Long-term efficacy and safety of enavogliflozin in Korean people with type 2 diabetes: A 52-week extension of a Phase 3 randomized controlled trial.

AIMS: To evaluate the long-term safety and efficacy of enavogliflozin monotherapy (0.3 mg/day) in individuals with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Following a 24-week randomized, double-blind treatment period with enavogliflozin 0.3 mg/day (n = 77) or placebo (n = 69), consenting participants received enavogliflozin 0.3 mg/day for an additional 28 weeks during an open-label extension (OLE) period. The safety and efficacy of enavogliflozin were assessed at Week 52. RESULTS: A total of 37 participants continued enavogliflozin (maintenance group), and 26 participants switched from placebo to enavogliflozin (switch group). No additional adverse drug reactions related to enavogliflozin were observed during the OLE period. At Week 52, glycated haemoglobin (HbA1c) and fasting plasma glucose were significantly lower than at the baseline, by 0.9% and 24.9 mg/dL, respectively, in the maintenance group (p < 0.0001 for both), and by 0.7% and 18.0 mg/dL, respectively, in the switch group (p < 0.0001 and p = 0.002). The proportions of participants reaching HbA1c 7.0% (53 mmol/mol) at Week 52 were 69.4% in the maintenance group and 65.4% in the switch group. A significant increase in urine glucose-to-creatinine ratio was observed at Week 52, by 84.9 g/g and 67.1 g/g in the maintenance and switch groups, respectively (p < 0.0001 for both). Body weight in both groups decreased significantly (p < 0.0001) from baseline to Week 52, by 3.5 kg and 3.8 kg in the maintenance and switch groups, respectively. CONCLUSIONS: Enavogliflozin 0.3 mg monotherapy provides long-term glycaemic control in T2DM and is safe and well tolerated during a 52-week treatment period.

A randomized, double-blind trial assessing the efficacy and safety of two doses of dulaglutide in Japanese participants with type 2 diabetes (AWARD-JPN).

AIM: To assess the efficacy and safety of dulaglutide 1.5 mg versus dulaglutide 0.75 mg in Japanese participants with type 2 diabetes (T2D). MATERIALS AND METHODS: A Phase 3, multicentre, randomized, double-blind, parallel-group study was conducted in Japanese participants aged ≥20 years, with T2D for ≥6 months and inadequate glycaemic control, while on a single oral antihyperglycaemic medication (NCT04809220). The primary objective was to evaluate superiority of dulaglutide 1.5 mg versus dulaglutide 0.75 mg measured by mean change in glycated haemoglobin (HbA1c) from baseline to 26 weeks. Other efficacy and safety endpoints were evaluated at 26 and 52 weeks. All statistical analyses were conducted using the intention-to-treat population. RESULTS: Overall, 591 participants were randomized to once-weekly dulaglutide 1.5 mg or 0.75 mg. At Week 26, dulaglutide 1.5 mg was superior to dulaglutide 0.75 mg in HbA1c reduction from baseline (least squares mean [LSM] difference -0.29% [95% confidence interval {CI} -0.43, -0.14]). At Week 52, the dulaglutide 1.5-mg arm had a significantly greater proportion of participants who achieved HbA1c <7.0% (46.3% vs. 38.5%; p = 0.03) and showed significantly greater reduction in fasting serum glucose (LSM difference -9.4 mg/dL [95% CI -14.4, -4.3]; p < 0.001) versus the dulaglutide 0.75-mg arm. No statistically significant change in body weight was observed in either treatment arm. Overall, 442 participants (75.4%) experienced treatment emergent adverse events (TEAEs). Constipation (11.3%), diarrhoea (9.6%) and pyrexia (9.0%) were the most commonly reported TEAEs. CONCLUSIONS: Dulaglutide 1.5 mg once weekly demonstrated superior glycaemic control versus dulaglutide 0.75 mg once weekly, with comparable safety and tolerability, in Japanese people with T2D.

