PASS of Xromi Comparing Safety and Effectiveness in Children Under 2 Years With Sickle Cell Disease [PRECISE PASS]

Official title

A Comparative Observational Study to Evaluate the Safety and Effectiveness of Xromi (Hydroxycarbamide Oral Solution 100mg/ml) for the Prevention of Vaso-occlusive Complications of Sickle Cell Disease in Children Under 2 Years of Age.

Overview

This post-authorisation safety and efficacy study (PRECISE PASS) evaluates the use of Xromi® (hydroxycarbamide 100 mg/mL oral solution) in children aged 9 months to under 2 years with sickle cell disease (SCD). The objective is to assess the safety profile and clinical effectiveness of Xromi® under routine clinical conditions. The study includes a prospective cohort of Xromi®-treated patients and a matched retrospective comparator cohort of untreated patients. Participants will be followed for 24 months from treatment initiation or matched index date.

Detailed description

The PRECISE study is a combined Post-Authorisation Safety Study (PASS) (Category 3) and a Post-Authorisation Efficacy Study that aims to provide data on the safety and effectiveness of hydroxycarbamide 100mg/ml oral solution (Xromi ®) administered prospectively to children under 2 years of age, over a follow-up period of 24 months compared to matched retrospective comparators who were treatment naïve.

This is a non-interventional, matched cohort study involving children with SCD aged 9 to under 24 months. The study comprises two groups:

* A prospective Xromi®-exposed cohort, enrolled at the time of treatment initiation and followed for 24 months. * A retrospective comparator cohort, matched 2:1 by site, age, and β-globin genotype, identified from clinical records of children not treated with hydroxycarbamide at the index date.

The primary objective is to compare the incidence of adverse events of special interest (AESIs) between the two cohorts. Secondary analyses will assess the comparative effectiveness of Xromi® on clinical events, laboratory parameters, and physiological assessments. Exploratory analyses will examine treatment-related safety and effectiveness by dose, subgroups, and exposure to hydroxycarbamide during follow-up.

Data will be sourced from routine clinical practice through chart reviews and follow-up visits. No study-specific interventions will be introduced. The study is planned across specialist sites in the UK and Germany, with potential expansion to other European countries if recruitment targets require.

Interventions

• Drug Xromi
  Xromi is indicated for the prevention of vaso-occlusive complications of Sickle Cell Disease in patients over 9 months of age as part of standard clinical practice

Primary outcome measures

• AESI - Myelosuppression (Neutropenia) [Time frame: Pre-baseline, Baseline to 24 months]
• AESI - Myelosuppression (Reticulocytopenia) [Time frame: Pre-baseline, Baseline to 24 months]
• AESI - Myelosuppression (Thrombocytopenia) [Time frame: Pre-baseline, Baseline to 24 months]
• AESI - Myelosuppression (Anaemia) [Time frame: Pre-baseline, Baseline to 24 months]
• AESI - Abnormal Weight Gain [Time frame: Baseline to 24 months]
• AESI - Abnormal Weight Loss [Time frame: Baseline to 24 months]
• AESI - Increase in Hepatic Enzyme (ALT) [Time frame: Baseline to 24 months]
• AESI - Increase in Hepatic Enzyme (AST) [Time frame: Baseline to 24 months]
• AESI - Alopecia [Time frame: Pre-baseline, Baseline to 24 months]
• AESI - Other Hair Loss [Time frame: Pre-baseline, Baseline to 24 months]

Secondary outcome measures (12)

• Other Adverse Events [Time frame: Baseline to 24 months]
• Painful Vaso-occlusive Crisis (VOC) [Time frame: Pre-baseline, Baseline to 24 months]
• Acute Chest Syndrome (ACS) [Time frame: Pre-baseline, Baseline to 24 months]
• Splenomegaly [Time frame: Pre-baseline, Baseline to 24 months]
• Priapism [Time frame: Baseline to 24 months]
• Hepatobiliary disorder [Time frame: Pre-baseline, Baseline to 24 months]
• Splenic Sequestration Crisis [Time frame: Pre-baseline, Baseline to 24 months]
• Surgery [Time frame: Pre-baseline, Baseline to 24 months]
• Blood Transfusion [Time frame: Pre-baseline, Baseline to 24 months]
• Cerebrovascular accident [Time frame: Pre-baseline, Baseline to 24 months]
• Abnormal or Conditional TCD [Time frame: Pre-baseline, Baseline to 24 months]
• Hospitalisations for SCD [Time frame: Pre-baseline, Baseline to 24 months]

