Impact of the COVID-19 Pandemic on a Clinical Trial: A Quantitative Report on Study Engagement and Strategies.

INTRODUCTION: The COVID-19 pandemic impacted clinical research worldwide potentially altering research findings. The study purpose was to measure the effect of the pandemic on recruitment, retention, assessment, and intervention completion rates. METHODS: Enrollment and participation data from a clinical trial evaluating efficacy of a physical therapy intervention for high-risk preterm infants were compared across 3 pandemic periods (February 2019 through November 2021). RESULTS: Recruitment, retention, assessment, and intervention completion rates were lowest during the peak pandemic period. CONCLUSIONS: In compliance with the Human Subjects Review Board, and for the participants' and staff safety, transition from in-person to telehealth or hybrid visits was required to continue this longitudinal study. Despite the negative effect of the pandemic, parental resilience and commitment to the study was clear. Flexibility, quick action, dedication, and efficiency of the research team were key elements enabling study continuation with successful transition to telehealth assessments/interventions during the peak pandemic period.

Long-Term Treatment of Tamoxifen and Raloxifene Alleviates Dystrophic Phenotype and Enhances Muscle Functions of FKRP Dystroglycanopathy.

The third most common form of limb-girdle muscular dystrophies is caused by mutations of the Fukutin-related protein (FKRP) gene, with no effective therapy available. Selective estrogen receptor modulators, tamoxifen and raloxifene, have been widely used for human conditions for their anti-inflammatory, antifibrosis, prevention of bone loss, and muscle building effects (essential features for muscular dystrophy therapies). We evaluated therapeutic values of tamoxifen and raloxifene in FKRPP448L mutant mouse with severe dystrophic phenotype. The mice were treated with the drugs for 1 year through daily gavage. We demonstrate that tamoxifen and raloxifene significantly ameliorated the disease progression. The improvement includes increase in grip force production, extended running time and distance in treadmill test, and enhancement in cardiac and respiratory functions. Significant reduction in muscle pathology includes diminished fibrosis and fiber degeneration. Tamoxifen and raloxifene also significantly mitigated bone loss. Tamoxifen, but not raloxifene, caused severe adverse effects on male reproductive organs. The results demonstrate that tamoxifen and raloxifene hold significant potential for treating FKRP-related muscular dystrophy and probably other muscular dystrophies. Sex-related differential effects of the drugs call for a careful consideration for the drug and dosage selection in male and female patient populations.

Glucocorticoid Steroid and Alendronate Treatment Alleviates Dystrophic Phenotype with Enhanced Functional Glycosylation of α-Dystroglycan in Mouse Model of Limb-Girdle Muscular Dystrophy with FKRPP448L Mutation.

Fukutin-related protein-muscular dystrophy is characterized by defects in glycosylation of α-dystroglycan with variable clinical phenotypes, most commonly as limb-girdle muscular dystrophy 2I. There is no effective therapy available. Glucocorticoid steroids have become the standard treatment for Duchenne and other muscular dystrophies with serious adverse effects, including excessive weight gain, immune suppression, and bone loss. Bisphosphonates have been used to treat Duchenne muscular dystrophy for prevention of osteoporosis. Herein, we evaluated prednisolone and alendronate for their therapeutic potential in the FKRPP448L-mutant mouse representing moderate limb-girdle muscular dystrophy 2I. Mice were treated with prednisolone, alendronate, and both in combination for up to 6 months. Prednisolone improved muscle pathology with significant reduction in muscle degeneration, but had no effect on serum creatine kinase levels and muscle strength. Alendronate treatment did not ameliorate muscle degeneration, but demonstrated a limited enhancement on muscle function test. Combined treatment of prednisolone and alendronate provided best improvement in muscle pathology with normalized fiber size distribution and significantly reduced serum creatine kinase levels, but had limited effect on muscle force generation. The use of alendronate significantly mitigated the bone loss. Prednisolone alone and in combination with alendronate enhance functionally glycosylated α-dystroglycan. These results, for the first time, demonstrate the efficacy and feasibility of this alliance treatment of the two drugs for fukutin-related protein-muscular dystrophy.

Safety and efficacy of viltolarsen in ambulatory and nonambulatory males with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by mutations in the dystrophin gene, causing motor and pulmonary function decline. Viltolarsen is indicated for patients with dystrophin gene mutations amenable to exon 53 skipping. Here, we report safety, motor function, and the first pulmonary function results from the open-label, phase II Galactic53 trial of viltolarsen (NCT04956289). Male participants aged ≥ 8 years with DMD received 80 mg/kg intravenous viltolarsen once weekly for 48 weeks. Results from participants receiving viltolarsen were compared with an external control cohort group-matched for multiple variables. All treatment-emergent adverse events were mild or moderate, 4 were considered treatment-related, and no participants discontinued. Participants receiving viltolarsen experienced clinically meaningful benefits in pulmonary function with higher percent predicted forced vital capacity and higher peak cough flow at Week 49 compared with the control cohort for both ambulatory and nonambulatory participants. Viltolarsen also stabilized upper limb motor function over the Treatment Period. These results support viltolarsen as an important part of the treatment armamentarium for both ambulatory as well as nonambulatory patients with DMD.

Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of > 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). OBJECTIVE: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. METHODS: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to < 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. RESULTS: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. CONCLUSIONS: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.

