The impact of severe haemophilia and the presence of target joints on health-related quality-of-life.

BACKGROUND: Joint damage remains a major complication associated with haemophilia and is widely accepted as one of the most debilitating symptoms for persons with severe haemophilia. The aim of this study is to describe how complications of haemophilia such as target joints influence health-related quality of life (HRQOL). METHODS: Data on hemophilia patients without inhibitors were drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost-of-illness assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the UK). Physicians provided clinical and sociodemographic information for 1285 adult patients, 551 of whom completed corresponding questionnaires, including EQ-5D. A generalised linear model was developed to investigate the relationship between EQ-5D index score and target joint status (defined in the CHESS study as areas of chronic synovitis), adjusted for patient covariates including socio-demographic characteristics and comorbidities. RESULTS: Five hundred and fifteen patients (42% of the sample) provided an EQ-5D response; a total of 692 target joints were recorded across the sample. Mean EQ-5D index score for patients with no target joints was 0.875 (standard deviation [SD] 0.179); for patients with one or more target joints, mean index score was 0.731 (SD 0.285). Compared to having no target joints, having one or more target joints was associated with lower index scores (average marginal effect (AME) -0.120; SD 0.0262; p < 0.000). CONCLUSIONS: This study found that the presence of chronic synovitis has a significant negative impact on HRQOL for adults with severe haemophilia. Prevention, early diagnosis and treatment of target joints should be an important consideration for clinicians and patients when managing haemophilia.

Understanding burden of illness for child growth hormone deficiency.

PURPOSE: Research demonstrates that children and adolescents with growth hormone deficiency (GHD) are impacted in multiple ways beyond their short stature; however, there are no disease-specific measures to assess these impacts. The purpose of this study was to examine the burden of GHD on children and adolescents, and to conduct concept elicitation to develop a model of the impact of GHD to support a disease-specific outcome measure. METHODS: Four focus groups and 52 telephone interviews were conducted with children with GHD and parents/guardians of children with GHD to understand the experience and impacts from the child's perspective, reported by children or parent-observers about the impact on the child. The interviews and focus groups were conducted in Germany, the United Kingdom, and the United States. Interview transcripts were analyzed thematically based on modified grounded theory principles. RESULTS: There were 73 descriptions of patient's experiences elicited from 70 respondents, as three respondents spoke for two children each. A majority of GHD descriptive narratives refer to boy children (n = 51, 69.9%) and a majority of children had taken GHD treatment (n = 64, 89%). Analysis identified four major areas of GHD impact: Signs and Symptoms (beyond short stature), Physical Aspects of Daily Life, Social Well-Being, and Emotional Well-Being. CONCLUSIONS: The burden of GHD in children and adolescents is considerable and not limited to short stature. The severity of GHD impact on children and adolescents appears to be variable and individualized, but these data indicate that early identification and growth hormone treatment may lead to fewer impacts.

Developing a health economic model for Asians with type 2 diabetes based on the Japan Diabetes Complications Study and the Japanese Elderly Diabetes Intervention Trial.

INTRODUCTION: Cost-effectiveness analyses are becoming increasingly important in Japan following the introduction of a health technology assessment scheme. The study objective was to develop an economic model to evaluate the cost-effectiveness of two interventions for type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS: The Japan Diabetes Complications Study/Japanese Elderly Diabetes Intervention Trial risk engine (JJRE) Cost-Effectiveness Model (JJCEM) was developed, incorporating validated risk equations in Japanese patients with type 2 diabetes from the JJRE. Weibull regression models were developed for progression of the model outcomes, and a targeted literature review was performed to inform default values for utilities and costs. To illustrate outcomes, two simulated analyses were performed in younger (aged 40 years) and older (aged 80 years) Japanese populations, comparing a hypothetical treatment with placebo. RESULTS: The model considers a population based on user-defined values for 11 baseline characteristic parameters and simulates rates of diabetic complications over a defined time horizon. Costs, quality-adjusted life years, and an incremental cost-effectiveness ratio are estimated. The model provides disaggregated results for two competing interventions, allowing visualization of the key drivers of cost and utility. A scatterplot of simulations and cost-effectiveness acceptability curve are generated for each analysis. CONCLUSIONS: This is the first cost-effectiveness model for East Asian patients with type 2 diabetes, developed using Japan-specific risk equations. This population constitutes the largest share of the global population with diabetes, making this model highly relevant. The model can be used to evaluate the cost-effectiveness of anti-diabetic interventions in patients with type 2 diabetes in Japan and other East Asian populations.

