Patient engagement in clinical trial design for rare neuromuscular disorders: impact on the DELIVER and ACHIEVE clinical trials.

BACKGROUND: Engaging individuals living with disease in drug development and regulatory processes leads to more thoughtful and sensitive trial designs, drives more informative and meaningful outcomes from clinical studies, and builds trust between the public, government, and industry stakeholders. This engagement is especially important in the case of rare diseases, where affected individuals and their families face many difficulties getting information, treatment, and support. Dyne Therapeutics is developing therapeutics for people with genetically-driven muscle diseases. During the development of potential treatments for Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1), Dyne sought the opinions of individuals living with these diseases to inform its clinical trial design and to decrease the difficulties that participants and families might experience participating in them. METHODS: Dyne engaged individuals and families living with DMD and DM1 as expert partners in its clinical development programs. Dyne convened panels of affected individuals and care partners/parents of individuals living with DMD (n = 8) or DM1 (n = 18). Workshops focused on how affected individuals and their families evaluate and select clinical trials for participation, the importance, quality, and burden associated with individual trial design elements, participation considerations such as site location and the study visit design, patient privacy, the suitability and scope of travel and participant support programs, and the accessibility of content in the informed consent (or assent) forms. Dyne also engaged the DMD Community Advisory Board (CAB) to collect feedback and advice on designing optimal and meaningful clinical trials and measuring relevant outcomes. RESULTS: The issues most important to individuals living with DM1 and DMD regarding clinical trials were the ability to participate/access to the trial, perceptions of benefit and risk of trials and potential treatments, the flexibility of participation, clear communication from the sponsor, availability of information from trusted sources, and patient enrollment. In response to the patient advisory workshops and CAB feedback, Dyne refined clinical trial inclusion/exclusion criteria and clinic visit design, developed a travel service program to address the burden of clinical trial travel and enable long-distance and cross-border participation, planned for home visits when feasible, and allowed for adequate rest before clinic visit initiation and between assessments. Additionally, Dyne developed and implemented a transparent and consistent communications plan (including age-appropriate content) for trial participants and community members, and assessed and adjusted procedures to provide maximum participant comfort and lower anxiety, particularly with younger participants. CONCLUSIONS: Ongoing communication with the Duchenne CAB and with DMD and DM1 patient advisory committee members allows Dyne to stay current with disease community perspectives and feedback on the needs and preferences of those affected and has provided valuable insights into the participant experience thereby helping Dyne initiate clinical trials that better meet the needs of affected individuals and their families.

WHY IS THIS IMPORTANT?: Including the viewpoint of people living with chronic diseases when developing new therapeutics helps address their specific needs and improve their quality of life. This is very important for rare diseases, where individuals and their families face many challenges getting information, treatment, and support. WHAT DID WE DO?: Dyne Therapeutics, a company focused on developing potential medicines for rare muscle diseases, actively involved individuals living with Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1) in their drug development process. Dyne organized workshops for individuals and families living with DMD and DM1 and participated in community advisory boards to gather input from patient advocacy organization leaders. HOW DID THIS HELP?: Partnering with individuals and families living with DMD and DM1 helped Dyne improve clinical trial design and reduce the difficulties affected individuals and their families face when participating in these trials. This valuable feedback has allowed Dyne to design clinical trials to better address the needs of those living with DMD and DM1.

A Combined Prospective and Retrospective Comparison of Long-Term Functional Outcomes Suggests Delayed Loss of Ambulation and Pulmonary Decline with Long-Term Eteplirsen Treatment.

BACKGROUND: Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care. OBJECTIVE: To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls. METHODS: Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures. RESULTS: Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: -3.3 vs. -6.0 percentage points annually, p < 0.0001). CONCLUSIONS: Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls.

Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial.

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients versus -181.4 m for external controls (P = 0.067), and loss of ambulation occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial.

Importance: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). Objective: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. Design, Setting, and Participants: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). Interventions: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Main Outcomes and Measures: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Results: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. Conclusions and Relevance: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03375164.

Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia.

Healthcare utilization and costs in patients beginning pharmacotherapy for generalized anxiety disorder: a retrospective cohort study.

BACKGROUND: Patterns of healthcare utilization and costs in patients beginning pharmacotherapy for generalized anxiety disorder (GAD) have not been well characterized. METHODS: Using a large US health insurance database, we identified all patients with evidence of GAD (ICD-9-CM diagnosis code 300.02) who initiated pharmacotherapy with medications commonly used to treat GAD (eg, selective serotonin reuptake inhibitors [SSRIs], venlafaxine, benzodiazepines) between 1/1/2003 and 12/31/2007. We examined healthcare utilization and costs over the 12-month periods preceding and following date of initial receipt of such therapy ("pretreatment" and "follow-up", respectively). Patients with incomplete data were excluded. RESULTS: A total of 10,275 patients met all study inclusion criteria. Forty-eight percent of patients received SSRIs; 34%, benzodiazepines; and 6%, venlafaxine. SSRIs and venlafaxine were about three times more likely to be used on a long-term basis (> 90 days) than benzodiazepines (p < 0.01). In general, levels of healthcare utilization were higher during follow-up than pretreatment. Mean (SD) total healthcare costs increased from $4812 ($10,006) during pretreatment to $7182 ($22,041) during follow-up (p < 0.01); costs of GAD-related pharmacotherapy during follow-up were $420 ($485). CONCLUSIONS: More than one-half of patients initiating pharmacotherapy for GAD receive either SSRIs or venlafaxine. Levels of healthcare utilization and costs are greater in the year following initiation of therapy than in the immediately preceding one.

