Placebo-controlled crossover assessment of mecasermin for the treatment of Rett syndrome.

Objective: To measure the efficacy of mecasermin (recombinant human insulin-like growth factor 1, rhIGF-1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double-blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF-1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28-week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory- and electroencephalography (EEG)-based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation: As in the phase 1 trial, rhIGF-1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.

Non-invasive assessment of muscle injury in healthy and dystrophic animals with electrical impedance myography.

INTRODUCTION: Dystrophic muscle is particularly susceptible to eccentric contraction-induced injury. We tested the hypothesis that electrical impedance myography (EIM) can detect injury induced by maximal-force lengthening contractions. METHODS: We induced injury in the quadriceps of wild-type (WT) and dystrophic (mdx) mice with eccentric contractions using an established model. RESULTS: mdx quadriceps had significantly greater losses in peak twitch and tetany compared with losses in WT quadriceps. Injured muscle showed a significant increase in EIM characteristic frequency in both WT (177 ± 7.7%) and mdx (167 ± 7.8%) quadriceps. EIM also revealed decreased extracellular resistance for both WT and mdx quadriceps after injury. DISCUSSION: Our results show overall agreement between muscle function and EIM measurements of injured muscle, indicating that EIM is a viable tool to assess injury in dystrophic muscle. Muscle Nerve 56: E85-E94, 2017.

Electrical impedance myography for assessment of Duchenne muscular dystrophy.

OBJECTIVE: Sensitive, objective, and easily applied methods for evaluating disease progression and response to therapy are needed for clinical trials in Duchenne muscular dystrophy (DMD). In this study, we evaluated whether electrical impedance myography (EIM) could serve this purpose. METHODS: In this nonblinded study, 36 boys with DMD and 29 age-similar healthy boys underwent multifrequency EIM measurements for up to 2 years on 6 muscles unilaterally along with functional assessments. A linear mixed-effects model with random intercept and slope terms was used for the analysis of multifrequency EIM values and functional measures. Seven DMD boys were initiated on corticosteroids; these data were analyzed using a piecewise linear mixed-effects model. RESULTS: In boys > 7.0 years old, a significant difference in the slope of EIM phase ratio trajectories in the upper extremity was observed by 6 months of -0.074/month, p = 0.023, 95% confidence interval (CI) = -0.013, -0.14; at 2 years, this difference was -0.048/month, p < 0.0001, 95% CI = -0.028, -0.068. In boys ≤ 7.0 years old, differences appeared at 6 months in gastrocnemius (EIM phase slope = -0.83 °/kHz/mo, p = 0.007, 95% CI = -0.26, -1.40). EIM outcomes showed significant differences earlier than functional tests. Initiation of corticosteroids significantly improved the slope of EIM phase ratio (0.057/mo, p = 0.00019, 95% CI = 0.028, 0.086) and EIM phase slope (0.14 °/kHz/mo, p = 0.013, 95% CI = 0.028, 0.25), consistent with corticosteroids' known clinical benefit. INTERPRETATION: EIM detects deterioration in muscles of both younger and older boys by 6 months; it also identifies the therapeutic effect of corticosteroid initiation. Because EIM is rapid to apply, painless, and requires minimal operator training, the technique deserves to be further evaluated as a biomarker in DMD clinical therapeutic trials. Ann Neurol 2017;81:622-632.

Effect of Angiofibromas on Quality of Life and Access to Care in Tuberous Sclerosis Patients and Their Caregivers.

BACKGROUND/OBJECTIVES: Facial angiofibromas (AF) have the potential to cause disfigurement in children with tuberous sclerosis complex (TSC). Facial disfigurement can impact the quality of life (QoL) of individuals and their families, leading to negative psychosocial outcomes. QoL has not been studied in TSC patients with AF. METHODS: We conducted a cross-sectional survey study to investigate QoL of TSC patients with AF and their caregivers and to explore the current state of access to treatment for AF. TSC patients and caregivers in TSC clinic at Boston Children's Hospital and through the Tuberous Sclerosis Alliance were recruited to complete QoL surveys including the CADIS, CDLQI, and Skindex-teen questionnaires, and a survey on access to treatment of AF. RESULTS: Fifty-eight patients with TSC and 161 caregivers participated in the study. Caregivers of patients with AF had significantly poorer QoL scores compared to caregivers of those without AF, as measured by a modified CADIS questionnaire (mean 31.7 vs. 11.7, p = 0.004). Among patients with AF, those who received treatment had significantly better QoL scores compared with those without treatment, as measured by the CDLQI (mean 3.8 vs. 9.5, p = 0.001). Forty-one and two-tenths percent of subjects reported never receiving treatment for AF. Forty-seven and three-tenths percent of subjects were prescribed topical rapamycin, 47.7% of whom experienced difficulty with insurance coverage. CONCLUSIONS: Presence and lack of treatment of AF significantly impacts QoL in TSC patients and their caregivers. Access to care for AF is limited by multiple factors and should be addressed by clinicians working with this patient population.