Lower Drug Cost of Successfully Treating Patients with Type 2 Diabetes to Targets with Once-Weekly Semaglutide versus Once-weekly Dulaglutide in Japan: A Short-Term Cost-Effectiveness Analysis.

INTRODUCTION: In the head-to-head trial (SUSTAIN 7), the novel, injectable, once-weekly GLP-1 analogue semaglutide showed superiority in both glycemic outcomes and body weight reduction, compared with once-weekly dulaglutide in the treatment of type 2 diabetes (T2D). However, no economic evaluation using these data has yet been conducted in the Japanese setting. The objective of this analysis was to assess the short-term cost-effectiveness in Japan of once-weekly semaglutide 0.5 mg (the approved maintenance dose in Japan) compared with once-weekly dulaglutide 0.75 mg (the only licensed dose in Japan) over a 1-year period using Japanese cost data. METHODS: Responder endpoints were obtained from the SUSTAIN 7 trial to assess the cost of successfully treating patients to these targets ("cost of control"). Responder endpoint definitions consisted of single, dual, and triple composite endpoints related to glycemic control, body weight, and hypoglycemia outcomes. The cost of treatment was accounted from a healthcare payer perspective, capturing drug costs only. RESULTS: Treatment with once-weekly semaglutide 0.5 mg was associated with a lower cost and a lower cost per patient treated to target for all endpoints, compared with once-weekly dulaglutide 0.75 mg. For each JPY 1 spent on bringing patients to target with once-weekly semaglutide 0.5 mg, JPY 1.58, JPY 1.44, JPY 1.60, JPY 2.10, and JPY 2.33 would need to be spent on once-weekly dulaglutide 0.75 mg to achieve an equivalent outcome for endpoints of HbA1c ≤ 6.5%, HbA1c < 7.0%, HbA1c < 7.0% without hypoglycemia, and no weight gain, weight loss ≥ 5%, and ≥ 1.0% HbA1c reduction and ≥ 3.0% weight loss, respectively. CONCLUSIONS: These findings suggest that once-weekly semaglutide is a cost-effective treatment option compared with once-weekly dulaglutide for patients with T2D in Japan. In the future, this finding should be extrapolated to traditional long-term cost-effectiveness analysis, using common outcomes such as quality-adjusted life years.

Comparative efficacy of once-weekly semaglutide versus SGLT-2 inhibitors in patients inadequately controlled with one to two oral antidiabetic drugs: a systematic literature review and network meta-analysis.

OBJECTIVE: To determine the comparative efficacy of once-weekly semaglutide relative to sodium-glucose cotransporter 2 inhibitors (SGLT-2is) licensed in Europe and North America among patients with type 2 diabetes (T2D) inadequately controlled with 1-2 oral antidiabetics (OADs), using a network meta-analysis (NMA). Design systematic review and network meta-analysis. Data Sources EMBASE, MEDLINE and CENTRAL were searched from January 1994 to August 2017. METHODS: Randomised controlled trials with ≥20 weeks of treatment evaluating once-weekly semaglutide or SGLT-2is. Primary outcomes included change from baseline in: HbA1c, weight, systolic blood pressure, postprandial blood glucose and fasting plasma glucose. Fixed-effect and random-effect Bayesian NMA were used to indirectly compare treatment effects at 26 (±4) weeks. Metaregression and sensitivity analyses were conducted. Model selection was performed using the deviance information criterion and consistency was assessed by comparing indirect (edge-splitting) to direct evidence. RESULTS: Forty-eight publications representing 21 trials were included. The mean differences (MD) in change from baseline in HbA1c of once-weekly semaglutide 1.0 mg versus SGLT-2is ranged from -0.56% for canagliflozin 300 mg (95% credible interval (CrI): -0.76 to -0.33%), to -0.95% for dapagliflozin 5 mg (95% CrI: -1.20 to -0.69%). The MD in change from baseline in weight of once-weekly semaglutide 1.0 mg versus SGLT-2is ranged from -1.35 kg for canagliflozin 300 mg to -2.48 kg for dapagliflozin 5 mg, while change from baseline in fasting plasma glucose ranged from -0.41 mmol/L for canagliflozin 300 mg to -1.37 mmol/L for dapagliflozin 5 mg. Once-weekly semaglutide was not statistically differentiable than all SGLT-2is in reducing systolic blood pressure. NMA was not feasible for postprandial blood glucose and safety outcomes. CONCLUSION: Once-weekly semaglutide demonstrated statistically significant and clinically meaningful reductions in HbA1c and body weight in T2D patients inadequately controlled with 1-2 OADs compared to all SGLT-2is licensed in Europe and North America.

