Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Context: Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. Objective: To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Design/setting: Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. Patients: GH-naïve and non-naïve patients with AGHD. Intervention: Norditropin® (somatropin). Main outcome measures: Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. Results: The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Conclusion: Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

Early GH Treatment Is Effective and Well Tolerated in Children With Turner Syndrome: NordiNet® IOS and Answer Program.

CONTEXT: Despite having normal growth hormone (GH) secretion, individuals with Turner syndrome (TS) have short stature. Treatment with recombinant human GH is recommended for TS girls with short stature. OBJECTIVE: This work aimed to evaluate the effectiveness and safety of Norditropin (somatropin, Novo Nordisk) with up to 10 years of follow-up in children with TS. METHODS: Secondary analysis was conducted of Norditropin data from 2 non-interventional studies: NordiNet® IOS (NCT00960128) and the ANSWER program (NCT01009905). RESULTS: A total of 2377 girls with TS were included in the safety analysis set (SAS), with 1513 in the treatment-naive effectiveness analysis set (EAS). At the start of treatment, 1273 (84%) participants were prepubertal (EAS); mean (SD) age was 8.8 (3.9) years. Mean (SD) dose received at the start of GH treatment was 0.045 (0.011) mg/kg/day (EAS). Mean (SD) baseline insulin-like growth factor-1 (IGF-I) SD score (SDS) was -0.86 (1.52), and mean (SD) duration of GH treatment (SAS) was 3.8 (2.8) years.Height SDS (HSDS) increased throughout follow-up, with near-adult HSDS reached by 264 (17%) participants (mean [SD] -1.99 [0.94]; change from baseline +0.90 [0.85]). During the study, 695 (46%) participants (EAS) entered puberty at a mean (SD) age of 12.7 (1.9) years (whether puberty was spontaneous or induced was unknown). Within the SAS, mean IGF-I SDS (SD) at year 10 was 0.91 (1.69); change from baseline +1.48 (1.70). Serious adverse reactions were reported in 10 participants (epiphysiolysis [n = 3]). CONCLUSION: GH-treated participants with TS responded well, without new safety concerns. Our real-world data are in agreement with previous studies.

Reduced CV risk with long-term GH replacement in AGHD: data from two large observational studies.

Adult growth hormone deficiency (AGHD) is associated with an increased risk of cardiovascular (CV) disease. Long-term growth hormone (GH) treatment could improve CV outcomes. The objective of this study was to evaluate CV disease risk in patients with AGHD who received GH replacement therapy for up to 10 years as part of NordiNet® IOS (NCT00960128) and the ANSWER Program (NCT01009905). The studies were observational, non-interventional and multicentre, monitoring long-term effectiveness and safety of GH treatment. NordiNet® IOS involved 23 countries (469 sites) across Europe and the Middle East. The ANSWER Program was conducted in the USA (207 sites). This analysis included patients aged 18-75 years who were GH naïve at study entry, who had ≤10 years of GH treatment data and who could be assessed for CV risk for at least 1 follow-up year. The main outcome measure was risk of CV disease by age 75 years, as calculated with the Multinational Cardiovascular Risk Consortium model (Brunner score) using non-high-density lipoprotein cholesterol adjusted for age, sex and CV risk factors. The results of this analysis showed that CV risk decreased gradually over the 10-year period for GH-treated patients. The risk was lower for patients treated for 2 and 7 years vs age- and sex-matched control groups (not yet started treatment) (14.51% vs 16.15%; P = 0.0105 and 13.53% vs 16.81%; P = 0.0001, respectively). This suggests that GH treatment in people with AGHD may reduce the risk of CV disease by age 75 years compared with matched controls.

European Medicines Agency Policy 0070: an exploratory review of data utility in clinical study reports for academic research.

BACKGROUND: Clinical study reports (CSRs) have been increasingly utilised within academic research in recent years. European Medicines Agency (EMA) Policy 0070 'Phase 1,' which came into effect in January 2015, requires the publication of regulatory documents such as CSRs from central applications in an anonymised format. EMA Policy 0070 requires sponsors to demonstrate careful consideration of data utility within anonymised CSRs published within the scope of the policy, yet the concept of data utility is not clearly defined in the associated anonymisation guidance. OBJECTIVE: To review the use of data from CSRs in published academic research and to hypothesise the potential data utility of CSRs anonymised under the objectives of EMA Policy 0070 for future academic research. METHODS: Review of the objectives, research methodologies and findings of academic research reports using unpublished data from CSRs (prior to EMA Policy 0070). Semi-structured interviews with authors of academic research reports, including questions related to data utility of anonymised CSRs published under EMA Policy 0070. RESULTS: Thirteen academic research reports were identified and reviewed. The research purposes ranged from assessment of reporting bias, comparison of methods and results with published data sources, detailed evaluation of harms and adverse events, re-analysis and novel analyses including systematic reviews and meta-analysis. All of the examples identified required access to the methods and results sections of CSRs (including aggregated summary tables) and research purposes relating to evaluation of adverse events also required access to participant narratives. Retaining anonymised participant narratives relating to interventions, findings and events, while maintaining an acceptably low risk of participant re-identification, may provide an important gain in data utility and further understanding of drug safety profiles. CONCLUSIONS: This work provides an initial insight into the previous use of CSR data and current practices for including regulatory data in academic research. This work also provides early guidance to qualitatively assess and document data utility within anonymised CSRs published under EMA Policy 0070.

Quality of life after intracerebral hemorrhage: results of the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial.

