Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome

Participants were enrolled in two consecutive studies, the first of which was previously published [9]. In both studies, treatment with IGF-1 or placebo was divided into two Phases (1 and 2). Participants were randomly assigned to receive either IGF-1 or placebo for 12-weeks in Phase 1 and were then switched to the other treatment condition (Phase 2) after a four-week wash-out period. The second study was completed in September, 2016 and results are presented herein, along with results combining the two studies.

The first study screened and enrolled nine children with PMS (6 females and 3 males) aged 5 to 15 years old (mean = 8.6; SD = 4.0) [9]. This second study screened 11 children and enrolled 10,one dropped out during the screening procedures. Participants were between 5 and 9 years old (mean = 6.5; standard deviation = 1.4); 6 participants were male and 4 were female. Nine of 10 participants met criteria for ASD based on clinical consensus using the Autism Diagnostic Observation Schedule, Second Edition [13], the Autism Diagnostic Interview-Revised [14], and the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition [15].

Potential participants were excluded if any of the following were applicable: (1) closed epiphyses; (2) active or suspected neoplasia; (3) intracranial hypertension; (4) hepatic insufficiency; (5) renal insufficiency; (6) cardiomegaly/valvulopathy; (7) allergy to IGF-1; (8) patients with comorbid conditions deemed too medically compromised to participate.

IGF-1 is an aqueous solution for injection containing human insulin-like growth factor-1 (Increlex; Ipsen Biopharmaceuticals, Inc) produced by recombinant DNA technology. Placebo was normal saline prepared in identical bottles by the research pharmacy at the Icahn School of Medicine at Mount Sinai. Dose titration was initiated at 0.04 mg/kg twice daily by subcutaneous injection, and increased, as tolerated, every week by 0.04 mg/kg per dose to a maximum of 0.12 mg/kg twice daily. Medication was administered subcutaneously twice daily with meals and glucose monitoring was performed by parents prior to each injection and at bedtime.

Participants underwent comprehensive medical evaluations, including physical and neurological examination, routine hematology and blood chemistry, bone X-ray for bone age, electrocardiography, and echocardiography to determine eligibility for participation and repeated throughout the study to assess safety. Tolerability was monitored using a safety monitoring report form. Patients were monitored at weeks 2, 4, 6, 8, and 12 in both treatment phases. The most common side effects of IGF-1 are related to its insulin-like activity and hypoglycemic risks. Training was conducted with parents at baseline visits for drawing finger stick blood glucose levels and monitoring for signs and symptoms of hypoglycemia. Training in administering subcutaneous injections was also performed. Hypoglycemia was defined as glucose < 50 mg/dL.

The clinical outcome measures were administered at baseline and weeks 4, 8, and 12. Measures included the ABC [16], the Repetitive Behavior Scale—Revised (RBS-R; [17]), the Sensory Profile (SP; [18]), and the Clinical Global Impressions—Improvement and Severity Scales (CGI; [19]). Results from the SP and CGI were not previously reported in the first IGF-1 trial.

All statistical analyses were conducted in the statistical package R. Before testing for efficacy, we conducted analyses to test for potential bias in study design. We first performed a pre-test to check the assumption of negligible carryover effects between Phase 1 and Phase 2 of the crossover trial, as previously described [20], to ensure data collection was highly standardized across all patients and that the wash-out period was successful in removing significant carry-over effects. In brief, the sum of the values measured in the two phases was calculated for each subject and compared across the two sequence groups by means of a statistical test for independent samples. This trial used a randomized crossover design; thus, order (phase) of assessment is nested (repeated) within treatment and treatment is nested within subjects. Therefore, in terms of efficacy measurement, we applied a treatment × time interaction analysis using two-way repeated measures analysis of variance (ANOVA), which estimates the differential change in the two treatments on the outcome measures. We also specified an error term to account for individual variation. Subsequently, data derived from the first IGF-1 study (n = 9) [9], which was also a randomized crossover design, were assembled with the current study (n = 10) to generate a larger pooled data set (N = 19). Using this pooled data set, we applied the same treatment × time interaction analysis while controlling for baseline measurements and data set effects as covariates. Finally, because of the small sample size and to cast a wide net of informative treatment effects at threshold significance level, we applied an exploratory approach implementing a Mann–Whitney U-test on fold-changes observed at week 12 for each treatment group using the combined sample (N = 19).