Assessing the Impact of Growth Hormone Deficiency (GHD) in Adults: Interpreting Change of the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD).

BACKGROUND: This study's purpose was to assess the minimal important difference (MID) for the Treatment-Related Impact Measure-Adult Growth Hormone Deficiency (TRIM-AGHD), a patient-reported outcome measure assessing growth hormone deficiency (GHD) impacts. The measure was demonstrated to have adequate psychometric measurement properties, and be reliable and valid. For scores to be interpretable, the TRIM-AGHD must be responsive to treatment benefit and the MID in scores quantified. METHODS: A prospective, non-interventional, observational, clinic-based survey study of naïve-to-treatment adult GHD patients (N = 98) was conducted. Key assessments were at baseline and follow-up (between 4 and approximately 8 weeks), with weekly telephone monitoring post-baseline (last n = 34 patients). Responsiveness was evaluated using the effect size of change scores from baseline to follow-up. MID estimates were derived from distribution-based (half standard deviation [0.5 SD], standard error of measurement [SEm]) and anchor-based methods (patient global rating of change [PGRC]) using change scores from baseline to initial report of minimal improvement in GHD severity. Findings from each method were converged to establish an acceptable MID. RESULTS: Patients were mean age 49.7 years, 65.6% female, and 76.0% Caucasian. The TRIM-AGHD was highly responsive to treatment with the total score effect size being 1.38. For the total score, the 0.5 SD was 8.09 and the SEm was 2.66. The difference found using the PGRC was 20.43. The converged MID value for the total score was 10 points. CONCLUSIONS: The TRIM-AGHD is a highly responsive measure assessing AGHD treatment impacts. A 10-point change score is considered a clinically meaningful improvement.

A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving Basal Insulin.

INTRODUCTION: Once-weekly semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is currently available as 1.0 mg and 0.5 mg dose for the treatment of type 2 diabetes (T2D). Currently, no head-to-head trial investigating once-weekly semaglutide as an add-on to basal insulin vs other GLP-1 receptor agonists (GLP-1 RAs) is available. The aim of this study was to conduct a network meta-analysis (NMA) to assess the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin. METHODS: A systematic literature review was performed to identify all trials of GLP-1 RAs as an add-on to basal insulin in patients with T2D. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in an NMA), including the change from baseline in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure, and the incidence of nausea, vomiting, and diarrhea. Data were synthesized using a NMA and a Bayesian framework. RESULTS: In total, eight studies were included across the base-case analyses. The results demonstrate that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c (- 0.88% to - 1.39% vs comparators) and weight (- 1.49 to - 4.69 kg vs comparators) and similar odds of experiencing nausea, vomiting, or diarrhea vs all GLP-1 RA comparators. Once-weekly semaglutide 1.0 mg was also equally effective at reducing systolic blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg significantly reduced HbA1c vs the majority of other GLP-1 RAs, except liraglutide 1.8 mg QD. The odds of experiencing nausea were significantly lower with once-weekly semaglutide 0.5 mg compared with all GLP-1 RA comparators. CONCLUSION: Once-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the most efficacious GLP-1 RA for reducing HbA1c and weight from baseline after 6 months of treatment. The efficacy of once-weekly semaglutide is not associated with a significant increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs. FUNDING: Novo Nordisk.

A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving 1-2 Oral Anti-Diabetic Drugs.

