26-Week Open-Label Extension Study Evaluating the Safety and Tolerability of Flexible Doses of Oral Ziprasidone in Children and Adolescents with Bipolar I Disorder (Most Recent Episode Manic).

Objective: To describe the longer-term effectiveness, safety, and tolerability of open-label ziprasidone in children and adolescents with bipolar I disorder (BD-I). Methods: A subset of 23 participants aged 10-17 years, who were previously treated in a multi-site, 4-week randomized controlled trial received open-label ziprasidone (20-80 mg twice a day) for up to 26 weeks. Results: The most common adverse events (AEs) were fatigue (30%), somnolence (17%), and nausea (13%). Effects on weight, body mass index, and metabolic parameters (glucose, cholesterol, and triglycerides) were minimal. No participant had a Fridericia-corrected QT interval ≥ 460 msec or a change from baseline of ≥60 msec, and there were no cardiac-related AEs. Both the participants who continued ziprasidone and those who initiated ziprasidone in the open-label extension showed improvements in their symptoms of mania. Conclusions: The overall findings of the study are consistent with the accumulating knowledge on the safety profile of ziprasidone in the acute and long-term treatment of children and adolescents with BD-I, in the midst of a manic episode. ClinicalTrial.gov ID: NCT03768726.

Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Aspart (MYL-1601D) Compared with Originator Insulin Aspart (Novolog®) in Patients with Type 1 Diabetes After 24 Weeks: A Randomized Open-Label Study.

BACKGROUND: MYL-1601D is a proposed biosimilar of originator insulin aspart, Novolog®/NovoRapid® (Ref-InsAsp-US/Ref-InsAsp-EU). OBJECTIVE: This study assessed the immunogenicity, efficacy, and safety of MYL-1601D with Ref-InsAsp-US in patients with type 1 diabetes mellitus (T1D). METHODS: This was a 24-week, open-label, randomized, phase III study. Patients were randomized 1:1 to mealtime MYL-1601D or Ref-InsAsp-US in combination with insulin glargine (Lantus SoloSTAR®) once daily. The treatment-emergent antibody response (TEAR) rate (defined as patients who were anti-insulin antibody [AIA] negative at baseline and became positive at any timepoint post-baseline or patients who were AIA positive at baseline and demonstrated a 4-fold increase in titer values at any timepoint post-baseline) was the primary endpoint. The study also compared the change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, 7-point self-monitored blood glucose (SMBG) profiles, immunogenicity, and adverse events (AEs) including hypoglycemia. RESULTS: In total, 478 patients were included in the intent-to-treat analysis (MYL-1601D: 238; Ref-InsAsp-US: 240) set. The 90% confidence interval (CI) for the primary endpoint was within the pre-defined equivalence margin of ±11.7% and the treatment differences (SE) in TEAR responders between the treatment groups was - 2.86 (4.16) with 90% CI - 9.71 to 3.99. The mean (SD) changes from baseline for HbA1c, FPG, and insulin dosages were similar in both groups at week 24. The safety profiles including hypoglycemia, immune-related events, AEs, and other reported variables were similar between the treatment groups at week 24. CONCLUSIONS: MYL-1601D demonstrated similar immunogenicity, efficacy, and safety profiles to Ref-InsAsp-US in patients with T1D over 24 weeks. CLINICAL TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03760068.

Efficacy, Safety, and Tolerability of Flexibly Dosed Ziprasidone in Children and Adolescents with Mania in Bipolar I Disorder: A Randomized Placebo-Controlled Replication Study.

