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

• ClinicalTrials.gov Identifier: NCT03474965
• Recruitment Status: Recruiting
• First Posted: March 23, 2018
• Last Update Posted: January 23, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: March 16, 2018
• First Posted Date: March 23, 2018
• Last Update Posted Date: January 23, 2023
• Actual Study Start Date: October 1, 2018
• Estimated Primary Completion Date: May 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 12, 2020)

• PK (AUCd15) after 1st dose [ Time Frame: Day 15 ]
  Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
• PD (AUCd15) after 1st dose [ Time Frame: Day 15 ]
  Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
• PK (AUCtau) after multiple dose [ Time Frame: Week 15 ]
  Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old
• PD (AUCtau) after multiple dose [ Time Frame: Week 15 ]
  Confirm appropriate dosing of Crizanlizumab in participants aged 2 to < 18 years old
• PK (Cmax) after 1st dose and multiple dose [ Time Frame: Week 1 and Week 15 ]
  Confirm appropriate dosing of crizanlizumab in participants aged 2 to < 18 years (Parts A)
• PK pre-dose concentrations [ Time Frame: Week 1 to Week 19 ]
  Confirm appropriate dosing of crizanlizumab in participants aged 6 months to less than 24 months of age (Part B)
• Frequency of any adverse events (AEs) as a measure of safety and tolerability [ Time Frame: 6 months, 2 years ]
  Safety of crizanlizumab in participants aged 6 months to < 18 years (Parts A and B)

Original Primary Outcome Measures (submitted: March 16, 2018)

• AUC d15 for PK and PD parameters [ Time Frame: Week 1 and Week 15 ]
  Confirm appropriate dosing of crizanlizumab in patients ages 2 to < 18 years (Parts A)
• AUCtau for PK and PD parameters [ Time Frame: Week 1 to Week 15 ]
  Confirm appropriate dosing of crizanlizumab in patients ages 2 to < 18 years (Parts A)
• Cmax for PK parameters [ Time Frame: Week 1 and Week 15 ]
  Confirm appropriate dosing of crizanlizumab in patients ages 2 to < 18 years (Parts A)
• PK pre-dose concentrations [ Time Frame: Week 3 to Week 19 ]
  Confirm appropriate dosing of crizanlizumab in patients aged 6 months to less than 24 months of age (Part B)
• Frequency of any adverse events (AEs) as a measure of safety and tolerability [ Time Frame: 6 months and 2 years ]
  Safety of crizanlizumab in patients ages 6 months to < 18 years (Parts A and B)

Current Secondary Outcome Measures (submitted: October 1, 2021)

• Annualized rate Vaso Occlusive Crisis (VOC) events leading to healthcare visit in clinic/ER/hospital [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Annualized rate Vaso Occlusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Annualized rate each subcategory of VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Annualized rate hospitalizations and ER visits (both overall and VOC-related) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Annualized rate days of ER/hospitalization (both overall and VOC-related) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Annualized rate of dactylitis events [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old participants at the time of study entry (Parts A and B)
• Number, seriousness, severity, and causality assessments of treatment emergent adverse events and other data as considered appropriate. [ Time Frame: 6 months, 2 years ]
  To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry
• Absolute change from baseline in hemoglobin [ Time Frame: Baseline, 6 months, 2 years ]
  To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry
• Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab [ Time Frame: Week 1, Week 3, Week 15, Week 27, End of Treatment (EOT) (approx. 2 years) and Post-treatment follow-up (last infusion +105 days) ]
  To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry
• Electrocardiogram (ECGs) at relevant PK time points [ Time Frame: Screening, Week 7, Week 11, week 15, week 27 and Week 51 ]
  To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry
• Growth and sexual maturation assessments (Tanner stage) [ Time Frame: Screening, Week 51 and End of Treatment (EOT) ]
  To assess other safety measures in participants aged 6 months to < 18 years at the time of study entry
• PK pre-dose concentrations prior to each study drug dose. [ Time Frame: Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 ]
  Characterize long-term PK and PD of crizanlizumab in participants aged 6 months to >18 years
• Percentage P-selectin inhibition prior to dosing [ Time Frame: Week 1, Week 3, Week 7, Week 15, Week 19, Week 23, Week 27, Week 31, Week 35, Week 39, Week 43, Week 47 and Week 51 ]
  Characterize long-term PK and PD of crizanlizumab in participants aged 6 months to >18 years

