Assessing physical symptoms, daily functioning, and well-being in children with achondroplasia.

This study's purpose was to provide qualitative evidence to support the development of two observer-reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty-six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM-Symptom and ACEM-Impact. ACEM-Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM-Impact consisted of 31 major impacts in the domains of daily functioning, emotional well-being, social well-being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation-ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia.

Assessing the impacts of having a child with achondroplasia on parent well-being.

PURPOSE: This study's purpose was to develop a better understanding of the experiences of parents of children with achondroplasia and to provide qualitative evidence to support the development of a patient-reported outcome (PRO) measure of parent impacts. METHODS: Concept elicitation (CE) individual/focus group interviews were conducted with parents of children aged 2 to < 12 years with achondroplasia in the United States and Spain. The qualitative analysis informed the PRO measure development. Cognitive debriefing (CD) interviews were conducted to ensure parent understanding and item relevance. RESULTS: Thirty-six parents participated in individual/focus group CE interviews. The analysis identified parent impacts in four domains, including caretaking responsibilities, emotional well-being, family, and work, and results informed the development of the Achondroplasia Parent Experience Measure (APEM). Caretaking responsibilities included managing child's medical care (92%), helping child with self-care (67%), advocating for child (64%), assisting child (56%), and observing/monitoring child (e.g., to ensure safety; 47%). Impacts on parents' emotional well-being included worry about the future (75%), worry about child's physical health (67%), safety concerns (50%), feeling stressed/overwhelmed (44%), and worry about child's social relationships (42%). Impacts on family and work included family strain (56%), limiting/adapting family activities (42%), and missed work time (50%). CD interviews with an additional 16 parents of children with achondroplasia confirmed understanding and item relevance. CONCLUSION: The results improve our understanding of the experiences of parents of children with achondroplasia and provide qualitative evidence to support the content validity of the APEM. A psychometric study is needed to validate the measure.

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.

Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of BHT-3009 in relapsing-remitting multiple sclerosis (MS) and to confirm that BHT-3009 causes immune tolerance. METHODS: BHT-3009 is a tolerizing DNA vaccine for MS, encoding full-length human myelin basic protein. Relapsing-remitting MS patients were randomized 1:1:1 into three groups: placebo, 0.5 mg BHT-3009, or 1.5 mg BHT-3009, given intramuscularly at weeks 0, 2, 4, and every 4 weeks thereafter until week 44. The primary end point was the 4-week rate of occurrence of new gadolinium-enhancing lesions on brain magnetic resonance images from weeks 28 to 48. Protein microarrays were used to measure levels of anti-myelin autoantibodies. RESULTS: Compared with placebo, in the 267 patient analysis population the median 4-week rate of new enhancing lesions during weeks 28 to 48 was 50% lower with 0.5 mg BHT-3009 (p = 0.07) and during weeks 8 to 48 was 61% lower with 0.5 mg BHT-3009 (p = 0.05). The mean volume of enhancing lesions at week 48 was 51% lower on 0.5 mg BHT-3009 compared with placebo (p = 0.02). No significant improvement in magnetic resonance imaging lesion parameters was observed with 1.5 mg BHT-3009. Dramatic reductions in 23 myelin-specific autoantibodies in the 0.5 mg BHT-3009 arm were observed, but not with placebo or 1.5 mg BHT-3009. CONCLUSIONS: In relapsing-remitting MS patients, treatment with the lower dose (0.5 mg) of BHT-3009 for 44 weeks nearly attained the primary end point for reduction of the rate of new enhancing magnetic resonance imaging lesions (p = 0.07) and achieved several secondary end points including a reduction of the rate of enhancing magnetic resonance imaging lesions from weeks 8 to 48 (p = 0.05). Immunological data in a preselected subgroup of patients also indicated that treatment with 0.5 mg induced antigen-specific immune tolerance. The greater dose was ineffective.

Induction of antigen-specific tolerance in multiple sclerosis after immunization with DNA encoding myelin basic protein in a randomized, placebo-controlled phase 1/2 trial.

OBJECTIVE: To assess safety and immune modulation by BHT-3009, a tolerizing DNA vaccine encoding full-length human myelin basic protein, in patients with multiple sclerosis (MS). DESIGN: The study was a randomized, double-blind, placebo-controlled trial. Subjects receiving placebo were crossed over into an active arm after treatment unblinding. SETTING: The trial was conducted at 4 academic institutions within North America. Patients Thirty patients with relapsing-remitting or secondary progressive MS who were not taking any other disease-modifying drugs were enrolled in the trial. Further, the patients were required to have either 1 to 5 gadolinium-enhancing lesions on screening brain magnetic resonance imaging (MRI), a relapse in the previous 2 years, or disease worsening in the previous 2 years. INTERVENTIONS: BHT-3009 was administered as intramuscular injections at weeks 1, 3, 5, and 9 after randomization into the trial, with or without 80 mg of daily oral atorvastatin calcium in combination. Three dose levels of BHT-3009 were tested (0.5 mg, 1.5 mg, and 3 mg). MAIN OUTCOME MEASURES: The primary outcome measures were safety and tolerability of BHT-3009. Secondary outcome measures included the number and volume of gadolinium-enhanced lesions on MRI, relapses, and analysis of antigen-specific immune responses. RESULTS: BHT-3009 was safe and well tolerated, provided favorable trends on brain MRI, and produced beneficial antigen-specific immune changes. These immune changes consisted of a marked decrease in proliferation of interferon-gamma-producing, myelin-reactive CD4+ T cells from peripheral blood and a reduction in titers of myelin-specific autoantibodies from cerebral spinal fluid as assessed by protein microarrays. We did not observe a substantial benefit of the atorvastatin combination compared with BHT-3009 alone. CONCLUSION: In patients with MS, BHT-3009 is safe and induces antigen-specific immune tolerance with concordant reduction of inflammatory lesions on brain MRI.