Study of Dose Confirmation and Safety of Crizanlizumab in Pediatric Sickle Cell Disease Patients

NCT ID: NCT03474965

Last Updated: 2025-10-16

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 117 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-10-01
• Study Completion Date: 2024-11-06

Brief Summary

The purpose of this study was to confirm and to establish appropriate dosing and to evaluate the safety in pediatric participants ages 2 to <18 years with a history of Vaso-Occlusive Crisis (VOC) with or without Hydroxyurea/Hydroxycarbamide (HU/HC), receiving crizanlizumab for 2 years. The efficacy and safety of crizanlizumab was previously demonstrated in adults with sickle cell disease. The approach was to extrapolate from the pharmacokinetics (PK)/pharmacodynamics (PD) already established in the adult population. The study was designed as a Phase II, multicenter, open-label study.

Detailed Description

This was an open-label, single-arm study of crizanlizumab in sickle-cell disease (SCD) pediatric participants.

This study consisted of 2 parts, Part A and Part B. In Part A, the dose for 3 age groups (see groups below), was first confirmed on the basis of single and multiple dose (steady state) PK data and key safety data from an initial subgroup of participants. In Part B, safety and efficacy were collected from additional participants from 6 to <18 years (Groups 1 and 2, only).

At least 100 participants were planned to be enrolled in the trial in total, split in 3 age groups:

• Group 1 (age 12 to <18 years): at least 26 participants (≥8 in Part A and ≥18 in Part B),
• Group 2 (age 6 to <12 years): at least 26 participants (≥8 in Part A and ≥18 in Part B),
• Group 3 (age 2 to <6 years): at least 8 participants (≥8 Part A). Crizanlizumab was administered every 4 weeks with a loading dose 2 weeks after the first dosing (i.e., by i.v. infusion) on Week 1 Day 1, Week 3 Day 1, and then day 1 of every fourth week) for up to 2 years. The initial dose of crizanlizumab was 5 mg/kg dose for Group 1 and Group 2 Part A. It was later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation from emerging PK data analysis and safety considerations determined in Part A of the study.

Conditions

Sickle Cell Disease (SCD)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Crizanlizumab

SEG101 (crizanlizumab) 5 mg/kg or 8 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4-week cycle for up to 2 years. The initial dose of crizanlizumab was 5 mg/kg dose for Group 1 and Group 2 Part A. It was later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation from emerging PK data analysis and safety considerations determined in Part A of the study.

Group Type: EXPERIMENTAL

Crizanlizumab

Intervention Type: DRUG

Crizanlizumab (SEG101) is a concentrate for solution for infusion, i.v. use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab.

Interventions

Crizanlizumab

Crizanlizumab (SEG101) is a concentrate for solution for infusion, i.v. use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab.

Intervention Type: DRUG

Other Intervention Names

SEG101

Eligibility Criteria

Inclusion Criteria

1. Male or female patients ages 2 to <18 years

2. Confirmed diagnosis of SCD (any genotype including HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia patients, and others) by hemoglobin electrophoresis or/and high-performance liquid chromatography (HPLC) [performed locally]. Confirmation of diagnosis by two accepted methods is recommended.

3. Experienced at least 1 VOC within the preceding 12 months prior to screening, as determined by medical history. Prior VOC must have resolved at least 7 days prior to the first dose in the study and must include all the following: a.the occurrence of appropriate symptoms (see VOC definition in Section 7.2.1.1), b.either a visit to a medical facility or healthcare professional, c.receipt of oral/parenteral opioid or parenteral NSAIDs

4. If receiving HU/HC, L-glutamine or erythropoietin stimulating agent, must have been receiving the drug consistently for at least 6 months prior to screening and plan to continue taking it at the same dose and schedule during the trial. Patients who have not been receiving such drugs must have been off them for at least 6 months prior to screening. . Dose alterations of HU/HC, L-glutamine or erythropoietin stimulating agent during Part A are not allowed, and if this occurs, the participant will enter directly to Part B.

5. Received standard age-appropriate care for SCD, including penicillin prophylaxis, pneumococcal immunization, and parental education.

6. Performance status: Karnofsky ≥ 50% for patients >10 years of age, and Lansky ≥ 50 for patients ≤ 10 years of age.

7. Patient must meet the following laboratory values prior to Week 1 Day 1: Absolute Neutrophil Count ≥1.0 x 109/L , Platelets ≥75 x 109/L, Hemoglobin (Hgb) > 5.5 g/dL

8. Patient must have adequate renal and hepatic function as defined:Estimated Glomerular filtration rate (eGFR) ≥ 75 mL/min/1.73 m2 using Schwartz formula, Direct (conjugated) bilirubin ≤ 2.0 x ULN, Alanine transaminase (ALT) ≤ 3.0 x ULN,

9. Transcranial Doppler (TCD) for patients aged 2 to < 16 years at time of screening, with HbSS, HbSβ0-thalassemia, and HbSD disease indicating low risk for stroke (per investigator). Please refer to Section 7.2.2.6 for details

10. Written informed consent/assent, according to local guidelines, signed by the patient and / or by the parents or legal guardian prior to any study related screening procedures are performed.

11. Female of non-childbearing potential or with negative serum pregnancy test on Screening and a negative urine pregnancy test (dipstick) prior to dosing on Day 1.

