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Safety and tolerability of canakinumab, an IL-1? inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

ABSTRACT: We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM).Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.03 mg/kg i.v. once; N = 20), intermediate (0.1 and 0.3 mg/kg i.v. once, 5 and 15 mg s.c. monthly; N = 247), medium (1.5 mg/kg i.v. once, 50 mg s.c. monthly and 150 mg s.c. once; N = 268), and high doses (10 mg/kg i.v. once and 150 mg s.c. monthly; N = 137) and compared with placebo (N = 354). Incidences of adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs, deaths, AEs of special interest related to interleukin-1? inhibition and T2DM disease, and laboratory abnormalities related to haematology and biochemistry parameters were reported. Safety was also analysed by age (<65, ?65) and gender.Average exposure across all groups was???6 months (maximum ~17 months). No dose response in AEs was observed but a trend towards more patients having at least one AE across canakinumab groups relative to placebo (P?=?0.0152) was observed. SAEs were few and the incidence rate for most canakinumab groups was lower than that of placebo group except for the high-dose group (0.94% versus 0.58% per month in placebo). A total of five patients discontinued treatment due to AEs across treatment groups. No death was reported in any of the three studies. A small, non-significant increase in the incidence rate of infection AEs was observed on canakinumab groups relative to placebo. Canakinumab was associated with mostly mild decreases in WBC, neutrophils and platelet counts. Additionally, mild increases in SGPT, SGOT and bilirubin were reported. Overall, despite small differences, no clinically relevant findings were observed with respect to laboratory values and vital signs.This pooled analysis demonstrated that canakinumab was safe and well tolerated over a treatment period up to 1.4 years at the four pooled doses evaluated, in agreement with safety findings reported in the individual studies.

SUBMITTER: Howard C

PROVIDER: S-EPMC4033489 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Safety and tolerability of canakinumab, an IL-1β inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

Howard Campbell C Noe Adele A Skerjanec Andrej A Holzhauer Björn B Wernsing Margaret M Ligueros-Saylan Monica M Thuren Tom T

Cardiovascular diabetology 20140517

<h4>Background</h4>We aimed to assess the safety and tolerability of different doses of canakinumab versus placebo in patients with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>Data were pooled from three studies in 1026 T2DM patients with different routes of administration, treatment regimens and follow-up duration. Canakinumab groups were categorised as low (0.03 mg/kg i.v. once; N = 20), intermediate (0.1 and 0.3 mg/kg i.v. once, 5 and 15 mg s.c. monthly; N = 247), medium (1.5 mg/kg i.v. o ...[more]

PMID: 24884602

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Project description:INTRODUCTION:The aim of this analysis was to characterize the safety and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) who were randomized to empagliflozin (10/25 mg) or placebo in clinical trials. METHODS:Pooled data from 20 trials were analyzed for patients with T2DM treated with empagliflozin 10 mg (n?=?4858), empagliflozin 25 mg (n?=?5057), or placebo (n?=?4904). The dataset comprised 15 randomized phase I-III trials, an extension trial and dose escalation studies. Adverse events (AEs) were assessed descriptively in participants who took???1 dose of study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure between trials. RESULTS:Total exposure was 16,480 and 7857 patient-years in the pooled empagliflozin 10/25 mg and placebo groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was similar across groups. The frequency of serious AEs requiring hospitalization was 18.6% for the empagliflozin 10/25 mg group and 21.3% for the placebo group. The empagliflozin 10/25 mg group was not associated with a higher rate of confirmed hypoglycemia versus placebo, except in patients co-administered insulin and/or a sulfonylurea (31.5% vs. 30.2%, respectively). The incidence of events consistent with urinary tract infections (UTI) was also similar for the empagliflozin 10/25 mg group versus placebo (9.27 vs. 9.70/100 patient-years, respectively). History of UTI was identified as a risk factor for UTI during treatment. Events consistent with genital infections occurred more frequently with empagliflozin 10/25 mg than placebo (3.54 vs. 0.95/100 patient-years, respectively). The frequency of AEs consistent with volume depletion was similar across groups, but higher with empagliflozin 10/25 mg than placebo in patients aged 75 to?<?85 years and those on loop diuretics at baseline. CONCLUSION:This comprehensive analysis confirms that both empagliflozin 10 mg and 25 mg are well tolerated in patients with T2DM, reinforcing the established clinical safety profile of empagliflozin.

Project description:BackgroundTreatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo.MethodsWe did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047.FindingsFrom July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.InterpretationIn adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.FundingNational Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Dataset Information

Safety and tolerability of canakinumab, an IL-1? inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

Publications

Safety and tolerability of canakinumab, an IL-1β inhibitor, in type 2 diabetes mellitus patients: a pooled analysis of three randomised double-blind studies.

Similar Datasets

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