INTRODUCTION: Once-weekly semaglutide is a new glucagon-like peptide-1 (GLP-1) analogue administered at a 1.0 or 0.5 mg dose. As head-to-head trials assessing once-weekly semaglutide as an add-on to 1-2 oral anti-diabetic drugs (OADs) vs other GLP-1 receptor agonists (GLP-1 RAs) are limited, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of once-weekly semaglutide vs GLP-1 RAs in patients with type 2 diabetes (T2D) inadequately controlled on 1-2 OADs. METHODS: A systematic literature review (SLR) was conducted in order to identify trials of GLP-1 RAs in patients inadequately controlled on 1-2 OADs. Data at 24 ± 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in a NMA), which included the key outcomes of change from baseline in glycated hemoglobin (HbA1c), systolic blood pressure (SBP), and weight, as well as discontinuation due to adverse events (AEs). Data were synthesized using a NMA and a Bayesian framework. RESULTS: In total, 26 studies were included across the base case analyses. Once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c and weight vs all GLP-1 RA comparators. Once-weekly semaglutide 0.5 mg also achieved significantly greater reductions in HbA1c and weight compared with the majority of other GLP-1 RAs. Both doses of once-weekly semaglutide were associated with similar odds of discontinuation due to AEs compared with other GLP-1 RAs. CONCLUSION: Overall, once-weekly semaglutide 1.0 mg as an add-on to 1-2 OADs is the most efficacious GLP-1 RA in terms of the reduction of HbA1c and weight from baseline after 6 months of treatment. In addition, the analysis suggests that once-weekly semaglutide is well tolerated and not associated with an increase in discontinuations due to AEs compared with other GLP-1 RAs. FUNDING: Novo Nordisk.

Cost of Achieving HbA1c Treatment Targets and Weight Loss Responses with Once-Weekly Semaglutide Versus Dulaglutide in the United States.

INTRODUCTION: The National Health and Nutrition Examination Surveys show that many people with type 2 diabetes (T2D) in the USA fail to achieve recommended treatment targets. In the SUSTAIN 7 randomized controlled trial, once-weekly semaglutide (0.5 and 1.0 mg) was superior to comparative doses of dulaglutide (0.75 and 1.5 mg) in reducing glycated hemoglobin (HbA1c) and body weight in people with T2D. The present study estimated the cost per patient achieving HbA1c treatment targets and weight loss responses with once-weekly semaglutide and dulaglutide in the USA. METHODS: Numbers needed to treat and annual cost per patient achieving HbA1c targets (including a triple composite endpoint of HbA1c < 7% without hypoglycemia and no weight gain) or weight loss responses were calculated on the basis of data from SUSTAIN 7 and the annual cost of treatment from a US healthcare payer perspective. RESULTS: More patients reached HbA1c targets with once-weekly semaglutide than with dulaglutide, and once-weekly semaglutide showed lower costs of control for all modeled endpoints. The cost per patient achieving the triple composite endpoint was USD 11,916 with once-weekly semaglutide 1.0 mg and USD 15,204 with dulaglutide 1.5 mg, representing a 28% larger cost with dulaglutide 1.5 mg. The cost of reaching the target was 68% larger with dulaglutide 0.75 mg versus once-weekly semaglutide 0.5 mg. For each patient achieving an HbA1c < 7%, the cost would be 18% larger with dulaglutide 1.5 mg than with once-weekly semaglutide 1.0 mg. CONCLUSIONS: The cost of bringing one patient to the triple composite endpoint of an HbA1c < 7% without hypoglycemia and no weight gain would be 28% and 68% higher with dulaglutide 1.5 mg relative to once-weekly semaglutide 1.0 mg and dulaglutide 0.75 mg relative to once-weekly semaglutide 0.5 mg, respectively. Once-weekly semaglutide therefore provides better value for money than dulaglutide for the treatment of people with T2D in the USA. FUNDING: Novo Nordisk A/S.

Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis.

OBJECTIVE: Treatment intensification with additional anti-diabetic agents is recommended in type 2 diabetes (T2D) for patients inadequately controlled on metformin monotherapy. The present network meta-analysis (NMA) evaluated comparative efficacy and safety of once-weekly semaglutide and sodium-glucose co-transporter 2 inhibitors (SGLT-2is) in T2D patients inadequately controlled with metformin. METHODS: Randomized controlled trials with ≥20 weeks duration were searched in EMBASE, MEDLINE, and CENTRAL. Primary efficacy outcomes were: change from baseline in HbA1c, weight, systolic blood pressure (SBP), post-prandial blood glucose (PPG), and fasting blood glucose (FPG). Treatment effects at 26 (±4) weeks were compared using Bayesian NMAs. Meta-regression and sensitivity analysis were used to address the trial heterogeneity. RESULTS: Eight trials were found eligible for this NMA. Statistically significant reductions in HbA1c were observed with both 1.0 mg and 0.5 mg doses of once-weekly semaglutide when compared to SGLT-2is. The mean differences in change from baseline in HbA1c for once-weekly semaglutide 1.0 mg vs SGLT-2is ranged from -0.66% for canagliflozin 300 mg (95% Credible Intervals [CrI]: -0.82, -0.50%) to -1.11% for dapagliflozin 5 mg (95% CrI: -1.37, -0.85%). Once-weekly semaglutide 1.0 mg performed significantly better than all SGLT-2is of interest in reducing weight and improving FPG levels: however, SBP reduction was not statistically differentiable. Results of sensitivity analysis and meta-regressions aligned with base-case results. NMAs were not possible for PPG and safety outcomes, due to lack of data. CONCLUSION: Once-weekly semaglutide treatment is significantly better compared to SGLT-2is in achieving adequate glycemic control in T2D patients inadequately controlled with metformin monotherapy.