Eligibility criteria

Prospective Exposure Cohort

• Inclusion criteria:

• Aged from 9 months to under 2 years at the index date.
• Diagnosis of SCD.
• Known β-globin genotype at the index date.
• Prescribed Xromi® for the prevention of complications of SCD.
• Parent(s) (or a legal representative(s)) provides written informed consent to participate in the study, unless there is a waiver, non-opposition, or blanket written informed consent by the parent for research studies.
• Exclusion criteria:

• Previous use of hydroxycarbamide of any formulation before the index date.
• Receiving regular blood transfusions (occurring every 8 weeks or more frequently) at the index date.
• Known hypersensitivity to any of the excipients of Xromi® at the index date.
• Contraindications to the drug at the index date: severe hepatic impairment (Child-Pugh classification C); severe renal impairment (creatinine clearance: CrCl <30 ml/min); presence of at least one of the following: Absolute neutrophil count (ANC) < 1.0 x 10\^9/L, absolute reticulocyte count (ARC) <80 x 10\^9/L, platelets <80 x 10\^9/L.
• Participating in another clinical study of an investigational medicinal product (IMP) at the index date.
• Anti-retroviral medicinal products for human immunodeficiency virus (HIV) at the index date.
• Active malignancy at the index date.

Participants in the prospective exposure cohort who are prescribed Xromi® but do not initiate treatment will be excluded from the dataset.

Retrospective Comparator cohort

• Inclusion criteria:

• Aged from 9 months to under 2 years at the index date.
• Diagnosis of SCD.
• Known β-globin genotype.
• Matched to an exposed participant.
• Parent(s) (or a legal representative(s)) provides written informed consent to participate in the study, unless there is a waiver, non-opposition, or blanket written informed consent by the parent for research studies.
• Exclusion criteria:

• Use of hydroxycarbamide of any formulation before or at the index date.
• Receiving regular blood transfusions (occurring every 8 weeks or more frequently) at the index date.
• Presence at the index date of any of the following: severe hepatic impairment (Child-Pugh classification C); severe renal impairment (CrCl <30 ml/min); presence of at least one of the following: ANC < 1.0 x 10\^9/L, ARC < 80 x 10\^9/L, platelets < 80 x 10\^9/L).
• Participating in another clinical study of an IMP at the index date.
• Anti-retroviral medicinal products for HIV at the index date.
• Active malignancy at the index date.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United Kingdom · 10 centers

• Basildon University Hospital — Basildon
• Noah's Ark Children's Hospital for Wales — Cardiff
• Evelina London Children's Hospital — London
• Kings College Hospital — London
• North Middlesex University Hospital — London
• The Royal London Hospital — London
• University College London Hospital — London
• Whittington Hospital — London
• … and 2 more centers

Germany · 2 centers

• Universitätsklinikum Hamburg-Eppendorf — Hamburg
• Universitätsklinikum Heidelberg — Heidelberg

Publications

• Rankine-Mullings A, Keenan R, Chakravorty S, Inusa B, Telfer P, Velangi M, Ware RE, Moss JJ, Lloyd AL, Edwards S, Mulla H. Efficacy, safety, and pharmacokinetics of a new, ready-to-use, liquid hydroxyurea in children with sickle cell anemia. Blood Adv. 2023 Aug 22;7(16):4319-4322. doi: 10.1182/bloodadvances.2023010099. No abstract available. PMID 37171600
• Thompson BW, Miller ST, Rogers ZR, Rees RC, Ware RE, Waclawiw MA, Iyer RV, Casella JF, Luchtman-Jones L, Rana S, Thornburg CD, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik S, Howard TH, Luck L, Wang WC. The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer. 2010 Feb;54(2):250-5. doi: 10.1002/pbc.22269. PMID 19731330

Identifiers

NCT: NCT06923111 · NOVDD-001 · EUPAS1000000076 · CHIL 62837 · 334976

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