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Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study.

ABSTRACT: The study objective was to investigate the safety and tolerability of up-titration to high doses of taspoglutide, a once-weekly human glucagon-like peptide-1 analogue, in subjects with Type 2 diabetes inadequately controlled on metformin alone.In this double-blind phase II trial, subjects were randomized to placebo or taspoglutide (20 mg; three separate groups) administered once weekly by subcutaneous injection for 4 weeks. This was followed by dose maintenance at 20 mg, or titration to 30 mg (20/30) or 40 mg (20/40) once weekly with matched placebo for an additional 4 weeks. Subjects were monitored for adverse events (AEs) throughout the study and 4-week follow-up.One hundred and twenty-nine subjects were randomized and treated [mean age 57 years, mean baseline glycated haemoglobin (HbA(1c)), 7.9%]. The most frequently reported AEs were nausea and vomiting. The number of patients reporting gastrointestinal AEs did not increase following titration to higher doses of taspoglutide or when continuing the initial 20 mg regimen. Three subjects were withdrawn from the study as a result of gastrointestinal AEs (one before and two after titration to higher doses). Although not designed to investigate efficacy, improvement in glycaemic control was observed in all active arms of the study. The proportion of subjects achieving HbA(1c) < 7.0% after 8 weeks of treatment was 72, 53 and 70% in the 20/20-, 20/30- and 20/40-mg arms, respectively, vs. 19% for placebo.Taspoglutide was safe, well tolerated at high doses and efficacious for lowering HbA(1c). Up-titration of dose was not associated with a worsening AE profile.

SUBMITTER: Ratner R

PROVIDER: S-EPMC2948428 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study.

Ratner R R Nauck M M Kapitza C C Asnaghi V V Boldrin M M Balena R R

Diabetic medicine : a journal of the British Diabetic Association 20100501 5

<h4>Aims</h4>The study objective was to investigate the safety and tolerability of up-titration to high doses of taspoglutide, a once-weekly human glucagon-like peptide-1 analogue, in subjects with Type 2 diabetes inadequately controlled on metformin alone.<h4>Methods</h4>In this double-blind phase II trial, subjects were randomized to placebo or taspoglutide (20 mg; three separate groups) administered once weekly by subcutaneous injection for 4 weeks. This was followed by dose maintenance at 20 ...[more]

PMID: 20536952

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Project description:BackgroundExenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial.MethodsIn this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed.FindingsBetween June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions.InterpretationExenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.FundingMichael J Fox Foundation for Parkinson's Research.

Project description:The aim of this monocentric retrospective observational study was to evaluate the 18-month safety and effectiveness of GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) 1.5 mg/once weekly as an add-on to metformin (MET) or MET plus conventional insulin secretagogues in a study cohort with excess body weight and type 2 diabetes (T2D). Comparative efficacy versus liraglutide (LIRA) 1.2-1.8 mg/once daily in a study sample naïve to GLP-1 RAs, frequency matching for age, gender, T2D duration, degree of glycemic impairment, cardiovascular comorbidities, and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate-severe gastrointestinal AEs after a mean follow-up of 6 (4 standard deviations (SD)) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant mean HbA1c reduction of -0.85% (1.17 SD) with respect to baseline values (p < 0.001), which remained stable during 18 months follow-up. These results were accompanied by a moderate weight loss sustained over time, with a mean reduction of -2.0% (4.3 SD) at 6 months and -1.3% (4.8 SD) at 18 months (p = 0.091). At univariate analysis, a negative correlation between baseline body mass index (BMI) and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity against drug discontinuation was confirmed by logistic regression analysis. Neither gender, nor age, nor T2D duration, nor concomitant conventional insulin secretagogue use, nor switching to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in terms of HbA1c reduction ≥ 0.5% or body weight loss ≥ 5%. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and body weight in real-world experiences. With the advantage of once-weekly administration, at 18-month follow-up, a significantly larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p = 0.033). Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial responses to DU on a background of MET or MET plus insulin secretagogues are durable, especially in the presence of obesity and greater HbA1c impairment.

Project description:BackgroundTransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.MethodsACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 μg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).FindingsForty-two participants received TransCon CNP at doses of 6 μg (n = 10; 7 female), 20 μg (n = 11; 3 female), 50 μg (n = 10; 3 female), or 100 μg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 μg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 μg CNP/kg/week.InterpretationThis phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 μg CNP/kg/week in the ongoing pivotal trial.FundingAscendis Pharma, A/S.

