Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis.

BACKGROUND: The assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment. METHODS: The source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months. RESULTS: A weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, -0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%). CONCLUSIONS: Longitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death. TRIAL REGISTRATION NUMBERS: NCT01366209, NCT00287729, NCT00287716.

A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations.

Fospropofol is a sedative hypnotic with a slower onset and longer duration of action. Fospropofol has demonstrated successful dose-dependent sedation at 6.5 mg/kg. This study evaluated the efficacy and safety of a lower weight-adjusted dose compared with the approved dose (4.875 or 6.5 mg/kg depending on patient subgroup) in high-risk elderly patients undergoing colonoscopy. In this study, 153 subjects were classified into 3 subgroups based on the following: age, weight, and American Society of Anesthesiologist (ASA) physical status criteria. The patients were randomized to the approved dose or weight-adjusted dose of fospropofol in a 1:1 ratio. Subgroup 1 (n = 50) consisted of patients weighing <60 kg, age 18-65 years, and ASA I or II; subgroup 2 (n = 50) consisted of patients weighing <60 kg; age 65 years and above, and ASA I-IV; and subgroup 3 (n = 53) consisted of patients weighing ≥60 kg, age 65 years and above, and ASA I-IV. Sedation, modified sedation and treatment success, and safety parameters were assessed. The approved dose had a significantly higher sedation success compared with the weight-adjusted dose: 96% versus 72% for subgroup 1; 84% versus 72% for subgroup 2; and 96% versus 67.9% for subgroup 3. There was a decreased need for alternative sedatives in subgroups 1 and 3 and fewer sedation- and treatment-emergent adverse events in all the subgroups for the approved dose. Additionally, sedation success data pooled across subgroups and examined based on age, weight, and ASA categories showed a significantly higher rate of sedation success in the approved dose arm across all the subgroups. The rate of sedation, modified sedation, and treatment success were higher in patients administered the approved dose for all the subgroups. No clinically significant advantage was demonstrated using a lower modified dose in this study population. The approved dose is recommended in the elderly, more obese, and high-risk patients when used for moderate sedation.

Average IGF-1 Prediction for Once-Weekly Lonapegsomatropin in Children With Growth Hormone Deficiency.

CONTEXT: Serum insulin-like growth factor 1 (IGF-1) levels are relatively constant in somatropin-treated children with growth hormone deficiency (GHD), and guide dose adjustments for clinical efficacy and long-term safety. IGF-1 levels following treatment with long-acting growth hormones such as lonapegsomatropin (lonapegsomatropin-tcgd, TransCon hGH), a once-weekly somatropin prodrug, exhibit a characteristic profile over the dosing interval. OBJECTIVE: This study aimed to develop a method to predict average IGF-1 in lonapegsomatropin-treated GHD children to interpret IGF-1 data based on a single sample obtained any time at steady state. METHODS: A population nonlinear mixed-effect pharmacodynamic model for IGF-1 was developed based on 2 randomized, open-label trials of TransCon hGh in GHD children and used to develop a linear mixed model with Taylor series to fit simulated IGF-1 profiles of lonapegsomatropin-treated children. A TOTAL OF: 49 896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated GHD children were utilized for the final prediction model. The dosage range of TransCon hGh was 0.14 to 0.30 hGH mg/kg/week, and weekly average IGF-1 was calculated using IGF-1 profiles simulated from the nonlinear pharmacodynamic model. Predicted average IGF-1 was obtained by linear mixed model with Taylor series. RESULTS: The nonlinear mixed-effect model provided satisfactory model fit. The linear mixed model with Taylor series fit simulated IGF-1 data well, with a relatively straightforward prediction formula. IGF-1 values sampled at ~4.5 days post-dose coincided with weekly average IGF-1 at steady state. CONCLUSION: A formula to predict average IGF-1 from a single sample of IGF-1 at steady state was established to aid clinicians in interpreting IGF-1 levels in GHD children administered lonapegsomatropin.

Psychometric validation of the Hypoparathyroidism Patient Experience Scales (HPES).

