Sickle Cell Disease
Conditions
Keywords
Hydroxyurea, liquid formulation, HbS Disease, Hemoglobin S Disease, Sickle Cell Anemia, Sickle Cell Disease, Sickle Cell Disorders, Sickling Disorder Due to Hemoglobin S, Xromi, Hydroxycarbamide, paediatric, children, hemaglobinopathy in children, hemoglobinopathy, paediatric formuation
Brief summary
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
DRUGXromi
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
Sponsors
Nova Laboratories Limited
OXON Epidemiology
Study design
Observational model
COHORT
Time perspective
OTHER
Eligibility
Sex/Gender
ALL
Age
9 Months to 23 Months
Healthy volunteers
No
Inclusion 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. *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AESI - Myelosuppression (Neutropenia) | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Myelosuppression protocol definition of neutropenia is ANC \<1.0 x 10\^9/L |
| AESI - Myelosuppression (Reticulocytopenia) | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Myelosuppression protocol definition of reticulocytopenia is ARC \<80 x 10\^9/L, unless Hb \>90 g/L, |
| AESI - Myelosuppression (Thrombocytopenia) | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Myelosuppression protocol definition of thrombocytopenia defined as platelets \<80 x 10\^9/L. |
| AESI - Myelosuppression (Anaemia) | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Myelosuppression protocol definition of anaemia defined as Hb \<45 g/L. |
| AESI - Abnormal Weight Gain | Baseline to 24 months | Weight (kg) Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort and standard care guidelines |
| AESI - Abnormal Weight Loss | Baseline to 24 months | Weight (kg) Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort and standard care guidelines |
| AESI - Increase in Hepatic Enzyme (ALT) | Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort and normal laboratory ranges. Defined as an increase in hepatic enzyme Alanine transaminase (ALT) increased (U/L) |
| AESI - Increase in Hepatic Enzyme (AST) | Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort and normal laboratory ranges. Defined as an increase in hepatic enzyme Aspartate transaminase (AST) increased (U/L) |
| AESI - Alopecia | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in study protocol as presence of alopecia (a skin and subcutaneous tissue disorder). |
| AESI - Other Hair Loss | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in study protocol as presence of other hair loss (a skin and subcutaneous tissue disorder). |
| AESI - Skin Hyperpigmentation | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in study protocol as presence of skin hyperpigmentation, including oral and nail hyperpigmentation.(a skin and subcutaneous tissue disorder). |
| AESI - Rash | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in study protocol as presence of a rash (a skin and subcutaneous tissue disorder). |
| AESI - Skin Ulcers | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in study protocol as presence of skin ulcer, including leg ulcer (a skin and subcutaneous tissue disorder). |
| AESI - Growth Retardation | Pre-baseline, Baseline to 24 months | height/length (cm) Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort and standard care guidelines (as a drop of 2 or more centiles on growth charts over time). |
| AESI - Bacterial Infection | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in the protocol as a proven or treated bacterial infection. |
| AESI - Viral Infection | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in the protocol as a proven or treated viral infection. |
| AESI - Fungal Infection | Pre-baseline, Baseline to 24 months | Incidence of adverse events of special interest (AESIs) in children who have SCD and are treated with Xromi®, in comparison to a retrospective comparator cohort. Defined in the protocol as a proven or treated fungal infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Other Adverse Events | Baseline to 24 months | Occurrence of other adverse events (AE), adverse reactions (AR) and serious adverse events (SAE) or serious adverse reactions (SAR) will be collected during follow-up. |
| Painful Vaso-occlusive Crisis (VOC) | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. \- VOC events will include dactylitis. |
| Acute Chest Syndrome (ACS) | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Splenomegaly | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event Splenomegaly will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Priapism | Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Hepatobiliary disorder | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Splenic Sequestration Crisis | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Surgery | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. Defined in the protocol as any surgery that is planned, emergency, or due to pre-existing conditions e.g. SCD. |
