Human plasma-derived alpha1 -proteinase inhibitor in patients with new-onset type 1 diabetes mellitus: A randomized, placebo-controlled proof-of-concept study.

BACKGROUND: While circulating levels of alpha1 -proteinase inhibitor (alpha1 -PI) are typically normal, antiprotease activity appears to be compromised in patients with Type 1 diabetes mellitus (T1DM). Because alpha1 -PI [human] (alpha1 -PI[h]) therapy can inhibit pro-inflammatory mediators associated with ß-cell destruction and reduced insulin production, it has been proposed for T1DM disease prevention. The aim of this study was to evaluate safety, tolerability, and efficacy of intravenous (IV) alpha1 -PI[h] in preserving C-peptide production in newly diagnosed T1DM patients. PARTICIPANTS: Seventy-six participants (aged 6-35 years) were randomized at 25 centers within 3 months of T1DM diagnosis. METHODS: A Phase II, multicenter, partially blinded, placebo-controlled, proof-of-concept study evaluating four dosing regimens of alpha1 -PI[h] (NCT02093221, GTI1302): weekly IV infusions of either 90 or 180 mg/kg, each for either 13 or 26 weeks. Safety and efficacy were monitored over 52 weeks with an efficacy evaluation planned at 104 weeks. The primary efficacy endpoint was change from baseline in the 2-h area-under-the-curve C-peptide level from a mixed-meal tolerance test at 52 weeks. A battery of laboratory tests, including inflammatory biomarkers, constituted exploratory efficacy variables. RESULTS: Infusions were well tolerated with no new safety signals. All groups exhibited highly variable declines in the primary outcome measure at 52 weeks with no statistically significant difference from placebo. Interleukin-6 (IL-6) was reduced from baseline in all alpha1 -PI treatment groups but not the placebo group. CONCLUSION: Pharmacologic therapy with alpha1 -PI[h] is safe, well tolerated, and able to reduce IL-6 levels; however, due to variability in the efficacy endpoint, its effects on preservation of C-peptide production were inconclusive.

A phase 3 multicenter, open-label, prospective study designed to evaluate the effectiveness and ease of use of nasal glucagon in the treatment of moderate and severe hypoglycemia in children and adolescents with type 1 diabetes in the home or school setting.

OBJECTIVE: This multicenter, open-label study was designed to evaluate real-world effectiveness and ease of use of nasal glucagon (NG) in treating moderate or severe hypoglycemic events in children and adolescents with type 1 diabetes (T1D). METHODS: Caregivers were trained to administer NG (3 mg) to the child/adolescent with T1D during spontaneous, symptomatic moderate or severe hypoglycemic events, observe treatment response (defined as awakening or returning to normal status within 30 minutes), and measure blood glucose (BG) levels every 15 minutes. Data regarding adverse events and ease of use were solicited using questionnaires. RESULTS: The analysis population included 14 patients who experienced 33 moderate hypoglycemic events with neuroglycopenic symptoms and BG level ≤70 mg/dL. Patients returned to normal status within 30 minutes of NG administration in all 33 events. Mean BG levels increased from 55.5 mg/dL (range 42-70 mg/dL) at baseline to 113.7 mg/dL (range 79-173 mg/dL) within 15 minutes of NG administration. In most hypoglycemic events (93.9%), caregivers reported that NG administration was easy or very easy; they could administer NG within 30 seconds in 60.6% of events. There were no serious adverse events. CONCLUSIONS: A single 3-mg dose of NG was effective in treating moderate, symptomatic, hypoglycemic events in children and adolescents with T1D in a real-world setting. It was easy-to-use and reasonably well tolerated. NG shows promise as an effective, needle-free, and user-friendly alternative to injectable glucagon.

Recombinant human growth hormone plus recombinant human insulin-like growth factor-1 coadministration therapy in short children with low insulin-like growth factor-1 and growth hormone sufficiency: results from a randomized, multicenter, open-label, parallel-group, active treatment-controlled trial.