The relationship between target joints and direct resource use in severe haemophilia.

OBJECTIVES: Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. METHODS: Data on haemophilia patients without inhibitors was drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. RESULTS: Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1-10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). CONCLUSIONS: Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients.

Cost-Effectiveness of rFVIIa versus pd-aPCC in the Management of Mild to Moderate Bleeds in Pediatric Patients with Hemophilia A with Inhibitors in Mexico.

OBJECTIVE: To compare the costs and clinical consequences of treating mild-to-moderate joint bleeds with recombinant activated factor VII (rFVIIa) versus plasma-derived activated prothrombin complex concentrate (pd-aPCC) in pediatric patients with hemophilia A with inhibitors in Mexico. METHODS: A cost-effectiveness model was developed using TreeAge Pro v14.2.2 software (licensed in the USA) and adapted from a previously published model, with adjustments to reflect local clinical practice. Expert opinion was sought regarding patients' clinical management and resource utilization in Mexico to ensure that the current model was appropriate and relevant. The model compared rFVIIa and pd-aPCC for the treatment of mild-to-moderate joint bleeds in children <14 years old (assumed average weight: 30 kg). The analysis outcome was incremental cost per resolved mild-to-moderate joint bleed. One-way sensitivity analysis and probabilistic sensitivity analysis were used to assess specific assumptions and to address any uncertainty in the model. RESULTS: The cost of treating mild-to-moderate joint bleeds was lower for rFVIIa versus pd-aPCC after 7 days (MX$105,581 vs. MX$132,024), assuming complete bleed resolution. After 48 hours, rFVIIa was associated with an 8% improvement in bleed resolution versus pd-aPCC, resulting in cost savings of MX$16,754. Probabilistic sensitivity analysis indicated that rFVIIa treatment was more cost-effective than pd-aPCC in 67% (at 7 days) and 72% (at 48 hours) of Monte Carlo simulations. CONCLUSION: Accounting for model uncertainty, rFVIIa provided cost savings over pd-aPCC for the Mexican public health care payer in the management of mild-to-moderate joint bleeds in pediatric hemophilia A with inhibitors.

Understanding Treatment Burden for Children Treated for Growth Hormone Deficiency.

OBJECTIVE: Growth hormone deficiency (GHD) treatment for children requires growth hormone injections, typically administered daily until the child reaches adult height. Child GHD treatment burden is not well understood and no disease-specific measures exist to assess this burden. The purpose of the study was to explore GHD treatment burden for children and their parents by conducting concept elicitation interviews supporting a theoretical model of the impact of GHD treatment. METHODS: Four focus groups (in Germany) and 52 telephone interviews (in the UK and USA) were conducted with children/adolescents with GHD aged 8 to <13 years and parents of children with GHD aged ≥4 to <13 years. The purpose of the interviews was to understand the experience of GHD treatment from the child's perspective, and for parents, the impact of their child's treatment on themselves. Interview transcripts were analyzed thematically based on modified grounded theory principles. RESULTS: Interviews with 70 respondents who produced descriptions (n = 73) of patients experiences with GHD treatment (three parents spoke for two children each) were conducted. Analysis identified three major areas of GHD treatment burden for children: physical; emotional well-being; and interference. Parent burdens identified were: emotional well-being and interference. Modifiers such as treatment efficacy and duration, which may impact the degree of treatment burden severity, were identified. CONCLUSIONS: Overall treatment burden of child GHD is considerable for children and their parents. The concept elicitation and theoretical model can be used to develop a disease-specific outcome measure, which adequately reflects the burden of GHD treatment for children and their parents.