Development and Economic Evaluation of a Patient-Centered Care Model for Children With Duchenne Muscular Dystrophy: Protocol for a Quasi-Experimental Study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare progressive muscular disease that primarily affects boys. A lack of comprehensive care for patients living with DMD is directly associated with a compromised quality of life (QoL) for those affected and their caregivers. This disease also has a huge economic impact on families as its treatment requires substantial direct, indirect, and informal care costs. OBJECTIVE: This study presents a protocol developed to evaluate the feasibility and efficacy of a patient-centered care (PCC) model for children with DMD. The care model was designed with the aim to empower families, improve QoL, and reduce economic burden on their families. METHODS: This study is planned as a quasi-experimental study that will enroll 70 consecutive families with boys (aged 5-15 years) with DMD visiting a tertiary care center. The study is being conducted in 2 phases (preintervention and postintervention phases, referred to as phase 1 and phase 2, respectively). During phase 1, the patients received routine care. The study is now in phase 2, with the intervention currently being administered. The intervention is based on the PCC model individualized by the intervention team. The model has a comprehensive DMD telecare component that includes teleconsultation as one of its key components to reduce in-person physician visits at the health facility. Teleconsultation is especially beneficial for late-ambulatory and nonambulatory patients. Data on economic burden are being collected for out-of-pocket expenses for both phases during in-person visits via telephone or messaging apps on a monthly basis. QoL data for patients and their primary caregivers are being collected at 3 time points (ie, time of enrollment, end of phase 1, and end of phase 2). Outcome measures are being assessed as changes in economic burden on families and changes in QoL scores. RESULTS: Participant recruitment began in July 2021. The study is ongoing and expected to be completed by March 2023. The findings based on baseline data are expected to be submitted for publication in 2023. CONCLUSIONS: This paper outlines a research proposal developed to study the impact of a PCC model for patients with DMD in low- and middle-income countries (LMICs). This study is expected to provide evidence of whether a multicomponent, patient-centric intervention could reduce economic burdens on families and improve their QoL. The results of this study could guide policy makers and health professionals in India and other LMICs to facilitate a comprehensive care program for patients living with DMD. The economic impact of a rare disease is an important consideration to formulate or evaluate any health policy or intervention related to new treatments and financial support schemes. TRIAL REGISTRATION: Clinical Trials Registry India (ICMR-NIMS) CTRI/2021/06/034274; https://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=56650. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/42491.

Deflazacort dose optimization and safety evaluation in Duchenne muscular dystrophy (DOSE): A randomized, double-blind non-inferiority trial.

BACKGROUND: US food and drug administration has recently approved deflazacort for Duchenne muscular dystrophy (DMD) and recommended the dosage of 0.9 mg/kg/d for patients aged ≥5years. However, data assessing the minimal efficacious dose and need of dose-titration based on age or disease severity is limited. OBJECTIVE: To determine whether deflazacort 0.45 mg/kg/d (proposed lower dosage) is non-inferior to 0.9 mg/kg/d among newly diagnosed patients with DMD. METHOD: A double-blinded, non-inferiority, randomized trial, conducted between December 2018 and July 2020. Newly diagnosed patient aged 5-15 years with genetic or muscle biopsy confirmed DMD and baseline 6-min walk distance (6MWD) > 150 m were screened. Patients were randomly assigned (1:1), stratified to prespecified subgroups by age (≤7years and >7years), and baseline 6MWD (≤350 m and >350 m), to receive either 0.45 mg/kg/d or 0.9 mg/kg/d regimens. The primary endpoint was the change in 6MWD, from baseline to week-24 of intervention. The trial was powered with a predefined, non-inferiority margin of 30 m. The analyses were by modified intention-to-treat (mITT). RESULT: A total of 97 patients were enrolled, 40 receiving 0.45 mg/kg/d and 45 receiving 0.9 mg/kg/d deflazacort comprised of mITT population. For primary endpoint analysis the mean (SD) change in 6MWD from baseline to week-24 was 9.7 m (41.5) in deflazacort 0.45 mg/kg/d, and 34.7 m (43.5) for 0.9 mg/kg/d. The mean difference in change in 6MWD across the group was 24.8 m (95% CI 6.7 to 43, p value 0.008). The mean difference in change in 6MWD in the subgroups of boys ≤7 years of age was 21.8 m (95% CI -0.82, 44.5, p = 0.059), with baseline 6MWD of >350 m was 19.9 m (95% CI -2.4, 42.4; p = 0.08). The incidence of combined moderate to severe treatment-related adverse events was significant in the 0.9 mg/kg/d group by week 24 (odds ratio 0.36 [95% CI, 0.14 to 0.89], p = 0.03). DISCUSSION: The efficacy of proposed low dose deflazacort in comparison to the standard dose did not meet the prespecified criteria for non-inferiority. The low dose deflazacort was non-inferior in subgroup of patients with age ≤7 years and baseline 6MWD of >350 m. TRIAL REGISTRATION: Clinical Trial Registry-India Identifier: CTRI/2019/02/017388.

Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study.

OBJECTIVES: Boys with Duchenne Muscular Dystrophy (DMD) are at increased risk for compromised bone health, manifesting as low-impact trauma long bone fractures and vertebral compression fractures. METHODS: In a prospective observational study, we studied bone health parameters in North Indian boys with DMD. We consecutively enrolled ambulatory boys with DMD on glucocorticoid therapy. Bone health was evaluated with X-ray spine, Dual-energy X-ray absorptiometry (DXA), serum calcium, vitamin D3 (25[OH]D), 1,25-dihyroxyvitamin D3 (1,25[OH]2D3), serum osteocalcin, osteopontin, and N terminal telopeptide of type 1 collagen (Ntx) levels. RESULTS: A total of 76 boys with DMD were enrolled. The median age was 8.5 (interquartile range [IQR] 7.04-10.77) years. Among these, seven (9.2%) boys had long bone fractures, and four (5.3%) had vertebral compression fractures. Fifty-four (71%) boys underwent DXA scan, and among these 31 (57%) had low bone mineral density (BMD, ≤-2 z-score) at the lumbar spine. The mean BMD z-score at the lumbar spine was -2.3 (95% confidence interval [CI] = -1.8, -2.8), and at the femoral neck was -2.5 (95% CI = -2, -2.9). 25(OH)D levels were deficient in 68 (89.5%, n=76) boys, and 1,25(OH)2D3 levels were deficient in all. Mean serum osteocalcin levels were 0.68 ± 0.38 ng/mL (n=54), serum osteopontin levels were 8.6 ± 4.6 pg/mL (n=54) and serum Ntx levels were 891 ± 476 nmol/L (n=54). Boys with low BMD received glucocorticoids for longer duration, in comparison to those with normal BMD (median, IQR [16.9 (6-34) months vs. 7.8 (4.8-13.4) months]; p=0.04). CONCLUSIONS: Bone health is compromised in North Indian boys with DMD. BMD at the lumbar spine is reduced in more than half of boys with DMD and nearly all had vitamin D deficiency on regular vitamin D supplements. Longer duration of glucocorticoid therapy is a risk factor for low BMD in our cohort.

The Expanding Spectrum of Dystrophinopathies: HyperCKemia to Manifest Female Carriers.

