This is a non-randomised, non-interventional, comparative, observational, hybrid prospective and retrospective, post-authorisation cohort study (a matched cohort design) of children with SCD from 9 months to under 2 years of age to assess the safety and effectiveness of Xromi®.
There will be 2 cohorts:
i) a Xromi® exposure cohort, identified prospectively;
and ii) a retrospective comparator cohort with children with SCD unexposed to any formulation of hydroxycarbamide at the index date, identified using data from the last 10 years up to the date Xromi® was first used in children under 2 years of age at the sites. Comparator participants will be matched to exposed participants following a 2:1 ratio (comparator:exposed) based on study site, age at initiation of Xromi® of the exposed participant, and β-globin genotype.
Matching ratio and factors will be reviewed and adjusted (e.g., matching at country level), considering feasibility. Information will be collected from chart review. The index date will be defined as: i) prospective exposure cohort: the date of confirmed initiation of Xromi® or, if unknown, the date of the first prescription of Xromi®; or as ii) retrospective comparator cohort: the date of the recorded visit when their age was closest to the age at index date of the matched exposed participant (i.e., the selected visit for matching).
All participants will be followed up for up to 24 months from their index date, regardless of changes in their treatment regimen. This includes participants in the prospective exposure cohort who discontinue Xromi® or switch to another formulation of hydroxycarbamide, as well as participants in the comparator cohort who initiate any formulation of hydroxycarbamide after their index date.
The inclusion period for the participants within the prospective exposure cohort will be from the date the site is given a site initiation greenlight until 2 years after the study start date. These participants will be identified prospectively, and the follow-up will be prospective.
This period may vary depending on the time needed to achieve the recruitment target. For the retrospective comparator cohort, the inclusion period will begin up to 10 years before the date of first administration of Xromi® to children under 2 years of age at each study site. It will continue until the date of first administration of Xromi® to children under 2 years of age at each study site or 2 years before the study start date, whichever occurs first.
These participants will be identified retrospectively, and the follow-up will be retrospective.
The research question is to evaluate the safety and effectiveness of hydroxycarbamide oral solution 100mg/ml (Xromi®) administered to children under 2 years of age for the prevention of complications of SCD.
Study Sites
The study will seek the participation of European specialist sites (Haemoglobinopathy Coordinating Centres). The study population will consist of children with SCD who meet all the inclusion criteria and none of the exclusion criteria.
Variables
Information on demographics, anthropometrics, and other medical history will be collected at baseline and during follow-up. Information to describe SCD will be collected at baseline (e.g. age at first SCD symptoms, β-globin genotype, history of SCD manifestations and hospitalisations). Data about SCD management, including previous and concomitant use of treatments, will be collected at baseline and during follow-up.
To assess safety of Xromi®, occurrence of AEs, including AESIs (e.g. myelosuppression), will be collected during follow-up. To assess effectiveness of Xromi®, occurrence of the clinical events of interest (e.g. painful vaso-occlusive events, dactylitis, splenomegaly, acute chest syndrome, hospitalisations, blood transfusions, cerebrovascular accident [stroke]) will be collected during follow-up, and results from laboratory tests and physiological assessments conducted will be collected at baseline and during follow-up.
Data Sources
The data will be collected by the investigational team in participating sites from clinical records. Data obtained as part of participants' routine clinical practice will be collected during clinic visits for prospective data and from chart review for retrospective data.
Sample sizes were estimated assuming that 60 participants will be recruited to the Xromi® cohort, and each exposed participant will be matched to 2 comparators. All calculations were conducted using 80% power and a two-sided type I error rate of 5%. For safety, the minimum detectable hazard ratio (HR) was estimated by assuming the log rank test as the basis of the comparison. As it is possible that not all participants will be followed up for the full 24-month period, the calculations were repeated for average follow-up durations of 18 months and 12 months. For effectiveness, a similar approach was used.
Data analysis This study will be mainly exploratory and there are no a priori hypotheses to test. It will use a comparative matched cohort design. Descriptive analyses will describe the study participants using summary statistics, tabulations, and descriptive figures.
The primary safety analysis will examine the occurrence of safety events of interest. For each AESI the number of events, person-years of exposure and number of participants experiencing an AESI will be reported
Study Population
The study aims to recruit at least 180 participants in total: 60 participants administered Xromi® and 120 comparator participants, during a 4-year study period. Initially, up to 10 sites in the UK and up to 5 sites in Germany are planned to be invited to participate in the study. The inclusion of other potential European countries and sites will be assessed if needed.
Prospective Exposure Cohort
Children with SCD aged 9 months to under 2 years of age who are newly prescribed Xromi®, will be identified prospectively. These participants will be followed up for 24 months from their index date, regardless of whether they continue treatment with Xromi®, discontinue all hydroxycarbamide treatment, or switch to another formulation of hydroxycarbamide. The decision to prescribe Xromi® will be made solely by the physician independently of the study, as part of standard care.
Retrospective Comparator Cohort
Children with SCD and naïve to any hydroxycarbamide formulation at the index date. These participants will be identified retrospectively using the data from the last 10 years up to the date Xromi® was first used in children from 9 months to under 2 years of age at each individual site. The 24-month follow-up will be retrospective from the date they are matched to the exposed participant, irrespective of whether they start on any formulation of hydroxycarbamide during the follow-up.
The study population will consist of children with SCD who meet all the inclusion criteria and none of the exclusion criteria. Identification of participants will be conducted as follows:
• Prospective exposure cohort: Potential participants will be identified as they attend the participating sites where eligibility criteria will be assessed.
• Retrospective comparator cohort: Potential participants will be selected from clinical chart review.