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Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Saxagliptin, a new oral antihyperglycemic drug in the DPP-4 inhibitor class, had no effect on the risk of cardiovascular events in patients with type 2 diabetes. Although the drug does not increase cardiovascular risk, it also does not provide cardiovascular benefit. Type 2 diabetes mellitus doubles the risk of major cardiovascular complications in patients with and in patients without established cardiovascular disease, 1 – 3 such that the majority of patients with diabetes die of cardiovascular diseases. 4 Although improved glycemic control has repeatedly been shown to reduce microvascular diabetic complications, 5 uncertainty remains regarding whether any particular glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can actually lower cardiovascular risk. With the possible exception of trials of metformin 6 and insulin, 7 most reported trials to date evaluating the effects on cardiovascular outcomes of specific glucose-lowering strategies or medications either have . . .

Artefenomel (OZ439) is a novel synthetic trioxolane with improved pharmacokinetic properties compared with other antimalarial drugs with the artemisinin pharmacophore. Artefenomel has been generally well tolerated in volunteers at doses up to 1600 mg and is being developed as a partner drug in an antimalarial combination treatment. We investigated the efficacy, tolerability, and pharmacokinetics of artefenomel at different doses in patients with Plasmodium falciparum or Plasmodium vivax malaria. This phase 2a exploratory, open-label trial was done at the Hospital for Tropical Diseases, Bangkok, and the Shoklo Malaria Research Unit in Thailand. Adult patients with acute, uncomplicated P falciparum or P vivax malaria received artefenomel in a single oral dose (200 mg, 400 mg, 800 mg, or 1200 mg). The first cohort received 800 mg. Testing of a new dose of artefenomel in a patient cohort was decided on after safety and efficacy assessment of the preceding cohort. The primary endpoint was the natural log parasite reduction per 24 h. Definitive oral treatment was given at 36 h. This trial is registered with ClinicalTrials.gov, number NCT01213966. Between Oct 24, 2010, and May 25, 2012, 82 patients were enrolled (20 in each of the 200 mg, 400 mg, and 800 mg cohorts, and 21 in the 1200 mg cohort). One patient withdrew consent (before the administration of artefenomel) but there were no further dropouts. The parasite reduction rates per 24 h ranged from 0·90 to 1·88 for P falciparum, and 2·09 to 2·53 for P vivax. All doses were equally effective in both P falciparum and P vivax malaria, with median parasite clearance half-lives of 4·1 h (range 1·3–6·7) to 5·6 h (2·0–8·5) for P falciparum and 2·3 h (1·2–3·9) to 3·2 h (0·9–15·0) for P vivax. Maximum plasma concentrations, dose-proportional to 800 mg, occurred at 4 h (median). The estimated elimination half-life was 46–62 h. No serious drug-related adverse effects were reported; other adverse effects were generally mild and reversible, with the highest number in the 1200 mg cohort (17 [81%] patients with at least one adverse event). The most frequently reported adverse effect was an asymptomatic increase in plasma creatine phosphokinase concentration (200 mg, n=5; 400 mg, n=3; 800 mg, n=1; 1200 mg, n=3). Artefenomel is a new synthetic antimalarial peroxide with a good safety profile that clears parasitaemia rapidly in both P falciparum and P vivax malaria. Its long half-life suggests a possible use in a single-dose treatment in combination with other drugs. Bill & Melinda Gates Foundation, Wellcome Trust, and UK Department for International Development.

OBJECTIVE: This 24-week trial assessed the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes with inadequate glycemic control with metformin alone. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study of saxagliptin (2.5, 5, or 10 mg once daily) or placebo plus a stable dose of metformin (1,500-2,500 mg) in 743 patients (A1C greater-than-or-equal7.0 and [less-than or equal to]10.0%). Efficacy analyses were performed using an ANCOVA model using last observation carried forward methodology on primary (A1C) and secondary (fasting plasma glucose [FPG] and postprandial glucose [PPG] area under the curve [AUC]) end points. RESULTS: Saxagliptin (2.5, 5, and 10 mg) plus metformin demonstrated statistically significant adjusted mean decreases from baseline to week 24 versus placebo in A1C (-0.59, -0.69, and -0.58 vs. +0.13%; all P < 0.0001), FPG (-14.31, -22.03, and -20.50 vs. +1.24 mg/dl; all P < 0.0001), and PPG AUC (-8,891, -9,586, and -8,137 vs. -3,291 mg · min/dl; all P < 0.0001). More than twice as many patients achieved A1C <7.0% with 2.5, 5, and 10 mg saxagliptin versus placebo (37, 44, and 44 vs. 17%; all P < 0.0001). β-Cell function and postprandial C-peptide, insulin, and glucagon AUCs improved in all saxagliptin treatment groups at week 24. Incidence of hypoglycemic adverse events and weight reductions were similar to those with placebo. CONCLUSIONS: Saxagliptin once daily added to metformin therapy was generally well tolerated and led to statistically significant improvements in glycemic indexes versus placebo added to metformin in patients with type 2 diabetes inadequately controlled with metformin alone.

Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes. A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients. HbA(1c), fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA(1c) and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA(1c). MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.

Abstract Context Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies. Objective We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA + SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs). Design 24-week substudy of a randomized, open-label, 2-arm, parallel-group, phase 3b study. Setting Multicenter study (112 centers in 11 countries). Patients 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea. Interventions DAPA + SAXA vs INS. Main outcome measures Changes in CGM profiles, HbA1c, and PROs. Results Changes from baseline in HbA1c with DAPA + SAXA were similar to those observed with INS, with mean difference [95% confidence interval] between decreases of −0.12% [−0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA + SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (−0.7 ± 0.1 vs −0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being. Conclusion DAPA + SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA + SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes.

Aims/hypothesis Type 2 diabetes is difficult to manage in patients with a long history of disease requiring insulin therapy. Moreover, addition of most currently available oral antidiabetic agents increases the risk of hypoglycaemia. Vildagliptin is a dipeptidyl peptidase-IV inhibitor, which improves glycaemic control by increasing pancreatic beta cell responsiveness to glucose and suppressing inappropriate glucagon secretion. This study assessed the efficacy and tolerability of vildagliptin added to insulin therapy in patients with type 2 diabetes. Materials and methods This was a multicentre, 24-week, double-blind, randomised, placebo-controlled, parallel-group study in patients with type 2 diabetes that was inadequately controlled (HbA₁c = 7.5-11%) by insulin. Patients received vildagliptin (n = 144; 50 mg twice daily) or placebo (n = 152) while continuing insulin therapy. Results Baseline HbA₁c averaged 8.4 ± 0.1% in both groups. The adjusted mean change from baseline to endpoint (AMΔ) in HbA₁c was -0.5 ± 0.1% and -0.2 ± 0.1% in patients receiving vildagliptin or placebo, respectively, with a significant between-treatment difference (p = 0.01). In patients aged >=65 years, the AMΔ HbA₁c was -0.7 ± 0.1% in the vildagliptin group vs -0.1 ± 0.1% in the placebo group (p < 0.001). The incidence of adverse events was similar in the vildagliptin (81.3%) and placebo (82.9%) groups. However, hypoglycaemic events were less common (p < 0.001) and less severe (p < 0.05) in patients receiving vildagliptin than in those receiving placebo. Conclusions/interpretation Vildagliptin decreases HbA₁c in patients whose type 2 diabetes is poorly controlled with high doses of insulin. Addition of vildagliptin to insulin therapy is also associated with reduced confirmed and severe hypoglycaemia. ClinicalTrials.gov ID no.: NCT 00099931.

Introduction Effects of Dapagliflozin (Dapa) and Dapagliflozin-Saxagliptin combination (Combo) was examined on peripheral blood derived CD34 + Hematopoetic Stem Cells (HSCs) as a cellular CVD biomarker. Both Dapa (a sodium-glucose co-transporter 2 or SGLT2, receptor inhibitor) and Saxagliptin (a Di-peptydl-peptidase-4 or DPP4 enzyme inhibitor) are commonly used type 2 diabetes mellitus or T2DM medications, however the benefit of using the combination has not been evaluated for cardio-renal risk assessment, in a real-life practice setting, compared to a placebo. Hypothesis We hypothesized that Dapa will improve the outcomes when compared to placebo and the Combo maybe even more beneficial. Methods This is a pilot study evaluating low dose Dapagliflozin 10 mg or low dose Dapa + low dose Saxagliptin combination. 15 subjects were enrolled in 16 weeks, double-blind, three-arm, randomized placebo matched trial, with 10mg Dapa  + Saxa placebo ( n  = 4), 10 mg Dapa + 5 mg Saxa ( n  = 5) Combo , And Dapa placebo + Saxa placebo ( n  = 6), Placebo groups. T2DM subjects (age 30–70 yrs) with HbA1c of 7–10%, were included. CD34 + HSC number, migration, mRNA expression along with biochemistry and urine exosomes were measured. Data were collected at week 0, 8, and 16. For statistics, a mixed model regression analysis was used. Results Significant HbA1c ( p  = 0.0357) reduction was noted in Combo group versus Dapa alone and Placebo. hsCRP levels ( P  = 0.0317) and IL-6, two important inflammatory molecules, were significantly reduced in both Dapa and Combo vs. Placebo. Leptin levels decreased significantly in both Dapa alone ( p  = 0.035) and Combo group( p  = 0.015), vs. Placebo, however the Adiponectin levels were higher in Dapa alone group. Dapagliflozin alone reduced lipid parameters significantly particularly triglyceride (TG) when compared to placebo, with resultant visit 3 values at 99.5  ±  7.2 vs. 129  ±  12.3 and LDL/HDL ratio values were similar at 2.18  ±  0.08 vs. 2.13  ±  0.15. CD34 + cell migration improved significantly in both Dapa alone ( p  = 0.05) and Combo group ( p  = 0.05) vs. Placebo. Conclusions Several parameters showed significant improvement with both Dapa alone and Combo compared to placebo. However, when all outcome measures were taken into account, other than glycemic control the Combo didn’t seem to offer any further benefit, over Dapa alone. Therefore, contrary to our initial hypothesis we do not believe the more expensive Dapa + Saxa combination offers any specific cardiovascular benefit compared to Dapagliflozin alone. However it is noteworthy that both Dapa and its combination with Saxagliptin showed significant improvement compared to placebo in T2DM, particularly when progenitor cell based numbers and function were analyzed and taken into account. Trial Registration The trial was registered with Clinical Trials.gov number NCT03660683, last updated 06052023.

