Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

Development of the pyruvate kinase deficiency diary and pyruvate kinase deficiency impact assessment: Disease-specific assessments.

INTRODUCTION: Currently recommended patient-reported outcome (PRO) measures for patients with pyruvate kinase (PK) deficiency are non-disease-specific. The PK Deficiency Diary (PKDD) and PK Deficiency Impact Assessment (PKDIA) were developed to be more targeted measures for capturing the symptoms and impacts of interest to this patient population. METHODS: The instruments were developed based on concept elicitation interviews with 21 adults and modified based on 20 cognitive interviews. The domain structure and item concepts of the PKDD and PKDIA were compared with currently recommended measures, the EORTC QLQ-C30 and the SF-36v2®. RESULTS: The PKDD is a seven-item measure of the core signs and symptoms of PK deficiency. The PKDIA is a 14-item measure of the impacts of PK deficiency on patients' health-related quality of life (HRQoL). Minimal similarities were found between the new measures and the EORTC QLQ-C30 (eg, 43% of concepts were similar to the PKDD; 42% were similar to the PKDIA) and SF-36v2® (57% of concepts were similar to the PKDD; 17% were similar to the PKDIA). CONCLUSIONS: The PKDD and PKDIA fill a gap in the existing outcomes measurement strategy for PK deficiency. Future work includes psychometric evaluation of these newly developed measures.

Assessment of Patients with Neuromyelitis Optica Spectrum Disorder Using the EQ-5D.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by unpredictable attacks of the optic nerves and spinal cord that cause neurologic deficits, including weakness, numbness, bowel/bladder dysfunction, and pain and reduced vision and can ultimately lead to blindness and paralysis. We assessed the effects of NMOSD on quality of life. METHODS: Adult patients with NMOSD treated at a US academic neurology clinic completed the EQ-5D and several other measures of functional status and quality of life. The EQ-5D scores and correlations across measures were evaluated, and scores were compared with those of patients with multiple sclerosis and US norms. RESULTS: Twenty-one patients (90% women; mean age, 42.8 years; mean disease duration, 8.2 years) were included. The mean EQ-5D score was 0.74. Most patients reported at least some problems with mobility, pain/discomfort, usual activities, and/or anxiety/depression. Greater proportions of patients reported moderate or severe problems with mobility and pain/discomfort than they did with self-care, usual activities, or anxiety/depression. In a multivariate model, only the Brief Pain Inventory was a significant independent predictor of overall EQ-5D score. CONCLUSIONS: Neuromyelitis optica spectrum disorder has a substantial effect on multiple domains of quality of life. Pain seems to be among the primary drivers of the EQ-5D scores in NMOSD.

Cardiometabolic risk and health care utilization and cost for Hispanic and non-Hispanic women.

Cardiometabolic risk (CMR) is a specific set of risk factors that are associated with an increased chance of developing diabetes and cardiovascular disease. We conducted a retrospective study of female members of a health maintenance organization in the southwestern United States to: determine the prevalence of CMR for 4 different groupings of CMR factors, identify differences between Hispanics and non-Hispanics, and quantify differences in 2-year health care utilization and costs of CMR. Subjects were females who had bone mineral density tests during 2003-2004, and thus a measure of height and weight, allowing body mass index (BMI) calculation (n = 2578; 27.6% Hispanic). Risk factors used to define CMR groupings were: obesity (BMI), triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, and fasting glucose. Results showed that Hispanics had higher prevalence rates than non-Hispanics (65.8% versus 52.3%, respectively; P < 0.0001). Adjusting for age and ethnicity, total costs for CMR patients in the groupings that required the presence of diabetes were twice the costs of those without CMR (approximately $11,500 versus $5500, respectively; P < 0.0001). In all other groupings, costs for patients with and without CMR were approximately $7000 versus $5500, respectively (P < 0.0001). Non-Hispanics had significantly higher visit costs than Hispanics. There were no differences in pharmacy costs. Higher utilization and costs associated with CMR suggest the need to identify and monitor patients with CMR. Our findings suggest diabetes prevention could yield substantial cost savings. Higher costs for non-Hispanics, despite higher prevalence among Hispanics, may indicate underutilization of health care resources by Hispanics. Future research in CMR should explore ethnic differences in access to care and disease management programs.

Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States.