Original Secondary Outcome Measures (submitted: March 16, 2018)

• Number of Vaso Occusive Crisis (VOC) events leading to healthcare visit in clinic/ER/hospital [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number of Vaso Occusive Crisis (VOC) events treated at home (based on documentation by health care provider following phone contact with the patient) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number of each subcategory of VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number of hospitalizations and ER visits (both overall and VOC-related) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number of days of ER/hospitalization (both overall and VOC-related) [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number of dactylitis events [ Time Frame: 6 months, 2 years ]
  To assess the long-term efficacy of crizanlizumab in 6 months to < 18 year old patients at the time of study entry (Parts A and B)
• Number, seriousness, severity, and causality assessments of treatement emergent adverse events and other data as considered appropiate. [ Time Frame: 6 months, 2 years ]
  To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
• Absolute change from baseline in hemoglobin [ Time Frame: Baseline, 6 months, 2 years ]
  To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
• Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab [ Time Frame: Week 1, Week 3, Week 15, Week 27 and End of Treatment (EOT) ]
  To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
• Electrocardiogram (ECGs) at relevant PK time points [ Time Frame: Screening, Week 7, Week 11, week 15, week 27 and Week 51 ]
  To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
• Growth and sexual maturation assessments (Tanner stage) [ Time Frame: Screening, Week 51 and End of Treatment (EOT) ]
  To assess other safety measures in patients aged 6 months to < 18 years at the time of study entry
• PK and PD pre-dose concentrations prior to each study drug dose. [ Time Frame: week 1, week 3, week 7, week 15, week 19, week, 23, week 27, week 31, week 35, week 39, week 43, week 47 and week 51 ]
  Characterize long-term PK and PD of crizanlizumab in patients aged 6 months to >18 years
• Percentage P-selectin inhibition prior to dosing [ Time Frame: Week 3, week 15, week 27 and week 51 ]
  Characterize long-term PK and PD of crizanlizumab in patients aged 6 months to >18 years

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Dose Confirmation and Safety of Crizanlizumab in Pediatric Sickle Cell Disease Patients
• Official Title: A Phase 2,Multicenter,Open-Label Study to Assess Appropriate Dosing and to Evaluate Safety of Crizanlizumab,With or Without Hydroxyurea/Hydroxycarbamide,in Sequential,Descending Age Groups of Pediatric Sickle Cell Disease Patients With Vaso-Occlusive Crisis
• Brief Summary: The purpose of the Phase 2 CSEG101B2201 study is to confirm and to establish appropriate dosing and to evaluate the safety in pediatric participants ages 6 months to <18 years with a history of VOC with or without HU/HC, receiving crizanlizumab for 2 years. The efficacy and safety of crizanlizumab was already demonstrated in adults with sickle cell disease. The approach is to extrapolate from the PK/pharmacodynamics (PD) already established in the adult population. The study is designed as a Phase II, multicenter, open-label study.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sickle Cell Disease (SCD)

Intervention

Drug: 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.

Other Name: SEG101

Study Arms

Experimental: Crizanlizumab

SEG101 (crizanlizumab) administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4-week cycle

Intervention: Drug: Crizanlizumab

• Publications *: 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 11, 2022): 119
• Original Estimated Enrollment (submitted: March 16, 2018): 100
• Estimated Study Completion Date: December 17, 2025
• Estimated Primary Completion Date: May 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female patients ages 2 to <18 years (Group 3 will be expanded to allow enrolment of patients ages 6 to <24 months (and at least 7 kg) in Part B once the appropriate dose is confirmed in 2 to <6 year old participants).
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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 6 Months to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

• Listed Location Countries: Belgium, Brazil, Canada, Colombia, France, Germany, India, Italy, Lebanon, Oman, Spain, Switzerland, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03474965
• Other Study ID Numbers: CSEG101B2201; 2017-001747-12 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: January 2023