Development of a novel observer-reported outcome measure for the assessment of Respiratory Syncytial Virus (RSV) infection symptoms in pediatric clinical trials

Abstract

BackgroundRespiratory syncytial virus (RSV) is a seasonal infection affecting most children by 2 years of age and the leading cause of lower respiratory tract infection requiring hospitalization in infants. Novel antiviral medications are in development to improve the clinical outcomes of RSV; however, no clinical outcome assessments (COAs) for RSV have been developed in alignment with the United States Food and Drug Administration patient-reported outcome guidance to assist in the evaluation of new therapies. To address this need, an observer-reported outcome (ObsRO) measure designed to assess observable RSV symptoms was created.MethodsThe literature was reviewed to evaluate existing COAs and identify constructs of interest. Individual caregiver interviews elicited concepts that informed item development, and candidate items were subsequently evaluated in two rounds of cognitive testing. Separate cohorts of caregivers of RSV-infected nonhospitalized and hospitalized infants participated. Therapeutic-area experts provided input throughout the instrument development process.ResultsCaregivers of 39 children < 24 months old with RSV (31 nonhospitalized, 8 hospitalized) participated in in-depth, individual interviews during concept elicitation and cognitive debriefing, resulting in 21 concepts identified as potentially observable and relevant to young children with RSV. The item pool was reduced to 12 cardinal symptoms and behavior impacts reported to be directly observable by caregivers, with 10 daytime and 9 nighttime symptoms to capture diurnal variation in severity.ConclusionsThe RSV Caregiver Diary assesses RSV symptom severity and change from the parent or caregiver perspective in a standardized manner to measure treatment benefit. Following psychometric evaluation and refinement, this tool is expected to be suitable for assisting in the clinical development of RSV therapeutics.Electronic supplementary materialThe online version of this article (10.1186/s41687-018-0034-9) contains supplementary material, which is available to authorized users.

Patient-reported outcome measures for paediatric acute lower respiratory infection studies

“…The majority of identified studies were conducted after 2000 (n=15, 83.3%), including 10 studies (66.6%) published in the last 4 years. 10 were undertaken in Europe [ 14 , 15 , 18 , 19 , 25 – 27 ], two in Asia [ 16 , 20 ] and four in North America [ 7 , 11 , 13 , 17 ]. Two were conducted in more than one country [ 12 , 21 ].…”

“…Children's age groups were well represented: 11 studies were conducted in children 0–14 months old; 11 articles in children 15–59 months old; and nine articles in children aged 60–216 months old ( supplementary material 2 ). Studies were conducted in children with a broad spectrum of ALRIs, ranging from RSV-associated bronchiolitis (n=5) [ 13 , 17 , 18 , 20 , 21 ], influenza (n=6) [ 11 , 12 , 14 , 15 , 25 , 27 ], bronchitis (n=1) [ 23 ], community-acquired pneumonia (n=2) [ 24 , 26 ], ALRI (n=1) [ 19 ] and unspecified respiratory infections (n=4) [ 7 , 16 , 22 ].…”

“…The CARIFS was the most frequently used disease-specific PROM (n=5 studies) [7,11,12,15,16] and the EQ-5D-Y was the most frequently used generic PROM (n=2 studies) [14,15]. Three validated PROMs were applied in settings in which their use had been validated, including the CARIFS, the GRCD and the EQ-5D-Y [7,11,[13][14][15][16][17]. Six validated PROMs were used in settings in which they had not been validated.…”

“…Test-retest reliability was assessed via kappa coefficients and intraclass correlation coefficients were computed using the subset of patients assumed to be stable from day 13 ("test") to day 14 ("retest") because caregivers responded the same on the PGIC on both days. Item-level test-retest reliabilities range in strength from poor (overnight fever kappa =−0.00, daytime activity level kappa=−0.02) to perfect agreement (daytime fever kappa=1.00), with 17 Both PROMs established adequate content validity through development utilising literature review and subsequent paediatrician and caregiver focus groups for item generation and reduction. Significant discriminant validity was found for the CARIFS in terms of distinguishing children who were likely to require further healthcare visits (including to their general practitioner or to the hospital) subsequent to their initial presentation [7].…”

Infant with Clefts Observation Outcomes Instrument (iCOO): A New Outcome for Infants and Young Children with Orofacial Clefts

“…Our findings echo other recent studies in which ObsROs for assessing child health have been tested. Williams et al, found that caregivers were able to reliably report signs of respiratory syncytial virus infection and that reports generally had acceptable construct validity and were responsive to change (Lewis et al, 2017; Williams et al, 2017). Similarly, Edwards et al (2018) found that caregivers of young children (ages 0-6 years) with cystic fibrosis could reliably report respiratory signs that discriminated between well and sick periods.…”