Sickle Cell Disease (SCD)
Conditions
Keywords
Sickle cell disease, Sickle cell disorder, SCD, Sickle cell anemia, Hemoglobin SC disease, Sickling disorder due to hemoglobin S, Vaso-occlusive crisis, VOC, P-selectin, Crizanlizumab, SEG101
Brief summary
Sickle cell disease (SCD) is a genetic blood disorder. Crizanlizumab is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in patients with SCD aged 16 years and older. The purpose of this local Phase IV study was to evaluate the safety of crizanlizumab specifically in Indian patients with SCD aged 16 years or older with a history of VOC leading to healthcare visit.
Detailed description
Sickle cell disease (SCD) is a genetic blood disorder, caused by a mutation in the β-globin gene, which early on progresses into a systemic disease. Vaso-occlusion is a hallmark of SCD and can lead to serious acute and chronic complications. The purpose of this local Phase IV study was to evaluate the safety of crizanlizumab specifically in Indian patients with SCD aged 16 years or older with a history of VOC leading to healthcare visit. The study was open label and single armed. 140 patients were treated with crizanlizumab for approximately one year at a dose of 5 mg/kg in addition to receiving standard of care. The primary objective was to assess frequency, severity and causality of serious adverse events (SAEs) during the treatment period. Secondary objective was to assess overall safety and tolerability of crizanlizumab.
Interventions
DRUGcrizanlizumab
Crizanlizumab 5.0 mg/kg i.v. initial dose on Week 1 Day 1, second dose on Week 3 Day 1. Subsequently, Day 1 of every 4 weeks until Week 51, in addition of standard of care.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * Male or female participant aged 16 years and older * Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid chromatography (HPLC). All SCD genotypes are eligible. * History of VOC leading to healthcare visit prior to screening visit * Participants must meet the following central laboratory values at the screening visit: Absolute Neutrophil Count ≥1.0 x 109/L Platelet count ≥75 x 109/L Hemoglobin: for adults (Hb) ≥4.0 g/dL and for adolescents (Hb) ≥5.5 g/dL Glomerular filtration rate ≥ 45 mL/min/1.73 m2 using CKD-EPI formula Direct (conjugated) bilirubin \< 2.0 x ULN Alanine Aminotransferase (ALT) \< 3.0 x ULN * ECOG performance status ≤2 for adults and Karnofsky Performance Scale ≥ 50% for adolescents.
Exclusion criteria
* Contraindication or hypersensitivity to any drug or metabolites from similar class as study drug. History of severe hypersensitivity reaction to other monoclonal antibodies which in the opinion of the investigator may pose an increased risk of serious infusion reaction. * Participant has received crizanlizumab and/or other P-selectin inhibitor prior to the study or plans to receive it during the duration of the study. * Concurrent severe and/or uncontrolled medical conditions which, in the opinion of the Investigator, could cause unacceptable safety risks or compromise participation in the study. * Any condition which, in the opinion of the investigator, is likely to interfere with the successful collection of the measurements required for the study. * Participant has documented immunogenicity to a prior biological drug. * Participants who are on active treatment with Voxelotor, other investigational drug or other monoclonal antibody, or intend to initiate the same during the course of the trial. * Pregnant females or females who have given birth within the past 90 days prior screening or who are breastfeeding. * Women of childbearing potential unless using highly effective methods of contraception during dosing and for 15 weeks after stopping treatment * Significant bleeding disorder * Active HIV infection * Active Hepatitis B infection * Positive test for Hepatitis C RNA * Malignant disease * Active infection or immune deficiency
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Serious Adverse Events (SAEs) | Up to 15 months | Number of participants with treatment emergent SAEs and SAEs grade \>=3. Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. CTCAE ranges severity from Grade 1 through 5 being Grade 1 the lowest severity grade. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (AEs) | Up to 15 months | Number of participants with treatment emergent AEs, AEs grade \>=3, AEs led to study treatment discontinuation, AEs leading to dose adjustment/interruption, and AEs requiring additional therapy. Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. |
| Number of Participants With Adverse Events of Special Interest (AESI) | Up to 15 months | The AESIs were designated medical events, infections, infusion-related reaction (IRR), infusion-related reaction new combined and pain events. Pain events are potential infusion-related reactions presenting as pain events (occurred on the day of infusion). IRR (Standard search): Standard search, excluding infusion site-reaction and investigating the most common, nonspecific, potential signs and symptoms indicative of IRRs, and occurring on the day of infusion. IRR (Combined search): Comprised of severe reactions (e.g. bronchospasm, anaphylactic reaction etc.), that occurs any time after infusion (regardless of grade and causality) and pain events on the day of infusion along with the events that are covered under standard search. Designated medical events (DMEs): European Medicines Agency, as well as EEA Member States released a list of DMEs, to identify reports of suspected ADRs that deserve special attention, irrespective of statistical criteria used to prioritize safety reviews. |
Countries
India
Participant flow
Recruitment details
Participants took part in 8 investigative sites in India.