Ultra-rapid lispro improved postprandial glucose control compared to insulin lispro in predominantly Chinese patients with type 1 diabetes: A prospective, randomized, double-blind phase 3 study.

AIMS: To investigate the efficacy and safety of ultra-rapid lispro (URLi) versus insulin lispro in predominantly Chinese patients with type 1 diabetes (T1D) in a prospective, randomized, double-blind, treat-to-target, phase 3 study. MATERIALS AND METHODS: Following a lead-in period, during which insulin glargine U-100 or insulin degludec U-100 was optimized, patients were randomly assigned (1:1) to URLi (n = 176) or insulin lispro (n = 178). The primary objective was to test the noninferiority of URLi to insulin lispro in glycaemic control (noninferiority margin = 0.4% for glycated haemoglobin [HbA1c] change from baseline to week 26), with testing for the superiority of URLi to insulin lispro with regard to 1- and 2-hour postprandial glucose (PPG) excursions during a mixed-meal tolerance test and HbA1c change at week 26 as the multiplicity-adjusted objectives. RESULTS: From baseline to week 26, HbA1c decreased by 0.21% and 0.28% with URLi and insulin lispro, respectively, with a least squares mean treatment difference of 0.07% (95% confidence interval -0.11 to 0.24; P = 0.467). URLi demonstrated smaller 1- and 2-hour PPG excursions at week 26 with least squares mean treatment differences of -1.0 mmol/L (-17.8 mg/dL) and -1.4 mmol/L (-25.5 mg/dL), respectively (p < 0.005 for both) versus insulin lispro. The safety profiles of URLi and insulin lispro were similar. CONCLUSIONS: In this study, URLi administered in a basal-bolus regimen demonstrated superiority to insulin lispro in controlling PPG excursions, with noninferiority of HbA1c control in predominantly Chinese patients with T1D.

The impact of obesity on cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes treated with finerenone: Post hoc analysis of the FIDELITY study.

AIM: To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity. MATERIALS AND METHODS: A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low-risk or high-very high-risk (H-/VH-risk). RESULTS: Of 12 986 patients analysed, 90.8% occupied the H-/VH-risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low-risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72-1.47); finerenone reduced the risk in the H-/VH-risk WC group (HR 0.85; 95% CI, 0.77-0.93). For the kidney outcome, the risk was similar in the low-risk WC group (HR 0.98; 95% CI, 0.66-1.46) and reduced within the H-/VH-risk WC group (HR 0.75; 95% CI, 0.65-0.87) with finerenone versus placebo. There was no significant heterogeneity between the low-risk and H-/VH-risk WC groups for cardiovascular and kidney composite outcomes (P interaction = .26 and .34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H-/VH-risk WC patients may be because of the small size of the low-risk group. Adverse events were consistent across WC groups. CONCLUSION: In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity.

Efficacy and safety of enavogliflozin versus dapagliflozin added to metformin plus gemigliptin treatment in patients with type 2 diabetes: A double-blind, randomized, comparator-active study: ENHANCE-D study.

AIMS: This study evaluated the efficacy and safety of enavogliflozin, a novel sodium-glucose cotransporter 2 inhibitor, versus dapagliflozin in Korean patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin and gemigliptin. METHODS: In this multicenter, double-blind, randomized study, patients with inadequate response to metformin (≥ 1000 mg/day) plus gemigliptin (50 mg/day) were randomized to receive enavogliflozin 0.3 mg/day (n = 134) or dapagliflozin 10 mg/day (n = 136) in addition to the metformin plus gemigliptin therapy. The primary endpoint was change in HbA1c from baseline to week 24. RESULTS: Both treatments significantly reduced HbA1c at week 24 (-0.92% in enavogliflozin group, -0.86% in dapagliflozin group). The enavogliflozin and dapagliflozin groups did not differ in terms of changes in HbA1c (between-group difference: -0.06%, 95% confidence interval [CI]: -0.19, 0.06) and fasting plasma glucose (between-group difference: -3.49 mg/dl [-8.08;1.10]). An increase in urine glucose-creatinine ratio was significantly greater in the enavogliflozin group than in the dapagliflozin group (60.2 g/g versus 43.5 g/g, P < 0.0001). The incidence of treatment-emergent adverse events was similar between the groups (21.64% versus 23.53%). CONCLUSIONS: Enavogliflozin, added to metformin plus gemigliptin, was well tolerated and as effective as dapagliflozin in the treatment of patients with T2DM.

