessed consent) was obtained from all patients before initiation into the study.

Effects of baseline symptom burden on treatment response in COPD

RationaleIn symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear.ObjectiveTo investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment.Materials and methodsPost hoc analysis of the randomized OTEMTO® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George’s Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response.ResultsTiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0–1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference −3.44 [95% CI: −5.43, −1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0–1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P<0.0001 and 1.60 [95% CI: 1.09, 2.10]; P<0.0001, respectively). In patients with mMRC scores 0–1 and ≥2, tiotropium/olodaterol consistently improved TDI response rate and lung function vs placebo and tiotropium.ConclusionsPatients with COPD with more severe baseline dyspnea appear to derive greater health status benefit with tiotropium/olodaterol compared with tiotropium alone.

Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder

To assess the efficacy and safety of novel pediatric-appropriate, prolonged-release melatonin minitablets (PedPRM) versus placebo for insomnia in children and adolescents with autism spectrum disorder (ASD), with or without attention-deficit/hyperactivity disorder (ADHD) comorbidity, and neurogenetic disorders (NGD). A total of 125 children and adolescents (2-17.5 years of age; 96.8% ASD, 3.2% Smith-Magenis syndrome [SMS]) whose sleep failed to improve on behavioral intervention alone were randomized (1:1 ratio), double-blind, to receive PedPRM (2 mg escalated to 5 mg) or placebo for 13 weeks. Sleep measures included the validated caregivers' Sleep and Nap Diary (SND) and Composite Sleep Disturbance Index (CSDI). The a priori primary endpoint was SND-reported total sleep time (TST) after 13 weeks of treatment. The study met the primary endpoint: after 13 weeks of double-blind treatment, participants slept on average 57.5 minutes longer at night with PedPRM compared to 9.14 minutes with placebo (adjusted meantreatment difference PedPRM-placebo-32.43 minutes; p= .034). Sleep latency (SL) decreased by 39.6 minutes onaverage with PedPRM and 12.5 minutes with placebo (adjusted mean treatment difference-25.30 minutes; p= .011) without causing earlier wakeup time. The rate of participants attaining clinically meaningful responses in TST and/or SL was significantly higher with PedPRM than with placebo (68.9% versus 39.3% respectively; p= .001) corresponding to a number needed to treat (NNT) of 3.38. Overall sleep disturbance (CSDI) tended to decrease. PedPRM was generally safe; somnolence was more commonly reported with PedPRM than placebo. PedPRM was efficacious and safe for treatment of insomnia in children and adolescents with ASD with/without ADHD and NGD. The acceptability of this pediatric formulation in a population who usually experience significant difficulties in swallowing was remarkably high. Clinical trial registration information-Efficacy and Safety of Circadin in the Treatment of Sleep Disturbances in Children With Neurodevelopment Disabilities; http://clinicaltrials.gov/; NCT01906866.

A randomised, phase III trial of once-daily fluticasone furoate/vilanterol 100/25 μg versus once-daily vilanterol 25 μg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD

BackgroundThe contribution of fluticasone furoate (FF) on lung function in the FF/vilanterol (VI) 100/25 μg combination has been demonstrated numerically, but not statistically. MethodsThis multicentre, randomised, double-blind, controlled trial (GlaxoSmithKline study number 200820; clinicaltrials.gov NCT02105974) enrolled ≥40-year-old patients with chronic obstructive pulmonary disease (COPD), a ≥10-pack-year smoking history, a post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% of the predicted value, a FEV1/forced vital capacity ratio of ≤0.70, ≥1 COPD exacerbation in the previous 12 months requiring corticosteroids, antibiotics and/or hospitalisation, and current COPD symptoms. Participants received FF/VI 100/25 μg or VI 25 μg once daily. The primary endpoint was the change from baseline in trough FEV1 at day 84. Findings1620 patients were randomised and received at least one dose of FF/VI 100/25 μg (n = 806) or VI 25 μg (n = 814). At day 84, the FF/VI 100/25 μg group showed an adjusted mean treatment difference of 34 mL over VI 25 μg in change from baseline trough FEV1 (95% confidence interval [CI] 14–55; p = 0.001). There was no significant difference between the groups in the percentage of rescue medication-free 24-h periods. The FF/VI 100/25 μg group demonstrated a 42% risk reduction compared with the VI 25 μg group in time to first moderate/severe COPD exacerbation (95% CI 22–57; nominal p < 0.001). The incidence of on-treatment adverse events was similar between the groups. InterpretationThe contribution of FF in the FF/VI 100/25 μg combination on lung function in COPD was statistically significant. FundingGlaxoSmithKline.