Pre-assignment details
During the screening period, which occurred within 35 days before enrollment, participants signed written informed consent according to local guidelines. All screening evaluations were performed during this period.
Participants by arm
| Arm | Count |
|---|---|
| Crizanlizumab 5.0 mg/kg i.v. Crizanlizumab 5.0 mg/kg i.v. initial dose on Week 1 Day 1, second dose on Week 3 Day 1. Subsequently, Day 1 of every 4 weeks until Week 51, in addition of standard of care. | 140 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Guardian Decision | 1 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Withdrawal by Subject | 17 |
Baseline characteristics
| Characteristic | Crizanlizumab 5.0 mg/kg i.v. |
|---|---|
| Age, Continuous | 26.2 years STANDARD_DEVIATION 10.67 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 137 Participants |
| Race/Ethnicity, Customized Not reported | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 140 |
| other Total, other adverse events | 25 / 140 |
| serious Total, serious adverse events | 3 / 140 |
Outcome results
Primary
Number of Participants With Treatment Emergent Serious Adverse Events (SAEs)
Number of participants with treatment emergent SAEs and SAEs grade \>=3. Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. CTCAE ranges severity from Grade 1 through 5 being Grade 1 the lowest severity grade.
Time frame: Up to 15 months
Population: The Safety Set included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Serious Adverse Events (SAEs) | Serious adverse events | 3 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Serious Adverse Events (SAEs) | Serious adverse events grade >=3 | 3 Participants |
Secondary
Number of Participants With Adverse Events of Special Interest (AESI)
The AESIs were designated medical events, infections, infusion-related reaction (IRR), infusion-related reaction new combined and pain events. Pain events are potential infusion-related reactions presenting as pain events (occurred on the day of infusion). IRR (Standard search): Standard search, excluding infusion site-reaction and investigating the most common, nonspecific, potential signs and symptoms indicative of IRRs, and occurring on the day of infusion. IRR (Combined search): Comprised of severe reactions (e.g. bronchospasm, anaphylactic reaction etc.), that occurs any time after infusion (regardless of grade and causality) and pain events on the day of infusion along with the events that are covered under standard search. Designated medical events (DMEs): European Medicines Agency, as well as EEA Member States released a list of DMEs, to identify reports of suspected ADRs that deserve special attention, irrespective of statistical criteria used to prioritize safety reviews.
Time frame: Up to 15 months
Population: The Safety Set included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Designated medical events | 1 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Infections (All) | 10 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Infusion-related reaction (standard search) | 2 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Infusion-related reactions (IRR) (new combined search) | 3 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Pain events | 2 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Adverse Events of Special Interest (AESI) | Any AESI | 18 Participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AEs)
Number of participants with treatment emergent AEs, AEs grade \>=3, AEs led to study treatment discontinuation, AEs leading to dose adjustment/interruption, and AEs requiring additional therapy. Adverse events were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Time frame: Up to 15 months
Population: The Safety Set included all participants who received at least one dose of study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) | Adverse events | 53 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) | Adverse events grade >=3 | 6 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) | AEs leading to discontinuation | 3 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) | AEs leading to dose adjustment/interruption | 1 Participants |
| Crizanlizumab 5.0 mg/kg i.v. | Number of Participants With Treatment Emergent Adverse Events (AEs) | AEs requiring additional therapy | 46 Participants |