Objective: To evaluate the acute efficacy, safety, and tolerability of flexibly dosed ziprasidone in children and adolescents with Bipolar I Disorder (BD-I). Methods: Participants, 10-17 years of age, meeting The Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria, were randomized 1:1 in a 4-week double-blind (DB) study, to receive ziprasidone (20-80 mg/twice a day) or placebo. Some were then enrolled in a 26-week open-label extension (OLE) study. The primary efficacy measure was the Young Mania Rating Scale (YMRS) total score. Results: A total of 171 participants entered this randomized DB study and 23 continued into the OLE study. The mean (SD) age of the combined sample was 13.4 (2.1) years, 44.4% were male, and 66.7% were white. The demographic characteristics of participants who received ziprasidone (n = 86) or placebo (n = 85) were similar. The primary objective was met: the mean difference for ziprasidone versus placebo in the YMRS total score was -4.23 (95% confidence interval: -7.14 to -1.32; p = 0.005) indicating an effect size of 0.58. The most common adverse events (AEs) in the ziprasidone group were somnolence (31.4%), fatigue (22.1%), and nausea (14%). The mean Fridericia-corrected QT interval (QTcF) intervals in the ziprasidone group were moderately prolonged relative to the placebo group at all study visits. No participants had QTcF intervals ≥480 msec or an increase from baseline ≥60 msec. No AEs indicative of QT prolongation occurred. Weight, body mass index (BMI), and BMI z-scores, and metabolic measures were similar in both treatment groups. The data from the OLE study will be reported separately. Conclusions: Ziprasidone was effective in children and adolescents with BD-I in a manic episode, replicating the results of a previous study with a similar design (Findling et al. 2013). Overall, ziprasidone was safe and well tolerated with no meaningful effects on weight or metabolic parameters. Trial registration: ClinicalTrials.gov. NCT02075047 and NCT03768726.

Pharmacokinetic and pharmacodynamic bioequivalence of biosimilar MYL-1601D with US and European insulin aspart in healthy volunteers: A randomized, double-blind, crossover, euglycaemic glucose clamp study.

AIM: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL-1601D biosimilar with originator, NovoLog (Ref-InsAsp-US), and NovoRapid (Ref-InsAsp-EU). MATERIALS AND METHODS: This was a double-blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration-time curve from 0 to 12 hours (AUC0-12h ) and maximum plasma insulin aspart concentration (Cmax ). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUCGIR0-12h ) and maximum GIR (GIRmax ). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS-mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL-1601D vs. Ref-InsAsp-US) and 95% CIs (MYL-1601D vs. Ref-InsAsp-EU) of primary PD variables, were to be within 80% to 125% to show BE. RESULTS: MYL-1601D showed PK BE to both Ref-InsAsp-US (AUC0-12h geometric LS-mean ratio 102.17, 90% CI [100.26; 104.11]; Cmax 106.13 [100.71; 111.85]) and Ref-InsAsp-EU (AUC0-12h 101.84 [100.04; 103.67]; Cmax 105.74 [101.09; 110.60]). Likewise, MYL-1601D showed PD BE to Ref-InsAsp-US (AUCGIR_0-last 99.93; 90% CI [95.74; 104.30]; GIR_max 100.12 [94.46; 106.12]) and Ref-InsAsp-EU (AUCGIR_0-last 96.42; 95% CI [91.17; 101.98]; GIR_max 95.10 [89.37; 101.19]). All three insulin aspart products were well tolerated. CONCLUSION: MYL-1601D showed BE to Ref-InsAsp-US and Ref-InsAsp-EU with a comparable safety profile.

Similar immunogenicity profiles between the proposed biosimilar MYL-1501D and reference insulin glargine in patients with diabetes mellitus: the phase 3 INSTRIDE 1 and INSTRIDE 2 studies.