BACKGROUND: Hypoparathyroidism (HP) is a rare endocrine disorder characterized by absent or inappropriately low levels of circulating parathyroid hormone with associated significant physical and cognitive symptoms. This study evaluated the psychometric properties of the Hypoparathyroidism Patient Experience Scales (HPES), which were developed as disease-specific, patient-reported outcome (PRO) measures to assess the symptoms and impacts associated with HP in adults. METHODS: Data from a non-interventional, observational study (N = 300) and a Phase 2 clinical trial (N = 59) were used in the psychometric evaluation. Observational and trial assessments included: an online validation battery (baseline or screening) and retest (approximately 2 weeks after baseline or screening). In the trial, the primary efficacy endpoint was assessed at week 4 through re-administration of the HPES and validation battery subset. The observational study's larger sample size allowed for evaluation of the HPES descriptive properties, scoring algorithm, test-retest reliability, and construct validity. The trial data examined responsiveness, meaningful within-patient change estimates, and treatment impact on HPES scores. RESULTS: Demographic and self-reported medical characteristics results were similar across the 2 studies. Factor analysis confirmed domains in the HPES-Symptom (n = 2) and HPES-Impact (n = 4). For both measures, total and domain scores demonstrated acceptable reliability and validity for both the observational and trial samples. Internal consistency evidence was strong. Test-retest reliability estimates generally approached the recommended 0.70 threshold. The construct validity correlations with other PRO measures were mainly as hypothesized, thus supporting the HPES scores and constructs. Mean scores for both measures also differed as anticipated and significantly across known-groups, thus providing evidence for the scores discriminating between meaningful groups. Trial results supported both HPES total and domain scores' ability to detect change. The difference in mean total and domain scores for both measures demonstrated statistically significant improvements for TransCon PTH compared to placebo treated subjects despite the small sample and a short 4-week duration on fixed, non-optimized doses. CONCLUSIONS: The HPES were found to be conceptually sound with adequate evidence supporting their reliability and validity. Incorporation of the HPES into clinical and research settings will help to further elucidate and assess the patient experience of living with HP and identify treatment differences.

Weekly Lonapegsomatropin in Treatment-Naïve Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial.

CONTEXT: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin. DESIGN: The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727). SETTING: This trial took place at 73 sites across 15 countries. PATIENTS: This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD. INTERVENTIONS: Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily. MAIN OUTCOME MEASURE: The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS). RESULTS: Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups. CONCLUSIONS: The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

Placebo-controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy.

OBJECTIVE: This double-blind, randomized, placebo-controlled Phase 2 study (NCT01462292) assessed the 24-week efficacy, safety, tolerability, and pharmacokinetics of two different subcutaneous drisapersen doses, and the 24-week off-dose persistent effect, in ambulant Duchenne muscular dystrophy (DMD) patients. METHODS: Male DMD patients (≥5 years; time to rise from floor ≤15 s) were randomized to drisapersen 3 mg/kg/week, 6 mg/kg/week or placebo. The primary efficacy endpoint was change from baseline in 6-minute walking distance (6MWD) at week 24. Secondary endpoints included changes in timed function tests, muscle strength, and pulmonary function tests. RESULTS: Fifty-one patients were randomized to placebo (N = 16), drisapersen 3 mg/kg/week (N = 17) or 6 mg/kg/week (N = 18). All but 2 patients had baseline rise from floor time <7 s. This study was exploratory and not prospectively powered; however, a difference in mean 6MWD versus placebo in favor of drisapersen 6 mg/kg/week was observed at week 24 (27.1 m; P = 0.069) and maintained 24 weeks off-treatment (27.9 m; P = 0.177). The 3 mg/kg/week group showed no statistically significant difference in mean 6MWD versus placebo. For some secondary endpoints, a more positive response in favor of drisapersen 6 mg/kg/week compared to placebo was shown. Drisapersen had a long half-life with steady state reached after approximately 36 weeks. Most common adverse events in both drisapersen groups were related to injection site reactions and subclinical proteinuria. INTERPRETATION: Drisapersen 6 mg/kg/week for 24 weeks resulted in a treatment benefit in 6MWD, largely maintained 24 weeks off-treatment. This study provided insights for further studies to optimize dosage regimen.

A randomized placebo-controlled phase 3 trial of an antisense oligonucleotide, drisapersen, in Duchenne muscular dystrophy.