The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial.

To compare the efficacy and safety of mirabegron 50 mg and solifenacin 5 mg in overactive bladder (OAB) patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy. This randomized, double-blind, phase IIIb, noninferiority study, enrolled male and female patients aged ⩾18 years old, with symptoms of OAB for ⩾3 months, who were dissatisfied with their previous antimuscarinic drug due to lack of efficacy. A total of 1887 patients were randomized to receive mirabegron 50 mg (n = 943) or solifenacin 5 mg (n = 944) daily for 12 weeks. The primary efficacy endpoint was change from baseline to end of treatment in mean number of micturitions/24 h. Noninferiority was confirmed if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference between solifenacin and mirabegron was > -0.20. Secondary efficacy endpoints, which included change from baseline in mean number of incontinence episodes/24 h, urgency incontinence episodes/24 h, urgency episodes (grade 3 or 4)/24 h and nocturia episodes/24 h, were analyzed using analysis of covariance. For the primary endpoint, adjusted mean treatment difference (95% CI) in mean number of micturitions/24 h was -0.18 (-0.42, 0.06) and therefore noninferiority of mirabegron to solifenacin was not demonstrated. Both treatments demonstrated clinically meaningful reductions in efficacy variables and were well tolerated, with a lower incidence of dry mouth with mirabegron. Noninferiority of mirabegron compared with solifenacin for reduction in micturition frequency could not be demonstrated in this population of OAB patients who were dissatisfied with previous antimuscarinic therapy due to lack of efficacy. Both mirabegron and solifenacin improved key OAB symptoms with no statistically significant differences observed between the two treatments. Both drugs were well tolerated.

Attainment and characteristics of clinical remission according to the new ACR-EULAR criteria in abatacept-treated patients with early rheumatoid arthritis: new analyses from the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE).

IntroductionThis study evaluated various remission criteria in abatacept plus methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA). We aimed to investigate the time to, and sustainability of, remission, and to evaluate the relationship between remission, function and structure.MethodsPost hoc analyses were performed from the 12-month, double-blind period of the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE) in patients with early RA (≤2 years) and poor prognostic factors, comparing abatacept plus MTX (n = 210) versus MTX alone (n = 209).ResultsAt month 12, Disease Activity Score 28, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index and Boolean remission rates were, for abatacept plus MTX versus MTX alone: 47.6 % versus 27.3 %, 33.3 % versus 12.4 %, 34.3 % versus 16.3 %, and 23.8 % versus 5.7 %, respectively. Cumulative probability demonstrated higher proportions achieving first remission and first sustained remission for abatacept plus MTX versus MTX alone (e.g., 23.3 % [95 % confidence interval (CI): 17.6, 29.1] vs 12.9 % [8.4, 17.5] for first SDAI remission over 0–6 months). For patients in SDAI remission at month 3, mean Health Assessment Questionnaire-Disability Index at month 12 was 0.20 versus 0.50 for abatacept plus MTX versus MTX alone. Mean changes in radiographic score from baseline to month 12 were minimal for patients in SDAI remission at month 3 in both groups, while less structural damage progression was seen, 0.75 versus 1.35, respectively, for abatacept plus MTX versus MTX alone for patients with moderate/high disease activity at month 3 (adjusted mean treatment difference: −0.60 [95 % CI: −1.11, −0.09; P < 0.05]).ConclusionsHigh proportions of abatacept plus MTX-treated patients achieved stringent remission criteria. Remission was associated with long-term functional benefit; dissociation was seen between clinical and structural outcomes for abatacept. These findings highlight the impact of reaching stringent remission targets early, on physical function and structural damage, in MTX-naïve biologic-treated patients.Trial registrationClinicalTrials.gov identifier NCT00122382. Registered 19 July 2005.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0671-9) contains supplementary material, which is available to authorized users.

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid (p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast (p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS.

A randomized, placebo-controlled trial of the analgesic efficacy and safety of the p38 MAP kinase inhibitor, losmapimod, in patients with neuropathic pain from lumbosacral radiculopathy.

