Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.

There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes. STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete. Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m2 (6·9), waist circumference 120·1 cm (14·7), HbA1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported. Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia. Novo Nordisk. For the Spanish translation of the abstract see Supplementary Materials section.

McGowan BM ，Bruun JM ，Capehorn M ，Pedersen SD ，Pietiläinen KH ，Muniraju HAK ，Quiroga M ，Varbo A ，Lau DCW ，STEP 10 Study Group ... -  《-》

Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.

COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA1c 53.0-85.8 mmol/mol [7.0-10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; <3.0 mmol/l) or severe (level 3; associated with severe cognitive impairment requiring external assistance for recovery) hypoglycaemia (baseline to week 57). Overall, 683 participants were randomised using a Randomisation and Trial Supply Management system to IcoSema (n=342) or semaglutide 1.0 mg (n=341). Mean ± SD baseline characteristics were as follows: HbA1c 64.0±8.2 mmol/mol (8.0±0.7%); diabetes duration 12.6±6.9 years; and BMI 31.1±4.7 kg/m2. From baseline to week 52, mean change in HbA1c was -14.7 mmol/mol (-1.35%-points) in the IcoSema group and -9.88 mmol/mol (-0.90%-points) in the semaglutide group; the estimated treatment difference (ETD) was -4.85 (95% CI -6.13, -3.57) mmol/mol (-0.44 [95% CI -0.56, -0.33]%-points), confirming superiority of IcoSema to semaglutide (p<0.0001). The estimated mean change in fasting plasma glucose from baseline to week 52 was statistically significantly reduced with IcoSema vs semaglutide (-2.48 mmol/l vs -1.43 mmol/l, respectively; ETD -1.05 [95% CI -1.36, -0.75] mmol; p<0.0001). Mean change in body weight from baseline to week 52 was statistically significantly different between groups: +0.84 kg for IcoSema vs -3.70 kg for semaglutide (ETD 4.54 kg [95% CI 3.84, 5.23]; p<0.0001). There was no statistically significant difference in the rate of combined clinically significant or severe hypoglycaemia between IcoSema and semaglutide (0.042 vs 0.036 episodes per person-year of exposure; estimated rate ratio 1.20 [95% CI 0.53, 2.69]; p=0.66). The proportion of participants experiencing gastrointestinal adverse events was similar between treatment groups (IcoSema 31.4%; semaglutide 34.4%). In people living with type 2 diabetes inadequately managed with GLP-1 RA therapy, with or without additional oral glucose-lowering medications, switching to once-weekly IcoSema in comparison with once-weekly semaglutide 1.0 mg demonstrated superiority in HbA1c reduction, similar rates of clinically significant or severe hypoglycaemia, and similar frequency of gastrointestinal adverse events. However, weight change from baseline to week 52 was statistically significantly in favour of semaglutide 1.0 mg. ClinicalTrials.gov NCT05259033 FUNDING: This trial was funded by Novo Nordisk.

Lingvay I ，Benamar M ，Chen L ，Fu A ，Jódar E ，Nishida T ，Riveline JP ，Yabe D ，Zueger T ，Réa R ... -  《-》

Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn's disease (DIVERSITY): a phase 3, double-blind, randomised, placebo-controlled trial.

There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease. This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561. Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies. Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported. Galapagos.

Vermeire S ，Schreiber S ，Rubin DT ，D'Haens G ，Reinisch W ，Watanabe M ，Mehta R ，Roblin X ，Beales I ，Gietka P ，Hibi T ，Hospodarskyy I ，Ritter T ，Genovese MC ，Kwon P ，Santermans E ，Le Brun FO ，Barron R ，Masior T ，Danese S ... -  《The Lancet Gastroenterology &amp; Hepatology》

Weekly dihydroartemisinin-piperaquine versus monthly sulfadoxine-pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial.

In many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine-pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin-piperaquine and monthly sulfadoxine-pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine-pyrimethamine resistance of P falciparum in Uganda and Malawi. We did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin-piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine-pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099. Between April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin-piperaquine group and 357 participants in the sulfadoxine-pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2-18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin-piperaquine group and 43.7 events per 100 person-years in the sulfadoxine-pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14-0·30], p<0·0001). The incidence of hospitalisation with any malaria was lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (10·4 vs 37·0 events per 100 person-years; IRR 0·29 [0·20-0·42], p<0·0001) and the number of blood transfusions was also lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (52·1 vs 72·5 events per 100 person-years; IRR 0·70 [0·54-0·90], p=0·006). The incidence of all-cause unscheduled clinic visits and all-cause hospitalisations were similar between the two groups, however, participants in the dihydroartemisinin-piperaquine group had more clinic visits unrelated to malaria (IRR 1·12 [1·00-1·24], p=0·042) and more hospitalisations with lower respiratory tract events (16·5 vs 8·5 events per 100 person-years; IRR 1·99 [1·25-3·16], p=0·0036) than participants in the sulfadoxine-pyrimethamine group. The number of serious adverse events in the dihydroartemisinin-piperaquine group was similar to that in the sulfadoxine-pyrimethamine group (vaso-occlusive crisis [154 of 367 participants dihydroartemisinin-piperaquine group vs 132 of 357 participants in the sulfadoxine-pyrimethamine group] and suspected sepsis [115 participants vs 92 participants]), with the exception of acute chest syndrome or pneumonia (51 participants vs 32 participants). The number of deaths were similar between groups (six [2%] of 367 participants in the dihydroartemisinin-piperaquine group and eight (2%) of 357 participants in the sulfadoxine-pyrimethamine group). Malaria chemoprophylaxis with weekly dihydroartemisinin-piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine-pyrimethamine. However, monthly sulfadoxine-pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin-piperaquine should be considered as an alternative to sulfadoxine-pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years. Research Council of Norway and UK Medical Research Council. For the Chichewa, Acholi, Lusoga and Luganda translations of the abstract see Supplementary Materials section.

Idro R ，Nkosi-Gondwe T ，Opoka R ，Ssenkusu JM ，Dennis K ，Tsirizani L ，Akun P ，Rujumba J ，Nambatya W ，Kamya C ，Phiri N ，Joanita K ，Komata R ，Innussa M ，Tenywa E ，John CC ，Tarning J ，Denti P ，Wasmann RE ，Ter Kuile FO ，Robberstad B ，Phiri KS ... -  《-》

Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial.

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18-80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6-24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI -0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (-0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI -0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and -0·03 (-0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. Framework of the E-Rare Joint Transnational Call 2016 "Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases".

Koch JC ，Leha A ，Bidner H ，Cordts I ，Dorst J ，Günther R ，Zeller D ，Braun N ，Metelmann M ，Corcia P ，De La Cruz E ，Weydt P ，Meyer T ，Großkreutz J ，Soriani MH ，Attarian S ，Weishaupt JH ，Weyen U ，Kuttler J ，Zurek G ，Rogers ML ，Feneberg E ，Deschauer M ，Neuwirth C ，Wuu J ，Ludolph AC ，Schmidt J ，Remane Y ，Camu W ，Friede T ，Benatar M ，Weber M ，Lingor P ，ROCK-ALS Study group ... -  《-》