Adjuvant melatonin for uveal melanoma (AMUM): protocol for a randomized open-label phase III study.

BACKGROUND: Uveal melanoma is the most common primary intraocular tumor in adults. In Sweden, at least 100 patients are diagnosed with the disease each year. Almost half of the patients develop metastases, with a median survival time of 1 year once metastases are detected. The primary ocular tumor is typically treated with either enucleation or brachytherapy, and no adjuvant treatment is added. Melatonin is an indolamine hormone that has improved survival in previous trials with patients diagnosed with various cancers, including advanced cutaneous melanoma. Side effects have been mild. We aim to investigate if adjuvant treatment with melatonin for 5 years following diagnosis of non-metastasized uveal melanoma can decrease the occurrence of metastases. METHODS: An open-label, prospective, 5-year randomized clinical trial (RCT) will be conducted at St. Erik Eye Hospital. One hundred patients recently diagnosed with non-metastatic uveal melanoma will be randomized to either treatment with adjuvant melatonin 20 mg (4 tablets of 5 mg) at 10 pm for 5 years, or to standard follow-up (control group). The primary outcome measurement is the relative risk for having developed metastases 5 years after randomization. The secondary outcomes are overall survival, risk of developing other cancers, overall survival after detection of metastases, and differences in the occurrence of adverse events (AE) and serious adverse events (SAE) between the groups. DISCUSSION: Melatonin has been found to positively impact our immune system, inhibit angiogenesis, stimulate apoptosis in malignant cells, and act as a potent antioxidant. Previous clinical trials have used similar doses of melatonin with positive results, particularly in advanced stages of cancer. Previous animal and human studies have found the toxicity of the hormone to be low. Considering the potential benefits and limited risks of melatonin, as well as its global availability, it may be a suitable candidate for an adjuvant treatment in patients with uveal melanoma. TRIAL REGISTRATION: Our trial protocol has been approved and registered by the Swedish Medical Products Agency on June 22, 2022 (EudraCT 2022-500,307-49-00). Our trial registration number is NCT05502900, and the date of registration is August 16, 2022.

Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes.

AIM: Glucagon-like peptide-1 receptor agonists improve glycaemic control: some are now available as oral and subcutaneous formulations, and some have indications for reducing cardiovascular risk. The expanded scope for these therapies warrants comprehensive safety evaluations. We report the safety/tolerability of subcutaneous and oral semaglutide from the SUSTAIN and PIONEER clinical trial programmes, respectively. MATERIALS AND METHODS: Adverse events (AEs) from 16 randomized placebo- or active-controlled phase IIIa trials in patients with type 2 diabetes (n = 11 159) including once-weekly subcutaneous semaglutide (n = 3150; SUSTAIN trials) or once-daily oral semaglutide (n = 4116; PIONEER trials) were analysed. Data pools were analysed for each programme, with separate analyses of cardiovascular outcomes trials (CVOTs; n = 6480). RESULTS: In the phase IIIa pools, gastrointestinal disorders were reported in 41.9%/39.1% of patients with subcutaneous/oral semaglutide, respectively (most prevalent during initiation/escalation) versus 22.0%/24.8% with comparators. Rates of kidney disorders, acute pancreatitis, malignant neoplasms, hypoglycaemia, diabetic retinopathy, heart failure and other cardiovascular events were similar for semaglutide versus comparators. Cholelithiasis incidence was higher with subcutaneous and oral semaglutide versus placebo. Diabetic retinopathy incidence was higher with subcutaneous semaglutide versus placebo in SUSTAIN 6. Small pulse rate increases occurred with both formulations; there was no increased rate of arrhythmias. Fatal AE incidence was similar between semaglutide and comparators. Versus placebo, CVOTs showed a reduced risk of major adverse cardiovascular events with subcutaneous semaglutide and non-inferiority criteria were met with oral semaglutide. CONCLUSIONS: The most common AEs with semaglutide were gastrointestinal disorders, which decreased with continued therapy. These comprehensive safety/tolerability data may better inform patient selection and guidance in care.