Preclinical studies have demonstrated involvement of p38 mitogen-activated protein kinase signaling pathways in the development of persistent pain after peripheral nerve injury. A double-blind, randomized, placebo-controlled study was undertaken to evaluate the analgesic efficacy of losmapimod (GW856553), a novel p38α/β inhibitor, in patients with chronic neuropathic pain due to lumbosacral radiculopathy. A total of 144 patients with at least moderate baseline pain intensity (average daily score of ≥4 on an 11-point pain intensity numeric rating scale) were randomized to receive losmapimod, 7.5 mg bid orally or placebo. All patients underwent a blinded placebo run-in period for 7 days before receiving losmapimod/placebo for 28 days. Efficacy and safety evaluations were undertaken weekly. The adjusted mean treatment difference for the change from baseline to week 4 in numeric rating scale was -0.36 U (95% confidence interval, -0.84, 0.13; P=0.149) in favor of losmapimod over placebo; this was not considered clinically meaningful. Statistically significant differences in favor of losmapimod were observed, however, for several secondary endpoints of emotional, physical, and social functioning: Oswestry Disability Index; Profile of Mood States total score; Short-Form 36 Health Survey physical functioning, bodily pain, general health, role emotional, social functioning, and vitality domains; and Short-Form 36 physical, and mental components. There were no unexpected findings related to safety or tolerability following treatment with losmapimod. Losmapimod could not be differentiated from placebo in terms of analgesia. The lack of response could reflect insufficient losmapimod levels in the spinal cord or differences between lumbosacral radiculopathy and animal models of neuropathic pain.

Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: A randomized trial

This study investigated the efficacy and safety of the inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination fluticasone furoate (FF)/vilanterol (VI) in Asian asthma patients. A 12-week, double-blind, double-dummy, active-comparator, parallel-group, multicenter study. 309 Asian asthma patients (≥12 years, uncontrolled with high-strength ICS or mid-dose ICS/LABA) were randomized (1:1) and included in the intent-to-treat population; 155 received once-daily FF/VI 200/25 mcg and 154 received twice-daily fluticasone propionate (FP) 500 mcg. The primary endpoint was change from baseline in daily evening peak expiratory flow (PEF) averaged over 12 weeks. Secondary endpoints were mean change from baseline in % rescue-free 24-h periods, daily morning PEF, % symptom-free 24-h periods, and overall Asthma Quality of Life Questionnaire score. Safety assessments were performed. For change from baseline in daily evening PEF, the adjusted mean treatment difference for FF/VI versus FP of 28.5 L/min (95% confidence interval [CI]: 20.1, 36.9) was clinically and statistically significant (p < 0.001). For change from baseline in % rescue-free 24-h periods, the adjusted mean treatment difference (1.0%; 95% CI: -7.3, 9.2) was not statistically significant (p = 0.821). Statistical significance could not be inferred for the remaining endpoints due to the statistical hierarchy employed. Incidence of on-treatment adverse events was similar with FF/VI (26%; 3% treatment-related; n = 1 serious) and FP (27%; 3% treatment-related; n = 2 serious); none were fatal. No further safety concerns were identified. FF/VI improved evening PEF over 12 weeks versus FP in Asian patients, with a similar safety profile. The results are generally consistent with a global study comparing the same treatments.

Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial

Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD. We did a phase 3, randomised, double-blind, parallel-group, placebo-controlled trial at 127 centres in 15 countries. Patients with HbA1c of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate [eGFR] ≥60 to <90 mL/min per 1·73 m(2); n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR ≥30 to <60 mL/min per 1·73 m(2); n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA1c, and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA1c at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501. In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA1c at week 24 were -0·52% (95% CI -0·72 to -0·32) for empagliflozin 10 mg and -0·68% (-0·88 to -0·49) for empagliflozin 25 mg (both p<0·0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA1c at week 24 was -0·42% (-0·56 to -0·28) for empagliflozin 25 mg (p<0·0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe [16%] and 11 serious [12%]), 86 (88%) on empagliflozin 10 mg (six severe [6%] and six serious [6%]) and 78 (80%) on empagliflozin 25 mg (eight severe [8%] and seven serious [7%]). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe [8%] and 23 serious [12%]) and 156 (83%) on empagliflozin 25 mg (18 severe [10%] and 22 serious [12%]). In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA1c and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment. Boehringer Ingelheim, Eli Lilly.