BACKGROUND AND PURPOSE: Neurological impairment and physical disability are frequent and important complications of stroke with serious consequences for health-related quality of life (HRQOL). Little data exist, however, on the risk factors for poor HRQOL after intracerebral hemorrhage, the deadliest and most disabling form of stroke. METHODS: Factor Seven for Acute Hemorrhagic Stroke (FAST) was an international, randomized, double-blind, placebo-controlled trial conducted between May 2005 and February 2007 at 122 sites in 22 countries. All patients were followed for 3 months after stroke onset and HRQOL was assessed using the EuroQoL. Multivariate stepwise logistic regression was used to identify predictors of poor HRQOL based on demographic and clinical baseline characteristics and in-hospital complications. RESULTS: Six hundred fifty-seven patients survived until 3 months after stroke onset, and 621 (95%) completed the EuroQoL. Two percent had a utility score <0 (HRQOL worse than death), 15% a utility score <0.2, 32% a utility score <0.5, and 87% a score <0.87 (average score in the general population). At the other end of the scale, 13% had a utility score of 1 (perfect HRQOL). Independent predictors of poor HRQOL were advanced age (OR, 1.80; P<0.0001), higher baseline National Institutes of Health Stroke Scale score (OR, 1.11; P<0.0001), higher systolic blood pressure (OR, 1.05; P=0.0039), higher baseline intracerebral hemorrhage volume (OR, 1.11; P=0.015), deep (versus lobar) hematoma location (OR, 3.05; P=0.003), and increase in neurological deficit in first 72 hours after ICH onset (Delta Glasgow Coma Scale >or=2 or Delta National Institutes of Health Stroke Scale >or=4; OR, 2.04; P=0.006). The model explained a large amount of the variation in the utility score (C-statistic 0.77). CONCLUSIONS: The vast majority of survivors after intracerebral hemorrhage have very poor HRQOL. Critical care interventions designed to control blood pressure or prevent neuroworsening may improve HRQOL in intracerebral hemorrhage survivors.

Depressed mood after intracerebral hemorrhage: the FAST trial.

BACKGROUND AND PURPOSE: Depression is a frequent and important complication of stroke. Few data exist on the prevalence of depression/depressed mood after intracerebral hemorrhage (ICH) and the relationship between depression/depressed mood and the quality of life (QoL) more generally experienced by survivors of ICH. METHODS: Factor Seven for Acute Hemorrhagic Stroke (FAST) was a randomized, multicenter, double-blind, placebo-controlled trial conducted between May 2005 and February 2007 at 122 sites in 22 countries. All patients were evaluated at day 90 after ICH onset for depressed mood and QoL with the Hamilton Depression Rating Scale (HDRS) and the EuroQoL, respectively. Multivariate stepwise logistic regression was used to develop a predictive model for depressed mood at day 90. Relationships between HDRS and EuroQoL scores at day 90 were evaluated with Spearman correlation coefficients. RESULTS: 657 patients were alive at 3 months after ICH onset; 596 (91%) completed the HDRS. Twenty percent reported an HDRS score >10, indicating at least a minor degree of depressed mood; 6% endorsed symptoms of severely depressed mood. Significant predictors of depressed mood included comorbidities (p = 0.0022), moderate to severe neurological impairment according to the National Institutes of Health Stroke Scale (NIHSS) at day 15 (p = 0.0097), physical disability as measured by the Barthel Index (BI) at day 15 (p = 0.0486), and female gender (p = 0.04), but not hemorrhage severity or a history of depression. Irrespective of the presence of post-ICH disability and impairment, the severity of depressed mood at day 90 was significantly correlated with poor QoL. CONCLUSION: Depressed mood affects approximately 20% of ICH survivors and adversely affects QoL. Physicians should be vigilant to ensure that chronically ill and severely impaired survivors of ICH are adequately monitored and treated for depression after ICH.

Impact of recombinant activated factor VII on health-related quality of life after intracerebral hemorrhage.

BACKGROUND: We recently demonstrated that recombinant activated factor VII (rFVIIa) given to patients presenting within 3 h of acute spontaneous intracerebral hemorrhage (ICH) reduces mortality (18% vs. 29%) and poor outcome (modified Rankin Scale, mRS, 4-6, 53 vs. 69%). This analysis was performed to determine the impact of rFVIIa on health-related quality of life (HRQoL) in those patients. METHODS: In a prospective, randomized controlled trial, 399 patients (mean age, 66 years) received placebo, 40, 80 or 160 microg/kg of rFVIIa within 4 h of acute ICH. At 90 days, HRQoL was assessed with the EuroQoL (EQ-5D), a 5-dimensional measure of health which also includes the Visual Analogue Scale. Additionally, each level of the 90-day mRS was adjusted, using 4 different previously published utility values, to obtain a clearer picture of perceived HRQoL. RESULTS: Among the 5 dimensions of EQ-5D, only mobility rating was significantly better for rFVIIa-treated patients (serious problems, 34 vs. 54%; p = 0.01). Yet, the utility value (scaled 1.0 = perfect health and 0.0 = dead) associated with the composite EQ-5D demonstrated significantly better HRQoL (0.48 vs. 0.36; p = 0.01). This was also true for the EQ-5D Visual Analogue Scale score (44 vs. 36; p = 0.04). Finally, all 4 algorithms for applying utility scores to the mRS indicated that rFVIIa was associated with significantly better perceived HRQoL (all p < 0.006). CONCLUSIONS: Treatment with rFVIIa within 4 h of acute spontaneous ICH improves HRQoL.