Rationale and design of the phase 3a development programme (ONWARDS 1-6 trials) investigating once-weekly insulin icodec in diabetes.

AIM: To describe the phase 3a ONWARDS clinical development programme investigating insulin icodec (icodec), a once-weekly basal insulin, including the design and rationale for each of the ONWARDS 1-6 trials. MATERIALS AND METHODS: Six randomized controlled trials have been initiated in adults with type 2 diabetes (T2D) (insulin-naive: ONWARDS 1, 3 and 5; previously insulin-treated: ONWARDS 2 and 4) and type 1 diabetes (T1D) (ONWARDS 6). Each trial will investigate icodec use in a unique clinical scenario, with consideration of long-term safety and varied comparator treatments (insulin glargine U100 or U300 or insulin degludec). ONWARDS 5 will incorporate real-world elements and a digital dose titration solution to guide icodec dosing. The primary objective for each of the trials is to compare the change in HbA1c from baseline to week 26 or week 52 between icodec and comparator arms. Secondary objectives include investigating other glycaemic control and safety parameters, such as fasting glucose, time in glycaemic range and hypoglycaemia. Patient-reported outcomes will assess treatment satisfaction. CONCLUSIONS: The ONWARDS 1-6 trials will evaluate the efficacy and safety of once-weekly icodec compared with currently available daily basal insulin analogues in T2D and T1D. These trials will generate comprehensive evidence of icodec use in diverse populations across the spectrum of diabetes progression and treatment experience.

Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study.

BACKGROUND: Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) have a poor prognosis. The phase III KESTREL study evaluated the efficacy of durvalumab [programmed death-ligand 1 (PD-L1) antibody] with or without tremelimumab [cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibody], versus the EXTREME regimen in patients with R/M HNSCC. PATIENTS AND METHODS: Patients with HNSCC who had not received prior systemic treatment for R/M disease were randomized (2 : 1 : 1) to receive durvalumab 1500 mg every 4 weeks (Q4W) plus tremelimumab 75 mg Q4W (up to four doses), durvalumab monotherapy 1500 mg Q4W, or the EXTREME regimen (platinum, 5-fluorouracil, and cetuximab) until disease progression. Durvalumab efficacy, with or without tremelimumab, versus the EXTREME regimen in patients with PD-L1-high tumors and in all randomized patients was assessed. Safety was also assessed. RESULTS: Durvalumab and durvalumab plus tremelimumab were not superior to EXTREME for overall survival (OS) in patients with PD-L1-high expression [median, 10.9 and 11.2 versus 10.9 months, respectively; hazard ratio (HR) = 0.96; 95% confidence interval (CI) 0.69-1.32; P = 0.787 and HR = 1.05; 95% CI 0.80-1.39, respectively]. Durvalumab and durvalumab plus tremelimumab prolonged duration of response versus EXTREME (49.3% and 48.1% versus 9.8% of patients remaining in response at 12 months), correlating with long-term OS for responding patients; however, median progression-free survival was longer with EXTREME (2.8 and 2.8 versus 5.4 months). Exploratory analyses suggested that subsequent immunotherapy use by 24.3% of patients in the EXTREME regimen arm contributed to the similar OS outcomes between arms. Grade 3/4 treatment-related adverse events (TRAEs) for durvalumab, durvalumab plus tremelimumab, and EXTREME were 8.9%, 19.1%, and 53.1%, respectively. CONCLUSIONS: In patients with PD-L1-high expression, OS was comparable between durvalumab and the EXTREME regimen. Durvalumab alone, and with tremelimumab, demonstrated durable responses and reduced TRAEs versus the EXTREME regimen in R/M HNSCC.