BACKGROUND: MYL-1501D is a proposed biosimilar to insulin glargine. The noninferiority of MYL-1501D was demonstrated in patients with type 1 diabetes and type 2 diabetes in 2 phase 3 trials. Immunogenicity of MYL-1501D and reference insulin glargine was examined in both studies. METHODS: INSTRIDE 1 and INSTRIDE 2 were multicenter, open-label, randomized, parallel-group studies. In INSTRIDE 1, patients with type 1 diabetes received MYL-1501D or insulin glargine over a 52-week period. In INSTRIDE 2, patients with type 2 diabetes treated with oral antidiabetic drugs, insulin naive or not, received MYL-1501D or reference insulin glargine over a 24-week period. Incidence rates and change from baseline in relative levels of antidrug antibodies (ADA) and anti-host cell protein (anti-HCP) antibodies in both treatment groups were determined by a radioimmunoprecipitation assay and a bridging immunoassay, respectively. Results were analyzed using a mixed-effects model (INSTRIDE 1) or a nonparametric Wilcoxon rank sum test (INSTRIDE 2). RESULTS: Total enrollment was 558 patients in INSTRIDE 1 and 560 patients in INSTRIDE 2. The incidence of total and cross-reactive ADA was comparable between treatment groups in INSTRIDE 1 and INSTRIDE 2 (P > 0.05 for both). A similar proportion of patients had anti-HCP antibodies in both treatment groups in INSTRIDE 1 at week 52 (MYL-1501D, 93.9 %; reference insulin glargine, 89.6 %; P = 0.213) and in INSTRIDE 2 at week 24 (MYL-1501D, 87.3 %; reference insulin glargine, 86.9 %; P > 0.999). CONCLUSIONS: In INSTRIDE 1 and INSTRIDE 2, similar immunogenicity profiles were observed for MYL-1501D and reference insulin glargine in patients with type 1 diabetes and type 2 diabetes, respectively. TRIAL REGISTRATION: ClinicalTrials.gov, INSTRIDE 1 ( NCT02227862 ; date of registration, August 28, 2014); INSTRIDE 2 ( NCT02227875 ; date of registration, August 28, 2014).

Efficacy and safety of MYL-1501D versus insulin glargine in people with type 1 diabetes mellitus: Results of the INSTRIDE 3 phase 3 switch study.

AIMS: To assess the efficacy, insulin dose, safety and immunogenicity when people with type 1 diabetes mellitus switched between MYL-1501D and reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey). MATERIALS AND METHODS: Eligible participants from INSTRIDE 1 who completed 52 weeks of reference insulin glargine treatment were randomized 1:1 to the reference sequence (n = 63; reference insulin glargine for 36 weeks) or to the treatment-switching sequence (n = 64; MYL-1501D [weeks 0-12], reference insulin glargine [weeks 12-24] and MYL-1501D [weeks 24-36]). Change in glycated haemoglobin (HbA1c) from baseline to week 36 was the primary efficacy endpoint used to demonstrate equivalence between the two treatment sequences. Secondary endpoints included: change in fasting plasma glucose (FPG), self-monitored blood glucose (SMBG) and insulin dose; immunogenicity; and adverse events, including hypoglycaemia. RESULTS: Mean changes in HbA1c (least squares [LS] mean [SE]) from baseline to week 36 were -0.05 (0.032) and -0.06 (0.034) for the treatment-switching and reference sequences, respectively (LS mean difference 0.01 [95% CI -0.085 to 0.101]). Treatment sequences were comparable in terms of secondary endpoints, including FPG, SMBG and insulin dose, and the safety and immunogenicity profiles of the two sequences were similar. CONCLUSIONS: Switching participants between MYL-1501D and reference insulin glargine demonstrated equivalent efficacy and similar safety and immunogenicity, showing that people taking reference insulin glargine can safely switch to MYL-1501D.

Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: Results of the phase III INSTRIDE 2 study.

AIMS: To assess the non-inferiority of MYL-1501D, a proposed biosimilar or follow-on biological agent to marketed insulin glargine, to reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey) based on change in glycated hemoglobin (HbA1c). MATERIALS AND METHODS: INSTRIDE 2 was a multicentre, open-label, randomized, parallel-group, phase III non-inferiority study comparing the efficacy and safety of MYL-1501D with those of reference insulin glargine in insulin-naive and insulin-non-naive patients with type 2 diabetes mellitus receiving oral antidiabetic drugs (OADs). The primary efficacy endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included metabolic readouts (eg, changes in fasting plasma glucose, insulin dosage, self-monitored blood glucose), immunogenicity and adverse events, including hypoglycaemia and nocturnal hypoglycaemic events. RESULTS: In all, 560 patients were randomized to MYL-1501D or insulin glargine in combination with OADs for 24 weeks. The mean change in HbA1c from baseline to week 24 was -0.60% (95% CI -0.78, -0.41) and - 0.66% (95% CI -0.84, -0.48) for MYL-1501D and reference insulin glargine, respectively. MYL-1501D was well tolerated and had a safety profile similar to that of reference insulin glargine. CONCLUSIONS: Demonstration of non-inferiority between MYL-1501D and reference insulin glargine for reduction of HbA1c during 24 weeks of treatment was achieved. The two treatment groups were similar in terms of secondary endpoints, including hypoglycaemia and nocturnal hypoglycaemia, local and systemic reactions, other safety variables, and immunogenicity.