This 48-week, randomized, placebo-controlled phase 3 study (DMD114044; NCT01254019) evaluated efficacy and safety of subcutaneous drisapersen 6 mg/kg/week in 186 ambulant boys aged ≥5 years, with Duchenne muscular dystrophy (DMD) resulting from an exon 51 skipping amenable mutation. Drisapersen was generally well tolerated, with injection-site reactions and renal events as most commonly reported adverse events. A nonsignificant treatment difference (P = 0.415) in the change from baseline in six-minute walk distance (6MWD; primary efficacy endpoint) of 10.3 meters in favor of drisapersen was observed at week 48. Key secondary efficacy endpoints (North Star Ambulatory Assessment, 4-stair climb ascent velocity, and 10-meter walk/run velocity) gave consistent findings. Lack of statistical significance was thought to be largely due to greater data variability and subgroup heterogeneity. The increased standard deviation alone, due to less stringent inclusion/exclusion criteria, reduced the statistical power from pre-specified 90% to actual 53%. Therefore, a post-hoc analysis was performed in 80 subjects with a baseline 6MWD 300-400 meters and ability to rise from floor. A statistically significant improvement in 6MWD of 35.4 meters (P = 0.039) in favor of drisapersen was observed in this subpopulation. Results suggest that drisapersen could have benefit in a less impaired population of DMD subjects.

Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes.

OBJECTIVE: Insulin glargine (LANTUS) is a once-daily basal insulin analog with a smooth 24-h time-action profile that provides effective glycemic control with reduced hypoglycemia risk (particularly nocturnal) compared with NPH insulin in patients with type 2 diabetes. A recent "treat-to-target" study has shown that more patients on insulin glargine reached HbA(1c) levels < or =7.0% without confirmed nocturnal hypoglycemia compared with NPH insulin. We further assessed the risk for hypoglycemia in a meta-analysis of controlled trials of a similar design for insulin glargine versus once- or twice-daily NPH insulin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: All studies were 24-28 weeks long, except one 52-week study, for which interim 20-week data were used. RESULTS: Patient demographics were similar between the insulin glargine (n = 1,142) and NPH insulin (n = 1,162) groups. The proportion of patients achieving target HbA(1c) (< or =7.0%) was similar between insulin glargine-and NPH insulin-treated patients (30.8 and 32.1%, respectively). There was a consistent significant reduction of hypoglycemia risk associated with insulin glargine, compared with NPH insulin, in terms of overall symptomatic (11%; P = 0.0006) and nocturnal (26%; P < 0.0001) hypoglycemia. Most notably, the risk of severe hypoglycemia and severe nocturnal hypoglycemia were reduced with insulin glargine by 46% (P = 0.0442) and 59% (P = 0.0231), respectively. CONCLUSIONS: These results confirmed that insulin glargine given once daily reduces the risk of hypoglycemia compared with NPH insulin, which can facilitate more aggressive insulin treatment to a HbA(1c) target of < or =7.0% in patients with type 2 diabetes.

Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials.

BACKGROUND: Pirfenidone is an oral antifibrotic agent that has been shown to reduce the decline in lung function in patients with idiopathic pulmonary fibrosis (IPF). We performed an integrated analysis of safety data from five clinical trials evaluating pirfenidone in patients with IPF. METHODS: All patients treated with pirfenidone in the three multinational Phase 3 studies (CAPACITY (studies 004 and 006), ASCEND (study 016)) and two ongoing open-label studies (study 002 and study 012 (RECAP)) were included in the analysis. Safety outcomes were assessed during the period from the first dose until 28 days after the last dose of study drug. RESULTS: A total of 1299 patients were included in the analysis. The cumulative total exposure to pirfenidone was 3160 person exposure years (PEY). The median duration of exposure was 1.7 years (range 1 week to 9.9 years), and the mean (±SD) daily dose was 2053.8 (±484.9) mg. Gastrointestinal events (nausea (37.6%), diarrhoea (28.1%), dyspepsia (18.4%), vomiting (15.9%)) and rash (25.0%) were the most common adverse events; these were generally mild to moderate in severity and without significant clinical consequence. Elevations in alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal occurred in 40/1299 (3.1%) patients (adjusted incidence, 2.3 per 100 PEY). Elevations were generally transient and reversible with dose modification or discontinuation. CONCLUSIONS: A comprehensive analysis of safety outcomes in a large and well-defined cohort of 1299 patients with IPF who were followed prospectively for up to 9.9 years demonstrated that long-term treatment with pirfenidone is safe and generally well tolerated. TRIAL REGISTRATION NUMBERS: NCT00287716, NCT00287729, NCT00662038, NCT01366209.