The efficacy and safety of GP40081 (insulin aspart biphasic 30) compared with NovoMix® 30 in Type 2 diabetes patients.

Aim: To evaluate the safety and efficacy of insulin Aspart-Mix biosimilar candidate GP40081 (GP-Asp30) compared with NovoMix® 30 (NN-Asp30). Materials & methods: In a randomized open-label, active-controlled, 26-week non-inferiority clinical trial 264 patients with Type 2 diabetes mellitus were randomized 1:1 to receive once-daily GP-Asp30 or NN-Asp30. The primary safety end point was the immune response rate. Efficacy outcomes were a mean change in HbA1c (primary), frequency of achieving a glycemic g fasting plasma glucose levels, 7-point glucose profiles, and insulin doses. Results: The immune response developed in 10/126 (8%) participants in the GP-Asp30 group and in 10/125 (8%) participants in the NN-Asp30 group (p = 1.000). The mean difference in HbA1c change between groups was 0.12 (95%CI [-0.14, 0.38]). Other secondary efficacy and safety outcomes weren't statistically different between the two groups. Conclusion: GP-Asp30 demonstrated similar safety and efficacy compared with NN-Asp30 and may be considered a biosimilar insulin.

Final overall survival data of sintilimab plus pemetrexed and platinum as First-Line treatment for locally advanced or metastatic nonsquamous NSCLC in the Phase 3 ORIENT-11 study.

OBJECTIVES: In ORIENT-11, first-line sintilimab + pemetrexed-platinum significantly improved PFS compared with placebo + pemetrexed-platinum in patients with advanced metastatic nonsquamous non-small-cell lung cancer (AMnsqNSCLC). The study met the primary endpoint of PFS as of 15November2019. Here we report final survival analysis from ORIENT-11 (NCT03607539) using a 15September2021 data cutoff. METHODS: Patients with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR or ALK genomic tumor aberrations were randomly assigned to sintilimab + pemetrexed-platinum (n = 266) or placebo + pemetrexed-platinum (n = 131). Patients were stratified by PD-L1 expression, platinum-chemotherapy, and gender. Treatment continued until PD, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo + pemetrexed-platinum arm could be sequenced to second-line sintilimab monotherapy, contingent upon PD. Response was assessed (RECISTv.1.1) by blinded independent radiographic review committee. Primary endpoint was PFS. OS was a secondary endpoint and defined from date of randomization to date of death due to any cause. Final OS analysis was defined as approximately 2 years after last patient randomized or when approximately 65 % of patients died, whichever first. RESULTS: At data cutoff of final OS analysis, median study follow-up was 30.8 months. Of 397 patients, 243 OS events were observed (sintilimab + pemetrexed-platinum:151[57 %];placebo + pemetrexed-platinum:92 [70 %]). Of the patients in placebo + pemetrexed-platinum arm, 47 % crossed over to sintilimab monotherapy per protocol. Median OS was 24.2 months in sintilimab + pemetrexed-platinum arm and 16.8 months in placebo + pemetrexed-platinum arm (HR:0.65[95 % CI:0.50,0.85]). Estimated 2-year OS rates were 50 %(sintilimab + pemetrexed-platinum) and 32 %(placebo + pemetrexed-platinum). After adjusting for the crossover effect, OS treatment effect was more pronounced with HR 0.52 (95 % CI:0.38,0.69). OS benefit across all prespecified subgroups was largely consistent with that observed in the ITT population. CONCLUSIONS: In the ORIENT-11 final OS analysis, sintilimab + pemetrexed-platinum demonstrated improved OS compared to placebo + pemetrexed-platinum when administered as first-line therapy in AMnsqNSCLC without EGFR or ALK genomic tumor aberrations.

Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.

AIM: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension. MATERIALS AND METHODS: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory. RESULTS: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables. CONCLUSIONS: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

Pembrolizumab for the treatment of advanced esophageal cancer.

The prognosis of patients with advanced esophageal cancer (EC) remains poor and there are limited effective therapeutic agents for EC. Pembrolizumab monotherapy exerts clinically meaningful benefits for advanced esophageal squamous cell carcinoma patients with a combined positive score of ≥10. Additionally, pembrolizumab plus doublet chemotherapy results in a significant survival benefit for patients with advanced EC as first-line treatment compared with chemotherapy alone. We provide an overview of immune checkpoint inhibitors and present important clinical data related to treatment for EC patients. In our opinion, pembrolizumab plus chemotherapy should be the standard first-line treatment for patients with advanced EC, regardless of histology and combined positive score. Biomarker studies to identify patient populations in which immune checkpoint inhibitors are expected to show efficacy are needed.

Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss.

AIM: We evaluated gastrointestinal (GI) adverse events (AEs) with once-weekly semaglutide 2.4 mg in adults with overweight or obesity and their contribution to weight loss (WL). MATERIALS AND METHODS: AE analyses pooled data from the Semaglutide Treatment Effect in People With Obesity (STEP) 1-3 trials for participants randomized to 68 weeks of semaglutide 2.4 mg (n = 2117) or placebo (n = 1262). WL was analysed by presence/absence of GI AEs. Mediation analysis estimated WL effects mediated by and unrelated to GI AEs. GI tolerability with semaglutide 2.4 mg maintenance and cessation after dose escalation was evaluated using STEP 4 data among 803 participants tolerating 20 weeks of semaglutide run-in. RESULTS: GI AEs were more common with semaglutide 2.4 mg than placebo, with most frequently nausea (43.9% vs. 16.1% of participants), diarrhoea (29.7% vs. 15.9%), vomiting (24.5% vs. 6.3%) and constipation (24.2% vs. 11.1%). Most GI AEs with semaglutide were non-serious (99.5% of AEs), mild-to-moderate (98.1%), transient and occurred most frequently during/shortly after dose escalation. Few semaglutide-treated participants (4.3%) permanently discontinued treatment for GI AEs. In STEP 1-3, mean WL with semaglutide 2.4 mg was similar in participants without (9.6%-17.1%) versus with GI AEs (11.4%-17.7%). Consistent with this observation, mediation analysis found that GI AEs contributed little to semaglutide-induced WL: of the additional 7.6%-14.4% WL with semaglutide versus placebo, <1 percentage point was mediated by GI AEs. In STEP 4, semaglutide 2.4 mg maintenance was well tolerated. CONCLUSIONS: GI AEs were more common with semaglutide 2.4 mg than placebo, but typically mild-to-moderate and transient. Semaglutide-induced WL was largely independent of GI AEs.

Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy.

AIM: To report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin. MATERIALS AND METHODS: This extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2 , and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy. RESULTS: Overall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET -4.89%, -0.41 L and -0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents. CONCLUSIONS: Overall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.

Glycaemic variability in patients with type 2 diabetes mellitus treated with dulaglutide, with and without concomitant insulin: Post hoc analyses of randomized clinical trials.