BACKGROUND: The US Advisory Committee on Immunization Practices (ACIP) recently expanded the influenza vaccine recommendation to include children 24-59 months of age. In a large head-to-head randomized controlled trial, live attenuated influenza vaccine, trivalent (LAIV) demonstrated a 54% relative reduction in culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) among children aged 24-59 months. OBJECTIVE: To evaluate the relative cost and benefit between two influenza vaccines (LAIV and TIV) for healthy children 24-59 months of age. METHODS: Using patient-level data from the clinical trial supplemented with cost data from published literature, we modeled the cost-effectiveness of these two vaccines. Effectiveness was measured in quality-adjusted life years (QALY) and cases of influenza avoided. The analysis used the societal perspective. RESULTS: Due to its higher acquisition cost, LAIV increased vaccination costs by USD7.72 per child compared with TIV. However, compared with TIV, LAIV reduced the number of influenza illness cases and lowered the subsequent healthcare use of children and productivity losses of parents. The estimated offsets in direct and indirect costs saved USD15.80 and USD37.72 per vaccinated child, respectively. LAIV had a net total cost savings of USD45.80 per child relative to TIV. One-way and probabilistic sensitivity analyses indicated that the model was robust across a wide range of relative vaccine efficacy and cost estimates. CONCLUSIONS: Due to its increased relative vaccine efficacy over TIV, LAIV reduced the burden of influenza and lowered both direct health care and societal costs among children 24-59 months of age.

Cost of illness of hyponatremia in the United States.

BACKGROUND: Hyponatremia is a disorder of fluid and electrolyte balance characterized by a relative excess of body water relative to body sodium content. It is the most common electrolyte disorder encountered in clinical medicine and is associated with negative outcomes in many chronic diseases. However, there is limited information in the literature about health care resource use and costs attributable to the effects of the condition. The purpose of this analysis was to estimate the annual cost of illness of hyponatremia in the United States. METHODS: The study utilized a prevalence-based cost of illness framework that incorporated data from publicly available databases, published literature and a consensus panel of expert physicians. Panel members provided information on: classification of hyponatremia patients, treatment settings for hyponatremia (i.e., hospital, emergency room, doctor's office), and health care resource use associated with the diagnosis and treatment of hyponatremia. Low and high prevalence scenarios were estimated and utilized in a spreadsheet-based cost of illness model. Costs were assigned to units of resources and summarized across treatment settings. RESULTS: The prevalence estimate for hyponatremia ranged from 3.2 million to 6.1 million persons in the U.S. on an annual basis. Approximately 1% of patients were classified as having acute and symptomatic hyponatremia, 4% acute and asymptomatic, 15%-20% chronic and symptomatic, and 75-80% chronic and asymptomatic. Of patients treated for hyponatremia, 55%-63% are initially treated as inpatients, 25% are initially treated in the emergency room, and 13%-20% are treated solely in the office setting. The direct costs of treating hyponatremia in the U.S. on an annual basis were estimated to range between $1.6 billion and $3.6 billion. CONCLUSION: Treatment of hyponatremia represents a significant healthcare burden in the U.S. Newer therapies that may reduce the burden of hyponatremia in the inpatient setting could minimize the costs associated with this condition.

Cost effectiveness of cardiac resynchronization therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.

OBJECTIVES: The analysis goal was to estimate incremental cost-effectiveness ratios (ICERs) for the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial patients who received cardiac resynchronization therapy (CRT) via pacemaker (CRT-P) or pacemaker-defibrillator (CRT-D) in combination with optimal pharmacological therapy (OPT) relative to patients with OPT alone. BACKGROUND: In the COMPANION trial, CRT-P and CRT-D reduced the combined risk of all-cause mortality or first hospitalization among patients with advanced heart failure and intraventricular conduction delays, but the cost effectiveness of the therapy remains unknown. METHODS: In this analysis, intent-to-treat trial data were modeled to estimate the cost effectiveness of CRT-D and CRT-P relative to OPT over a base-case seven-year treatment episode. Exponential survival curves were derived from trial data and adjusted by quality-of-life trial results to yield quality-adjusted life-years (QALYs). For the first two years, follow-up hospitalizations were based on trial data. The model assumed equalized hospitalization rates beyond two years. Initial implantation and follow-up hospitalization costs were estimated using Medicare data. RESULTS: Over two years, follow-up hospitalization costs were reduced by 29% for CRT-D and 37% for CRT-P. Extending the cost-effectiveness analysis to a seven-year base-case time period, the ICER for CRT-P was 19,600 dollars per QALY and the ICER for CRT-D was 43,000 dollars per QALY relative to OPT. CONCLUSIONS: For the COMPANION trial patients, the use of CRT-P and CRT-D was associated with a cost-effectiveness ratio below generally accepted benchmarks for therapeutic interventions of 50,000 dollars per QALY to 100,000 dollars per QALY. This suggests that the clinical benefits of CRT-P and CRT-D can be achieved at a reasonable cost.