Management of generalized anxiety disorder in primary care: identifying the challenges and unmet needs.

BACKGROUND: Generalized anxiety disorder (GAD) is one of the most common psychiatric disorders in primary care, although it is often underrecognized and undertreated. GAD is chronic, disabling, and associated with other health problems. Treatment response is often unsatisfactory, but the clinical evidence base for new treatments has expanded substantially in the past decade and suggests a growing range of options for reducing the burden of GAD. The objective of this article was to review current literature on GAD and its management to provide an overview of the clinical importance of GAD in primary care and available treatments. DATA SOURCES: Recent studies (ie, over the past decade) on the epidemiology and treatment of GAD were identified by searching Medline using the term generalized anxiety disorder only and in combination with the terms epidemiology and treatment and for each drug class (benzodiazepines, azapirones, antidepressants, antihistamines, alpha-2-delta ligands, and antipsychotics) and for named drugs (buspirone, venlafaxine, duloxetine, fluoxetine, escitalopram, olanzapine, paroxetine, pregabalin, quetiapine, and risperidone in addition to psychological therapies and cognitive-behavioral therapy. The literature search was conducted in August 2008 for the period 1987-2009. STUDY SELECTION: Studies were included if judged to be relevant to a review of the epidemiology and management of GAD. Articles were excluded if they were not written in English or were published more than 10 years before the literature search was conducted. A few older studies were included for which more recent research evidence was not available. Recent national and international guidelines for the management of GAD were also reviewed. DATA EXTRACTION/SYNTHESIS: Most currently available interventions have similar overall efficacy, and treatment choices should reflect the situation of individual patients. Important unmet needs exist for treatments (1) that work rapidly, with (2) broad spectrum benefits, (3) that can improve rates of remission and well-being, (4) are devoid of risk for withdrawal symptoms, and (5) have few if any adverse interactions with other drugs. Additional needs include (6) safer drugs for the elderly, (7) safe and effective drugs for children with GAD, (8) further evaluation of psychotherapy, and (9) understanding the appropriate circumstances for, and optimal choices of, drug combination. CONCLUSION: While the development of novel treatments evolves, current management approaches can focus on improving identification and defining optimal use of available therapies for GAD.

Measurement of non-restorative sleep in insomnia: A review of the literature.

OBJECTIVE: Non-restorative sleep (NRS) is a core symptom of insomnia, typically defined as a subjective feeling of being unrefreshed upon awakening. NRS symptoms have been less consistently studied than other symptoms of insomnia, and there is no consensus regarding measurement of NRS. Given its subjective nature, patient-reported outcome (PRO) instruments are important for evaluating NRS symptom severity and treatment-related changes. The objective of this literature review was to identify PROs used in insomnia populations that purport to measure NRS, and to evaluate their psychometric characteristics. METHODS: A comprehensive review of PRO instruments used in insomnia was conducted; instruments were reviewed for NRS content by two independent reviewers; a total of 26 instruments identified to contain NRS content were retained for further review. RESULTS: Of the 26 instruments reviewed, 23 contained at least one item evaluating subjective nighttime aspects of NRS; 17 contained at least one item evaluating daytime aspects of NRS. Only the Sleep Assessment Questionnaire contained a specific NRS domain score. However, little published evidence was available regarding measurement properties of the NRS domain in insomnia populations. CONCLUSIONS: There is currently no reliable and well-validated PRO instrument available for specifically evaluating NRS symptom severity and response to interventions in insomnia populations. Reliable and valid measurement tools are needed to measure the symptom of NRS in insomnia.

Progression of visual loss and time between initial assessment and treatment of wet age-related macular degeneration.

PURPOSE: To determine whether the time elapsed from initial (referral) diagnosis of neovascular (wet) age-related macular degeneration (AMD) to assessment and treatment by a retinal specialist is associated with visual deterioration in the intervening period. METHODS: A prospective pilot study of 38 consecutive AMD patients who presented with newly diagnosed subfoveal choroidal neovascularization was conducted in a tertiary care retinal practice. All eligible subjects underwent clinical examination and digital fluorescein angiography at the time of assessment by a retinal specialist. Correlations were performed to assess the association between continuous independent variables and any visual deterioration since initial diagnosis. Multivariate linear regression models with stepwise techniques were used to evaluate any association between visual progression and time elapsed, while controlling for potential clinical covariates. RESULTS: Of the 38 patients, 32 (84%) met the inclusion and exclusion criteria; no differences in important variables were noted between those included and those excluded. The median time between initial diagnosis and referral assessment and treatment was 28 days (interquartile range=36.5 days); some degree of visual loss developed in 14 (44%) of the subjects. The elapsed time was correlated with progression of visual loss (r=0.50, p=0.003). Multivariate linear regression demonstrated that only time elapsed and lesion type based on fluorescein angiography were associated with progression of visual loss (R2=0.491, F(4,28)=6.744, p=0.001); lesion size, age and sex were not significantly associated with progression of visual loss. INTERPRETATION: Delay in assessment and treatment of new-onset wet AMD by a retinal specialist is associated with a higher risk of visual loss.