Background Peficitinib (ASP015K), a novel oral Janus kinase inhibitor, has demonstrated efficacy and safety for the treatment of rheumatoid arthritis (RA) in randomized, controlled trials of up to 52 weeks’ duration. However, safety and effectiveness after long-term treatment have not been assessed. Methods This was an interim analysis of an ongoing open-label, multicenter extension study in RA patients who completed phase 2b (RAJ1; 12 weeks) and phase 3 (RAJ3 and RAJ4; 52 weeks) peficitinib studies in Asia (mainly Japan). Eligible patients ( n  = 843) received oral peficitinib once daily (100 mg, or 50 mg for patients transferring from RAJ1). The peficitinib dose could be increased (up to 150 mg) or reduced (to 50 mg) at the discretion of the investigator. Efficacy variables assessed included American College of Rheumatology (ACR) response rates, ACR components, and disease activity score in 28 joints based on C-reactive protein (DAS28-CRP). Results Results up to May 2018 are summarized. Mean peficitinib duration of exposure was 22.7 months and the maximum dose was 100 mg in most (66.5%) patients. ACR responses were maintained during the extension study, with ACR20/50/70 response rates of 71.6%, 52.1%, and 34.7% at week 0 and 78.9%, 61.4%, and 42.7% at end of treatment, respectively. ACR components and DAS28-CRP showed improvements from baselines of the preceding studies and continued to show improvements during the extension study. Treatment-emergent adverse events (TEAEs) were reported in 757/843 (89.8%) patients, the most common being nasopharyngitis (39.7%) and herpes zoster (11.7%). The majority of TEAEs were severity grade 1/2. Drug-related TEAEs leading to permanent study drug discontinuation occurred in 55/843 (6.5%) patients. Regarding AEs of special interest, the incidence per 100 patient-years of serious infections was 2.3 (95% CI 1.6 – 3.1), herpes zoster-related disease 6.8 (95% CI, 5.6 – 8.3), and malignancies 1.1 (95% CI, 0.7 – 1.8). One death from diffuse large B cell lymphoma during the study and one death from uterine sarcoma after the study were considered probably and possibly related to study drug, respectively. Conclusions The effectiveness of peficitinib was maintained or improved during long-term administration and treatment up to 6 years was well tolerated in Asian patients with RA. Trial registration ClinicalTrials.gov, NCT01638013 , registered retrospectively 11 July 2012.

OBJECTIVE:--We sought to evaluate the efficacy and safety of vildagliptin, a new dipeptidyl peptidase-4 inhibitor, added to metformin during 24 weeks of treatment in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--This was a double-blind, randomized, multicenter, parallel group study of a 24-week treatment with 50 mg vildagliptin daily (n = 177), 100 mg vildagliptin daily (n = 185), or placebo (n = 182) in patients continuing a stable metformin dose regimen (>=1,500 mg/day) but achieving inadequate glycemic control (A1C 7.5-11%). RESULTS:--The between-treatment difference (vildagliptin - placebo) in adjusted mean change (AMΔ) ± SE in A1C from baseline to end point was -0.7 ± 0.1% (P < 0.001) and -1.1 ± 0.1% (P < 0.001) in patients receiving 50 or 100 mg vildagliptin daily, respectively. The between-treatment difference in the AMΔ fasting plasma glucose (FPG) was -0.8 ± 0.3 mmol/l (P = 0.003) and -1.7 ± 0.3 mmol/l (P < 0.001) in patients receiving 50 or 100 mg vildagliptin daily, respectively. Adverse events (AEs) were reported by 63.3, 65.0, and 63.5% of patients receiving 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo, respectively. Gastrointestinal AEs were reported by 9.6 (P = 0.022 vs. placebo), 14.8, and 18.2% of patients receiving 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo, respectively. One patient in each treatment group experienced one mild hypoglycemic event. CONCLUSIONS:--Vildagliptin is well tolerated and produces clinically meaningful, dose-related decreases in A1C and FPG as add-on therapy in patients with type 2 diabetes inadequately controlled by metformin.