Factors Influencing Receipt and Type of Therapy Services in the NICU.

Understanding the type and frequency of current neonatal intensive care unit (NICU) therapy services and predictors of referral for therapy services is a crucial first step to supporting positive long-term outcomes in very preterm infants. This study enrolled 83 very preterm infants (<32 weeks, gestational age mean 26.5 ± 2.0 weeks; 38 male) from a longitudinal clinical trial. Race, neonatal medical index, neuroimaging, and frequency of therapy sessions were extracted from medical records. The Test of Infant Motor Performance and the General Movement Assessment were administered. Average weekly sessions of occupational therapy, physical therapy, and speech therapy were significantly different by type, but the magnitude and direction of the difference depended upon the discharge week. Infants at high risk for cerebral palsy based on their baseline General Movements Assessment scores received more therapy sessions than infants at low risk for cerebral palsy. Baseline General Movements Assessment was related to the mean number of occupational therapy sessions but not physical therapy or speech therapy sessions. Neonatal Medical Index scores and Test of Infant Motor Performance scores were not predictive of combined therapy services. Medical and developmental risk factors, as well as outcomes from therapy assessments, should be the basis for referral for therapy services in the neonatal intensive care unit.

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused by mutations in the DMD gene resulting in an absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes in viltolarsen treated patients were compared to a matched historical control group. OBJECTIVE: To evaluate long-term efficacy and safety of the anti-sense oligonucleotide viltolarsen in the treatment of patients with DMD amenable to exon 53 skipping therapy. METHODS: This trial (NCT03167255) is the extension of a previously published 24-week trial in North America (NCT02740972) that examined dystrophin levels, timed function tests compared to a matched historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study, CINRG DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53 skipping who were treated with viltolarsen. Both groups were treated with glucocorticoids. All 16 participants elected to enroll in this long-term trial (up to 192 weeks) to continue evaluation of motor function and safety. RESULTS: Time to stand from supine and time to run/walk 10 meters showed stabilization from baseline through week 109 for viltolarsen-treated participants whereas the historical control group showed decline (statistically significant differences for multiple timepoints). Safety was similar to that observed in the previous 24-week trial, which was predominantly mild. There have been no treatment-related serious adverse events and no discontinuations. CONCLUSIONS: Based on these results at over 2 years, viltolarsen can be a new treatment option for patients with DMD amenable to exon 53 skipping.

Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life. Objective: To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD). Design, Setting, and Participants: Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids. Interventions: The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day. Main Outcomes and Measures: Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)-challenge test. Results: Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo -0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, -1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency. Conclusions and Relevance: In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03439670.

Longitudinal Changes in the Sensorimotor Pathways of Very Preterm Infants During the First Year of Life With and Without Intervention: A Pilot Study.

Objective: Evaluate longitudinal changes in brain microstructure and volumes in very preterm infants during the first year of life with and without intervention.Design: Descriptive pilot study.Methods: Five preterm infants in a three-arm clinical trial, one SPEEDI Early, two SPEEDI Late, and two usual care. Brain structural and diffusion MRI's were acquired within 72 hours after neonatal intensive care unit discharge (n = 5), three months post-baseline (n = 5), and six months post-baseline (n = 3). Fractional anisotropy (FA), Mean diffusivity (MD), and volume metrics were computed for five brain regions.Results: More than 60% of eligible participants completed 100% of the scheduled MRIs. FA and volume increased from baseline to six months across all brain regions. Rate of white matter volume change from baseline to six months was highest in SPEEDI Early.Conclusions: Non-sedated longitudinal MRI is feasible in very preterm infants and appears to demonstrate longitudinal changes in brain structure and connectivity.

Efficacy of Supporting Play Exploration and Early Development Intervention in the First Months of Life for Infants Born Very Preterm: 3-Arm Randomized Clinical Trial Protocol.

OBJECTIVE: The aim of this project is to study the effect of a physical therapist intervention provided in the first months of life on developmental outcomes of infants born very preterm. Secondary aims are to investigate the impact of intervention timing on the efficacy and impact of the intervention on infants with and without cerebral palsy. METHODS: This study is a multisite longitudinal controlled trial comparing developmental outcomes from infants in the Supporting Play, Exploration, and Early Development Intervention (SPEEDI)_Late or SPEEDI_Early group to a usual care group. SETTINGS ARE URBAN: Urban and rural areas surrounding 2 academic medical centers. There will be 90 preterm infants enrolled in this study born at <29 weeks of gestation. SPEEDI is a developmental intervention provided by collaboration between a physical therapist and parent to support a child's motor and cognitive development. The primary outcome measure is the Bayley Scale of Infant and Toddler Development Cognitive and Gross Motor Scaled Scores. Secondary measures include behavioral coding of early problem solving skills, the Gross Motor Function Measure, and Test of Infant Motor Performance. IMPACT: More than 270,000 infants are born very preterm in the United States each year, 50% of whom will have neurological dysfunction that limits their ability to keep pace with peers who are typically developing. This study is a step toward understanding the impact that intensive developmental intervention could have in this population in the first months of life.

Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial.

Importance: An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease. Objective: To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping. Design, Setting, and Participants: This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019. Interventions: Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion. Main Outcomes and Measures: Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function. Results: Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit. Conclusions and Relevance: Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02740972.

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

BACKGROUND: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. RESULTS: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. CONCLUSIONS: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.