BACKGROUND/AIMS: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) both contribute to growth. To determine if recombinant human (rh)GH + rhIGF-1 therapy is more effective than rhGH alone to treat short stature, we assessed the efficacy and safety of coadministered rhGH + rhIGF-1 in short children with GH sufficiency and low IGF-1. METHODS: In a 3-year, randomized, multicenter, open-label trial, patients with height SD score ≤-2.0 and IGF-1 SD score ≤-1.0 for age and sex, and with stimulated GH ≥10 ng/ml for age and sex, were randomized to receive (all doses in µg/kg/day): 45 rhGH alone (group A), 45 rhGH + 50 rhIGF-1 (group B), 45 rhGH + 100 rhIGF-1 (group C) or 45 rhGH + 150 rhIGF-1 (group D). Height velocity (HV) and Δ height SD score were measured. RESULTS: The first-year HV (modified intention-to-treat population) was 9.3 ± 1.7 cm/year (group A), 10.1 ± 1.3 cm/year (group B), 9.7 ± 2.5 cm/year (group C) and 11.2 ± 2.1 cm/year (group D) (p = 0.001 for groups A vs. D). This effect was sustained, resulting in a height SD score improvement during the second and third years. Most treatment-emergent adverse events were mild and transient. CONCLUSION: In children with short stature, GH sufficiency and low IGF-1, coadministration of rhGH/rhIGF-1 (45/150 µg/kg) significantly accelerated linear growth compared with rhGH alone, with a safety profile similar to the individual monotherapies.

Ease of use and preference for a new disposable self-injection pen compared with a reusable pen for administering recombinant human growth hormone: A multicenter, 2-month, single-arm, open-label clinical trial in patient-caregiver dyads.

BACKGROUND: Improved ease of use of drug-delivery devices may enhance compliance. Development of an easier-to-use device for administration of recombinant human growth hormone (rhGH) may thus be beneficial for patients and their caregivers. OBJECTIVE: This study compared ease of use and preference for a new disposable rhGH injection pen relative to previous experience with the currently available reusable pen in standard practice. Both pens deliver the same formulation of rhGH. METHODS: This multicenter, single-arm, open-label study assessed ease of use and preference for the 2 injection pens in patient-caregiver dyads. Eligible children were aged 8 through 18 years, were currently being treated with rhGH, and had been compliant with use of the current reusable pen for ≥ 3 months before study entry. A validated self-reported Injection Pen Assessment Questionnaire was administered twice during the study-at baseline (to assess perceptions of the reusable pen) and after 2 months of use of the new disposable pen-to assess ease of use of the individual pens (rated on a 5-point Likert-type scale), the comparative ease of use of the 2 pens, and pen preference. The primary end point was the proportion of dyads who rated the new pen as no different or easier to use than the current pen. Regardless of treatment or suspected causal relationship to the investigational product, all observed or volunteered adverse events (AEs) were recorded and rated as mild, moderate, or severe. RESULTS: Of 137 screened dyads, 136 (91 boys, 45 girls) were included in the safety population and 133 were included in the efficacy population. The children had a mean age of 12.3 years, a mean weight of 42.2 kg, a mean height of 145.9 cm, and a mean body mass index of 19.3 kg/m(2); 84.6% of the children were white. The majority (82.4%) of adult dyad members were subjects' mothers. The adult dyad members were more likely than the child members to be responsible for preparing the injection (82.0%) and administering the injection (72.9%). Overall, 73.7% of dyads rated the new disposable pen no different or easier to use than the reusable pen (95% CI, 66.2%-81.2%), and 65.2% rated the disposable pen no different or preferable to the reusable pen (95% CI, 57.0%-73.3%). Overall, 60 all-causality AEs occurred in 28 subjects (20.6%), most of them (93.3%) either mild or moderate in intensity. Eight device-related AEs occurred in 7 subjects (5.1%) (injection-site hematoma in 3 and injection-site pain in 5). The most common AEs were headache (7 events), injection-site pain (5), upper respiratory tract infection (4), and pyrexia (4). No deaths or serious AEs were reported. CONCLUSIONS: Nearly three quarters of patients and caregivers reported that the new disposable pen was no different or easier to use than the reusable pen, and nearly two thirds preferred the disposable pen. No safety concerns were identified. The findings suggest that the improvements in the new pen were recognized by patients and caregivers.