Background: X-linked dystrophinopathies have a wide spectrum of manifestation. The most common forms are severe Duchenne muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD). However, less common manifestations are isolated cardiomyopathy, myalgia, cramps, rhabdomyolysis, hyperCKemia, and manifest female carriers. Materials and Methods: This case series is a part of an ongoing long-term prospective cohort of children with DMD and BMD from the year 2013. The clinical details are maintained in the clinic files and standard management protocols are followed. For this case series, clinical details were collected from the clinic files and recorded on a case record proforma. Details of cardiology, radiology, and genetic investigations were collected. Results: We report cases of classical DMD, BMD, manifest female carrier with proximal pelvic girdle weakness, a female carrier with isolated dilated cardiomyopathy, and infantile-onset asymptomatic hyperCKemia. We also report less common but notable clinical presentations of DMD, autism, intellectual disability, epilepsy, and asymptomatic transaminitis. Conclusions: It is important for clinicians to be aware of these less common clinical presentations for prompt diagnosis, and to avoid unnecessary investigations. Here, we report the clinical spectrum of dystrophinopathies seen in pediatric neuromuscular clinic and emphasize the variability and expanding knowledge about different manifestations of dystrophinopathies.

Comparative performance of verbal autopsy methods in identifying causes of adult mortality: A case study in India.

Background & objectives: Cause of death assignment from verbal autopsy (VA) questionnaires is conventionally accomplished through physician review. However, since recently, computer softwares have been developed to assign the cause of death. The present study evaluated the performance of computer software in assigning the cause of death from the VA, as compared to physician review. Methods: VA of 600 adult deaths was conducted using open- and close-ended questionnaires in Nandpur Kalour Block of Punjab, India. Entire VA forms were used by two physicians independently to assign the cause of death using the International Statistical Classification of Diseases and Related Health Problems (ICD)-10 codes. In case of disagreement between them, reconciliation was done, and in cases of persistent disagreements finally, adjudication was done by a third physician. InterVA-4-generated causes from close-ended questionnaires were compared using Kappa statistics with causes assigned by physicians using a questionnaire having both open- and close-ended questions. At the population level, Cause-Specific Mortality Fraction (CSMF) accuracy and P-value from McNemar's paired Chi-square were calculated. CSMF accuracy indicates the absolute deviation of a set of proportions of causes of death out of the total number of deaths between the two methods. Results: The overall agreement between InterVA-4 and physician coding was 'fair' (κ=0.42; 95% confidence interval 0.38, 0.46). CSMF accuracy was found to be 0.71. The differences in proportions from the two methods were statistically different as per McNemar's paired Chi-square test for ischaemic heart diseases, liver cirrhosis and maternal deaths. Interpretation & conclusions: In comparison to physicians, assignment of causes of death by InterVA- 4 was only 'fair'. Hence, it may be appropriate to continue with physician review as the optimal option available in the current scenario.

Social autopsy for identifying causes of adult mortality.

Verbal autopsy methods have been developed to determine medical causes of deathforprioritizing disease control programs. Additional information on social causesmay facilitate designing of more appropriate prevention strategies. Use of social autopsy in investigations of causes of adult deaths has been limited. Therefore, acommunity-based study was conducted in NandpurKalour Block of Fatehgarh Sahib District in Punjab (India)for finding social causes of adult deaths. An integrated verbal and social autopsy toolwas developed and verbal autopsies of 600 adult deaths, occurring over a reference period of one year, were conducted in 2014. Quantitative analysis described the socio-demographic characteristics of the deceased, number and type of consultations from health care providers, and type of care received during illness. Qualitative data was analyzed to find out social causes of death by thematic analysis. The median duration of illness from symptom onset till death was 9 days (IQR = 1-45 days). At the onset of illness, 72 (12%) deceased utilized home remedies and 424 (70.7%)received care from a clinic/hospital, and 104 (17.3%) died withoutreceiving any care. The number of medical consultations varied from one to six (median = 2). The utilization of government health facilities and qualified allopathic doctor increased with each consultation (p value<0.05). The top five social causes of adult deaths in a rural area of Punjab in India. (1) Non availability of medical practitioner in the vicinity, (2) communication gaps between doctor and patient on regular intake of medication, (3) delayed referral by service provider, (4) poor communication with family on illness, and (5) perception of illness to be 'mild' by the family or care taker. To conclude, social autopsy tool should be integrated with verbal autopsy tool for identification of individual, community, and health system level factors associated with adult mortality.