| Blood Transfusion | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Cerebrovascular accident | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. The protocol definition includes silent stroke |
| Abnormal or Conditional TCD | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. \- Transcranial Doppler Scan (TCD) |
| Hospitalisations for SCD | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. The reason for hospitalisation and duration will be collected. |
| Non-hospitalised Visit for SCD | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. Protocol definition includes Emergency department (ED) visits/treatment centres/paediatric ward/day unit attendances for SCD |
| Other Clinical Events | Pre-baseline, Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator to compare the Effectiveness of Xromi®. |
| Other Event - Death | Baseline to 24 months | Occurrence of the clinical event will be collected during follow-up in both cohorts by the investigator. Protocol definition includes any death occurring in the study both related and un-related to Xromi treatment |
| Haemoglobin (Hb) | Pre-baseline, Baseline to 24 months | (g/L) or (g/dl) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Foetal Haemoglobin (HbF) | Pre-baseline, Baseline to 24 months | (%) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Haemoglobin Fractions | Pre-baseline, Baseline to 24 months | (%) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. \- Haemoglobinopathy screen results including: HbS, HbA, HbA2, HbC |
| Absolute Neutrophil Count (ANC) | Pre-baseline, Baseline to 24 months | (10\^9/L or /nL) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Absolute Reticulocyte Count (ARC) | Pre-baseline, Baseline to 24 months | (10\^9/L or /nL) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Platelet Count | Pre-baseline, Baseline to 24 months | (10\^9/L or /nL) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| White Blood Cell Count (WBC) | Pre-baseline, Baseline to 24 months | (10\^9/L or /nL) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Mean Corpuscular Volume (MCV) | Pre-baseline, Baseline to 24 months | (fl) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Mean Corpuscular Haemoglobin (MCH) | Pre-baseline, Baseline to 24 months | (pg) Haematological Parameter. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Ferritin | Pre-baseline, Baseline to 24 months | (µg/L) Iron Profile. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Transferrin Saturation | Pre-baseline, Baseline to 24 months | (%) Iron Profile. Iron binding saturation or transferrin saturation. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Alanine Transaminase (ALT) | Pre-baseline, Baseline to 24 months | (U/L) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Alkaline Phosphatase (ALP) | Pre-baseline, Baseline to 24 months | (U/L) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Aspartate Transaminase (AST) | Pre-baseline, Baseline to 24 months | (U/L) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Total Bilirubin | Pre-baseline, Baseline to 24 months | (µmol/L or mg/dl) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Lactate Dehydrogenase | Pre-baseline, Baseline to 24 months | (U/L) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Gamma-Glutamyl Transferase (GGT) | Pre-baseline, Baseline to 24 months | (U/L) Liver Function tests. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Serum Creatinine | Pre-baseline, Baseline to 24 months | (µmol/L or mg/dl) Renal function test. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Estimated Glomular Filtration Rate (eGFR) | Pre-baseline, Baseline to 24 months | (ml/min/1.73m\^2) Renal function test. Calculated value, Interpreted in line with UK CKD guidelines from creatinine values. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Albumin-Creatinine Ratio (ACR) | Pre-baseline, Baseline to 24 months | (Calculated value). Renal function test. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Liver Size | Pre-baseline, Baseline to 24 months | (cm) from costal margin. Physiological Assessment. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Spleen Size | Pre-baseline, Baseline to 24 months | (cm) from costal margin. Physiological Assessment. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
| Maximum Time Averaged Mean Velocity (TAMV) | Pre-baseline, Baseline to 24 months | (cm/s) Cardiovascular function, assessed using transcranial doppler scan velocities. Results and dates of laboratory tests and physiological assessments will be collected, whenever available. At baseline, the most recent results, prior to Xromi® initiation in the prospective exposure cohort, will be collected. Results from laboratory tests and physiological assessments conducted during follow-up will also be collected. |
Countries
Germany, United Kingdom
Contacts
CONTACTHussain Mulla, PhD
CONTACTSarah Edwards, PhD
STUDY_DIRECTORHussain Dr Mulla, PhD
Nova Laboratories Ltd.
PRINCIPAL_INVESTIGATORSara Dr Trompeter, MD
University College London Hospitals
Outcome results
None listed