Primary triage, evacuation priorities, and rapid primary distribution between adjacent hospitals--lessons learned from a suicide bomber attack in downtown Tel-Aviv.

INTRODUCTION: Terrorist attacks have occurred in Tel-Aviv that have caused mass-casualties. The objective of this study was to draw lessons from the medical response to an event that occurred on 19 January 2006, near the central bus station, Tel-Aviv, Israel. The lessons pertain to the management of primary triage, evacuation priorities, and rapid primary distribution between adjacent hospitals and the operational mode of the participating hospitals during the event. METHODS: Data were collected in formal debriefings both during and after the event. Data were analyzed to learn about medical response components, interactions, and main outcomes. The event is described according to Disastrous Incidents Systematic AnalysiS Through-Components, Interactions and Results (DISAST-CIR) methodology. RESULTS: A total of 38 wounded were evacuated from the scene, including one severely injured, two moderately injured, and 35 mildly injured. The severe casualty was the first to be evacuated 14 minutes after the explosion. All of the casualties were evacuated from the scene within 29 minutes. Patients were distributed between three adjacent hospitals including one non-Level-1 Trauma Center that received mild casualties. Twenty were evacuated to the nearby, Level-1 Sourasky Medical Center, including the only severely injured patient. Nine mildly injured patients were evacuated to the Sheba Medical Center and nine to Wolfson Hospital, a non-Level-1 Trauma Center hospital. All the receiving hospitals were operated according to the mass-casualty incident doctrine. CONCLUSIONS: When a mass-casualty incident occurs in the vicinity of more than one hospital, primary triage, evacuation priority decision-making, and rapid distribution of casualties between all of the adjacent hospitals enables efficient and effective containment of the event.

Visually evoked cerebral vasomotor response in smoking and nonsmoking young adults, investigated by functional transcranial Doppler.

Smoking has been known to cause endothelial dysfunction and is an important risk factor for ischemic stroke. In our study we investigated whether chronic cigarette smoking affects the cerebral blood flow velocity response to a physiological, visual stimulus. By using a visual cortex stimulation paradigm, the flow velocity response in the posterior cerebral arteries (PCA) was measured bilaterally, in 32 young healthy adults (16 smokers, 16 nonsmokers). The stimulation protocol consisted of 10 cycles with a resting phase of 20 s and a stimulating phase of 40 s for each cycle. Besides functional transcranial Doppler (TCD), laboratory tests and measurement of intima-media-thickness (IMT) were also performed. Repeated-measure analysis of variance (ANOVA) was used to detect differences in visually evoked relative flow velocity time courses between smokers and nonsmokers. Repeated-measure ANOVA revealed marked difference in the peak systolic flow velocity time courses between smokers and nonsmokers (p< .001). Maximum percent change of visually evoked flow velocity after visual stimulation was 19+/-4% and 30+/-3% in smokers and nonsmokers, respectively (p< .0001). IMT values did not indicate atherosclerosis in young smokers. Infectious disease and hyperlipidemia were also ruled out by measurement of sensitive C-reactive protein and serum lipids. This is the first functional TCD study demonstrating impaired visually evoked flow velocity response caused by chronic cigarette smoking in otherwise healthy, young subjects. The impaired cerebral vasodilatory mechanism together with atherosclerosis may influence stroke occurrence and outcome in chronic smokers.