AIM: To investigate the association between treatment with dulaglutide and glycaemic variability (GV) in adult patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: Post hoc analyses of six randomized, phase 3 studies were conducted to investigate the association between treatment with dulaglutide 1.5 mg once weekly and GV in adult patients with T2D. Using data from seven- and eight-point self-monitored plasma glucose (SMPG) profiles over up to 28 weeks of treatment, GV in within- and between-day SMPG, and between-day fasting glucose from SMPG (FSMPG) was assessed according to standard deviation and coefficient of variation. RESULTS: Pooled data from five studies with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, revealed clinically meaningful reductions in within- and between-day SMPG, and between-day FSMPG variability from baseline in the dulaglutide group. Comparisons between treatment groups in two studies demonstrated that reductions from baseline in within-day and between-day SMPG, and between-day FSMPG variability were greater for treatment with dulaglutide compared with insulin glargine, as well as for treatment with dulaglutide when added to insulin glargine compared with insulin glargine alone. CONCLUSIONS: In patients with T2D, treatment with dulaglutide as monotherapy or added to oral glucose-lowering medication, without concomitant insulin treatment, was potentially associated with a reduction in GV. Treatment with dulaglutide was associated with a reduction in GV to a greater degree than insulin glargine. When added to insulin glargine, treatment with dulaglutide was associated with greater decreases in GV compared with insulin glargine alone. As reduced GV may be associated with better outcomes, these findings may have clinical relevance.

Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL).

OBJECTIVE: The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. METHODS: Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1-5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months), and prior chemotherapy lines (1-2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov, NCT02421588. RESULTS: 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1-3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7-3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. CONCLUSIONS: The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

Safety and Efficacy of Mirogabalin for Peripheral Neuropathic Pain: Pooled Analysis of Two Pivotal Phase III Studies.

PURPOSE: Mirogabalin besylate has been approved in several countries to treat peripheral neuropathic pain. This pooled analysis, using data from the two pivotal Phase III studies in Asian patients with diabetic peripheral neuropathic pain and post-herpetic neuralgia, aimed to provide clinicians with more detailed and precise information relating to mirogabalin's safety and efficacy. METHODS: Data were pooled from 2 multicenter, double-blind, placebo-controlled, parallel-group, 14-week treatment studies of mirogabalin conducted at ∼350 study sites (Japan, South Korea, Taiwan, Singapore, Malaysia, and Thailand). Eligible patients in both studies were randomized in a 2:1:1:1 ratio, stratified according to a baseline average daily pain score (ADPS) of <6 or ≥6, to placebo, mirogabalin 15-mg once daily (QD), mirogabalin 10-mg twice daily (BID), or mirogabalin 15-mg BID treatment groups. Safety was assessed based on treatment-emergent adverse events identified from the adverse events collected throughout both studies. The primary efficacy end point of both studies was the change from baseline in ADPS at week 14. FINDINGS: In total, 1587 patients (824 with diabetic peripheral neuropathic pain; 763 with post-herpetic neuralgia) who received at least 1 dose of study drug were analyzed (633 received placebo, 954 treated with mirogabalin). Treatment-emergent adverse events included somnolence (3.8%, 10.8%, 14.5%, and 19.1%) and dizziness (2.7%, 5.7%, 9.1%, and 13.1%) in patients receiving placebo, mirogabalin 15 mg QD, mirogabalin 10 mg BID, and mirogabalin 15 mg BID, respectively. In patients treated with mirogabalin 15 mg QD, 2 (0.6%) of 316 patients discontinued due to somnolence. In the mirogabalin 10-mg BID group, somnolence, edema, and peripheral edema each resulted in 3 (0.9%) of 318 patient discontinuations. In the mirogabalin 15-mg BID group, 6 (1.9%) of 320 patients discontinued due to dizziness and 3 (0.9%) due to somnolence. At week 14, mirogabalin 10 mg BID and 15 mg BID statistically significantly improved ADPS versus placebo, with least squares mean changes (95% CI) of -0.31 (-0.55, -0.08) and -0.63 (-0.86, -0.40). Post hoc analysis showed a statistically significant difference 2 days after administration in the mirogabalin 10-mg and 15-mg BID groups compared with placebo. Female sex, age ≥65 years, and baseline weight <60 kg may influence the safety of mirogabalin, particularly regarding the incidence of somnolence and dizziness, but had no notable impact on efficacy. ClinicalTrials.gov identifiers: NCT02318706 and NCT02318719. IMPLICATIONS: This pooled analysis showed that mirogabalin was efficacious and well-tolerated by Asian patients with peripheral neuropathic pain.