Project description:Background: Preclinical and clinical data suggest that a compound which binds potently to and inhibits the dopamine transporter, but with a slower onset and offset rate than cocaine and with less abuse potential and psychomotor stimulant activity, could be a useful adjunct in the treatment of cocaine dependence. Methods: We assessed the safety, tolerability, and pharmacokinetics (PK) of oral single doses (0.3, 1, 3, 6, 12, and 20 mg) of such an analog, RTI-336, in a randomized, double-blind, and placebo-controlled trial in healthy adult males. Pre-dose and post-dose safety assessments included physical examinations (including neurological examination); orthostatic vital signs; 6-lead continuous electrocardiogram (ECG) telemetry monitoring pre-dose to 8 h post-dose; 12-lead ECGs; clinical chemistry, hematology, and urinalysis; mini mental status examinations; and adverse events. RTI-336 PK was assessed in plasma and urine. Results: 22 participants were enrolled. RTI-336 was well-tolerated up to the maximum evaluated dose of 20 mg. PK analyses demonstrated good absorption with peak plasma maximum concentrations (Cmax) occurring around 4 h post-dose and consistent half-lives of around 17 h for the 6, 12, and 20 mg doses. Plasma drug exposure and Cmax increased in proportion to dose. Only 0.02% of RTI-336 excreted was unchanged in urine. Active metabolites UC-M5, UC-M8, and UC-M2 were measurable in plasma and urine, with plasma Cmax of UC-M5 and UC-M8 exceeding that of RTI-336. Three AE possibly were related to RTI-336 and resolved with discontinuation; the one serious AE was unrelated to RTI-336. 2 participants had transient and mild serum total bilirubin elevations (<1.5× upper limit of normal) at day 3 post-dose which resolved by day 8 post-dose. Conclusion: All doses including the highest (20 mg) showed excellent safety and tolerability, and further studies in humans are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT00808119.

Project description:AIM:To assess the effects of once-weekly exenatide on 24-hour glucose control and variability. MATERIALS AND METHODS:This double-blind, placebo-controlled trial randomized metformin-treated adults with type 2 diabetes to once-weekly exenatide 2.0 mg or placebo. Continuous glucose monitoring (CGM) was performed at baseline and weeks 4 and 10. The primary outcome was change in CGM-measured 24-hour mean glucose level. RESULTS:In the once-weekly exenatide (n = 60) and placebo (n = 56) groups (modified intention-to-treat population), the baseline glycated haemoglobin (HbA1c) concentrations were 8.2% and 8.0%, respectively, and the fasting plasma glucose (FPG) concentration was 9.86 and 9.32 mmol/L, respectively. Once-weekly exenatide significantly (p < 0.001) reduced 24-hour mean glucose level versus placebo (week 4, -1.44 vs -0.29 mmol/L; week 10, -1.71 vs -0.17 mmol/L), with consistent control throughout the week. Once-weekly exenatide significantly reduced FPG and 2-hour postprandial glucose (PPG) levels versus placebo at week 4 (FPG, -1.65 vs -0.11 mmol/L; PPG, -1.79 vs -0.11 mmol/L) and week 10 (FPG, -2.32 vs -0.28 mmol/L; PPG, -2.46 vs -0.33 mmol/L). At week 10, once-weekly exenatide reduced the mean amplitude of glucose excursions (MAGE; -0.84 vs 0.16 mmol/L) and standard deviation (s.d.) of mean glucose (-0.35 vs 0.04 mmol/L). By week 10, once-weekly exenatide-treated participants spent more time in euglycaemia (once-weekly exenatide, 77% vs placebo, 58%), less time in hyperglycaemia (22% vs 42%), and a similar time in hypoglycaemia (0.7% vs 0.3%). Common adverse events were injection-site nodule (once-weekly exenatide, 10.0% vs placebo, 0.0%), urinary tract infection (6.7% vs 8.9%) and nausea (6.7% vs 0.0%). CONCLUSIONS:In metformin-treated participants with type 2 diabetes, once-weekly exenatide significantly improved daily glucose control and reduced glycaemic variability at weeks 4 and 10, as shown by reductions in 24-hour glucose, FPG and PPG levels, MAGE and s.d., and increased time spent in euglycaemia.

Dataset Information

Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study.

Publications

Safety and tolerability of high doses of taspoglutide, a once-weekly human GLP-1 analogue, in diabetic patients treated with metformin: a randomized double-blind placebo-controlled study.

Similar Datasets

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