Cost and Utility Analysis of a Store-and-Forward Teledermatology Referral System: A Randomized Clinical Trial.

IMPORTANCE: The costs and utility of teledermatology are important features of implementation. Such an analysis requires a description of the perspective of the entity that will bear the cost. OBJECTIVE: To assess the costs and utility of a store-and-forward teledermatology referral process compared with a conventional referral process from the perspectives of the Department of Veterans Affairs (VA) and society. DESIGN, SETTING, AND PARTICIPANTS: Three hundred ninety-one randomized participants were referred from remote sites of primary care to the dermatology services of 2 VA medical facilities for ambulatory skin conditions from December 2008 through June 2010, and follow-up was completed in March 2011. The time trade-off utility measures and costs were collected during a 9-month period among participants in a 2-site parallel group randomized clinical trial. The perspectives of the VA and society were evaluated. The multiple imputation procedure or weighted means were used for missing data elements. Data were analyzed from January to July 2014. INTERVENTIONS: Referrals were managed using store-and-forward teledermatology or a conventional text-based referral process. MAIN OUTCOMES AND MEASURES: Total costs from the perspectives of the VA and society incurred during the 9-month follow-up were used to derive per-participant costs. Utility, using the time trade-off method, was the measure of effectiveness. RESULTS: From the VA perspective, the total cost for conventional referrals was $66 145 (minimum, $58 697; maximum, $71 635), or $338 (SD, $291) per participant (196 participants); the total cost for teledermatology referrals was $59 917 (mimimum, $51 794; maximum, $70 398), or $308 (SD, $298) per participant (195 participants). The $30 difference in per-participant cost was not statistically significant (95% CI, -$79 to $20). From the societal perspective, the total cost for conventional referrals was $106 194 (minimum, $98 746; maximum, $111 684), or $542 (SD, $403) per participant (196 participants); the total cost for teledermatology referrals was $89 523 (minimum, $81 400; maximum, $100 400) or $460 (SD, $428) per participant. This $82 difference in per-participant cost was statistically significant (95% CI, -$12 to -$152). From baseline to the 9-month follow-up, the time trade-off utility value improved by 0.02 in the conventional referral group and 0.03 in the teledermatology group. This difference was not statistically significant (P = .50). CONCLUSIONS AND RELEVANCE: Compared with conventional referrals, store-and-forward teledermatology referrals were performed at a comparable cost (VA perspective) or at a lower cost (societal perspective) with no evidence of a difference in utility as measured by the time trade-off method. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00488293.

Bayesian mixed-effects location and scale models for multivariate longitudinal outcomes: an application to ecological momentary assessment data.

In the statistical literature, the methods to understand the relationship of explanatory variables on each individual outcome variable are well developed and widely applied. However, in most health-related studies given the technological advancement and sophisticated methods of obtaining and storing data, a need to perform joint analysis of multivariate outcomes while explaining the impact of predictors simultaneously and accounting for all the correlations is in high demand. In this manuscript, we propose a generalized approach within a Bayesian framework that models the changes in the variation in terms of explanatory variables and captures the correlations between the multivariate continuous outcomes by the inclusion of random effects at both the location and scale levels. We describe the use of a spherical transformation for the correlations between the random location and scale effects in order to apply separation strategy for prior elicitation while ensuring positive semi-definiteness of the covariance matrix. We present the details of our approach using an example from an ecological momentary assessment study on adolescents.

Composite biomarkers for assessing Duchenne muscular dystrophy: an initial assessment.

BACKGROUND: Compared with individual parameters, composite biomarkers may provide a more effective means for monitoring disease progression and the effects of therapy in clinical trials than single measures. In this study, we built composite biomarkers for use in Duchenne muscular dystrophy by combining values from two objective measures of disease severity: electrical impedance myography and quantitative ultrasound and evaluating how well they correlated to standard functional measures. METHODS: Using data from an ongoing study of electrical impedance myography and quantitative ultrasound in 31 Duchenne muscular dystrophy and 26 healthy boys aged 2-14 years, we combined data sets by first creating z scores based on the normal subject data and then using simple mathematical operations (addition and multiplication) to create composite measures. These composite scores were then correlated to age and standard measures of function including the 6-minute walk test, the North Star Ambulatory Assessment, and handheld dynamometry. RESULTS: Combining data sets resulted in stronger correlations with all four outcomes than for either electrical impedance myography or quantitative ultrasound alone in six of eight instances. These improvements reached statistical significance (P < 0.05) in several cases. For example, the correlation coefficient for the composite measure with the North Star Ambulatory Assessment was 0.79 but was only 0.66 and 0.67 (respectively) for gray scale level and electrical impedance myography separately. CONCLUSIONS: Arithmetically derived composite scores can provide stronger correlations to functional measures than isolated biomarkers. Longitudinal study of such composite markers in Duchenne muscular dystrophy clinical trials is warranted.

Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 µg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.