Exclusion Criteria

1. History of stem cell transplant.

2. Received any blood products within 30 days prior to Week 1 Day 1 dosing.

3. Plan to participate in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) or undergo exchange transfusions/plasmapheresis during the study. Patients requiring episodic transfusion (simple or exchange) in response to worsened anemia or VOC are permitted.

4. Patients with bleeding disorders

6.Contraindication or hypersensitivity to any drug from similar class as study drug or to any excipients of the study drug formulation.

7.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 8.Received a monoclonal antibody or immunoglobulin-based therapy within 6 months of Screening, or has documented immunogenicity to a prior monoclonal antibody.

9.Received active treatment on another investigational trial within 30 days (or 5 half -lives of that agent, whichever is greater) prior to Screening or plans to participate in another investigational drug trial.

10.Pregnant females or females who have given birth within the past 90 days or who are breastfeeding.

11. Any documented history of a clinical stroke or intracranial hemorrhage, or an uninvestigated neurologic finding within the past 12 months. Silent infarcts (only present on imaging) are not excluding patients from study participation 12.Any abnormal TCD within the past 12 months. 13.Use of therapeutic anticoagulation (prophylactic doses permitted) or antiplatelet therapy (other than aspirin) within the 10 days prior to Week 1 Day 1 dosing.

14.Hospitalized within 7 days prior to Week 1 Day 1 dosing. 15.Planning to undergo a major surgical procedure during the duration of the study.

16.Planning to initiate or terminate HU/HC or L-glutamine while on study (except if needed to terminate for safety reasons).

17.Patient with active human immunodeficiency virus (HIV) infection (detectable viral load).

18.Patients with known active Hepatitis B infection. 19.Patients with known Hepatitis C history. 20.Significant active infection or immune deficiency (including chronic use of immunosuppressive drugs) in the opinion of the investigator.

21.Malignant disease. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; any completely resected carcinoma in situ.

22.Has a serious mental or physical illness, which, in the opinion of the Investigator would compromise participation in the study.

23.Any condition which, in the opinion of the investigator, is likely to interfere with the successful collection of the measurements required for the study 24.Resting QTcF ≥450 msec at pretreatment (baseline) for patients under 12 years of age and ≥450 msec for males and ≥460 msec for female patients 12 years and older.

25.Cardiac or cardiac repolarization abnormality, including any of the following: a. History of myocardial infarction (MI), uncontrolled congestive heart failure, unstable angina, or coronary bypass graft (CABG) within 6 months prior to starting study treatment, b. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (bifascicular block, Mobitz Type II, and third degree AV block), c. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome ( Risk factors for Torsade de Pointes (TdP), including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia, Inability to determine the QTcF).

26. Sexually active females who are unwilling to comply with reliable method of birth control until 15 weeks following last dose of study drug.

28.Not able to understand and to comply with study instructions and requirements.

29.Patients who are an employee of the sponsor or investigator or otherwise dependent on them.

30.Patients who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

31.Patients who received prior crizanlizumab treatment and/or other selectin targeting agents are not allowed 32.Patients having taken voxelotor less than 30 days prior to Screening, or planning to take voxelotor while on study are not allowed.

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

University Of Alabama

Birmingham, Alabama, United States

Childrens National Hospital

Washington D.C., District of Columbia, United States

University of Florida

Gainesville, Florida, United States

Joe DiMaggio Childrens Hospital

Hollywood, Florida, United States

Childrens Healthcare of Atlanta

Atlanta, Georgia, United States

Childrens Hosp Boston Dept of Hematology

Boston, Massachusetts, United States

Childrens Hospital at Montefiore

The Bronx, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

East Carolina University

Greenville, North Carolina, United States

Childrens Hospital Of Philadelphia

Philadelphia, Pennsylvania, United States

Medical Uni of South Carolina

Charleston, South Carolina, United States

Cook Childrens Medical Center

Fort Worth, Texas, United States

Novartis Investigative Site

Brussels, , Belgium

Novartis Investigative Site

Laken, , Belgium

Novartis Investigative Site

Liège, , Belgium

Novartis Investigative Site

Salvador, Estado de Bahia, Brazil

Novartis Investigative Site

Ribeirão Preto, São Paulo, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Cali, Valle del Cauca Department, Colombia

Novartis Investigative Site

Montería, , Colombia

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Heidelberg, , Germany

Novartis Investigative Site

Nagpur, Maharashtra, India

Novartis Investigative Site

Padua, PD, Italy

Novartis Investigative Site

Orbassano, TO, Italy

Novartis Investigative Site

Beirut, , Lebanon

Novartis Investigative Site

Tripoli, , Lebanon

Novartis Investigative Site

Muscat, , Oman

Novartis Investigative Site

Palma de Mallorca, Balearic Islands, Spain

Novartis Investigative Site

Barcelona, Catalonia, Spain

Novartis Investigative Site

Madrid, , Spain

Novartis Investigative Site

Adana, , Turkey (Türkiye)

Novartis Investigative Site

Mersin, , Turkey (Türkiye)

Novartis Investigative Site

London, , United Kingdom

Countries

United States; Belgium; Brazil; Canada; Colombia; France; Germany; India; Italy; Lebanon; Oman; Spain; Turkey (Türkiye); United Kingdom

References

Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available.

Reference Type: DERIVED

PMID: 34922648 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=2606

A Plain Language Trial Summary is available on www.novctrd.com

Other Identifiers

2017-001747-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CSEG101B2201

Identifier Type: -

Identifier Source: org_study_id