Abstract
Tuberous sclerosis complex (TSC) is a rare genetic disease associated with significant disease burden and considerable impact on health-related quality of life (HRQL). Currently no disease-specific clinical outcome assessments evaluate HRQL in individuals with TSC. A multi-center phase III study EXIST-3 (NCT01713946) assessed the efficacy and safety of two trough exposure ranges (Low exposure, LE: 3–7 ng/mL and high exposure, HE: 9–15 ng/mL) of adjunctive everolimus in patients aged 2–65 years with TSC and refractory partial-onset seizures (N = 366). Three age-specific HRQL measures were included as secondary endpoints including: quality of life in childhood epilepsy (QOLCE; caregiver-report for aged 2- < 11), the Quality of Life in Epilepsy Inventory for Adolescents-48 (QOLIE-AD-48; self-report, aged ≥ 11- < 18), and the Quality of Life in Epilepsy Inventory-31-Problems (QOLIE-31-P; self-report, aged ≥ 18). Intellectual ability was evaluated using the Wechsler Non-Verbal (WNV) Scale of Ability. Post hoc analyses were performed on the core phase primary data from EXIST-3 to evaluate the psychometric properties of the HRQL measures and calculate meaningful change estimates. Results showed that a significant subset of the trial sample (4–21 year olds) scored in the intellectual disability range, as assessed by the WNV. Psychometric analyses of the three epilepsy measures (including reliability, validity, and ability to detect change) supported the appropriateness for use in TSC. Distribution-based meaningful change estimates were generated for each HRQL measure, with estimates for the QOLIE-31-P total score largely consistent with the published literature. To our knowledge, this is the first evaluation using clinical trial data to establish the psychometric properties of the QOLCE, QOLIE-AD-48, and QOLIE-31-P for use in individuals with TSC. These findings increase confidence in the measures as valid and reliable for use in clinical trials and future research in patients with TSC.
Highlights
Tuberous sclerosis complex (TSC) is a rare genetic disease which causes benign tumors in many different organs (Henske et al, 2016)
Generating evidence of the psychometric properties of a clinical outcome assessments (COAs) measure in the relevant patient population is critical for acceptance by stakeholders, and may identify unique psychometric characteristics of importance for clinical practice or research in the specific rare disease (European Medicines Agency, 2005). This is the first evaluation using clinical trial data to establish the psychometric properties of the Quality of Life in Childhood Epilepsy (QOLCE), QOLIE-AD-48, and QOLIE-31-P for use in individuals with TSC
Our analysis demonstrated that a significant subset of the trial sample (4–21 year olds) scored in the intellectual disability range, as assessed by the Wechsler Non-Verbal (WNV), an observation consistent with the wide distribution of intellectual ability in individuals with TSC (Curatolo et al, 2015; de Vries et al, 2015; Leclezio and de Vries, 2016)
Summary
Tuberous sclerosis complex (TSC) is a rare genetic disease which causes benign tumors in many different organs (Henske et al, 2016). The disease burden associated with TSC is well-documented (Curatolo et al, 2015; de Vries et al, 2015; Leclezio and de Vries, 2016), there are currently no disease-specific clinical outcome assessments (COAs) that assess HRQL in individuals with TSC. This is most likely due to the relative rarity of the condition with a birth incidence around 1 in 6,000 live births (Osborne et al, 1991). In line with recommendations from the International Society For Pharmacoeconomics and Outcomes Research (ISPOR) Good Practices Task Force and European Organization for Rare Disorders (EURORDIS), existing item banks or COA measures on the target population or similar populations are considered a “practical solution given the obstacles associated with the development of a de novo COA for use in Rare Disease populations” (European Organisation for Rare Disorders, 2011; Benjamin et al, 2017)
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