Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle cell disease patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

16 Sep 2019 → ongoing

Decision date (initial)

2024-04-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508689-14-00

EudraCT number

2017-001746-10

ClinicalTrials.gov

NCT03814746

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the efficacy of 7.5 mg/kg of crizanlizumab versus placebo on the
annualized rate of VOC leading to healthcare visit, in addition to standard of
care
To compare the efficacy of 5.0 mg/kg of crizanlizumab versus placebo on the
annualized rate of VOC leading to healthcare visit, in addition to standard of
care

Secondary objectives 11

1. To compare the efficacy of 7.5 mg/kg versus placebo on the annualized rate of all VOCs (managed at home + leading to healthcare visit)
2. To compare the efficacy of 5.0 mg/kg versus placebo on the annualized rate of all VOCs (managed at home + leading to healthcare visit)
3. To assess the annualized rate of VOCs managed at home in each group
4. To assess the time to first and second VOC leading to healthcare visit in each group
5. To assess rate of participants free from VOC leading to healthcare visit in each group
6. To assess the duration of VOC leading to healthcare visit in each group
7. Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) in each group
8. To assess SCD-related renal damage in each group
9. To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg
10. To characterize the pharmacodynamic (PD) (P-selectin inhibition) of crizanlizumab at 5.0 and 7.5 mg/kg
11. To assess efficacy, safety and immunogenicity of crizanlizumab over the study period (taking into account potential treatment switch after primary analysis)

Conditions and MedDRA coding

Sickle cell disease

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD 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 review 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 availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Written informed consent must be obtained prior to any screening procedures
2. Male or female patients aged 12 years and older on the day of signing informed consent. Adolescents include patients aged 12 to 17 years old and adults ≥ 18 years
3. Confirmed diagnosis of SCD by Hb electrophoresis or high-performance liquid chromatography (HPLC) (performed locally). All SCD genotypes are eligible, genotyping is not required for study entry.
4. Experienced at least 2 VOCs leading to healthcare visit within the 12 months prior to screening visit as determined by medical history. Prior VOC leading to healthcare visit must resolve at least 7 days prior to Week 1 Day 1 and must include: 1. Pain crisis defined as an acute onset of pain for which there is no other medically determined explanation other than vaso- occlusion 2. which requires a visit to a medical facility and/or healthcare professional, 3. and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory drug (NSAID) analgesics Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be considered VOC in this study
5. If receiving HU/HC or L-glutamine (local HA approved medicinal product), must have been receiving the drug for at least 6 months and at a stable dose for at least 3 months prior to Screening visit and plan to continue taking it at the same dose and schedule until the subject has reached one year of study treatment. Patients who have not been receiving such drug must not have received it for at least 6 months prior to Screening visit to be included. Patients must have evidence of insufficient control of acute pain, such as at least one VOC leading to healthcare visit while on HU/HC or L-Glutamine treatment. If receiving erythropoietin stimulating agent, must have been receiving the drug for at least 6 months prior to Screening visit and plan to continue taking the treatment to maintain stable Hb levels at least until the subject has reached one year of study treatment
6. Patients must meet the following central laboratory values prior to Week 1 Day 1: • 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 in adults, and Shwartz formula in adolescents • Direct (conjugated) bilirubin < 2.0 x ULN • Alanine transaminase (ALT) < 3.0 x ULN
7. ECOG performance status ≤ 2.0 for adults and Karnofsky ≥ 50% for adolescents

Exclusion criteria 9

1. History of stem cell transplant.
2. Participating in a chronic transfusion program (pre-planned series of transfusions for prophylactic purposes) and/or planning on undergoing an exchange transfusion during the duration of the study; episodic transfusion in response to worsened anemia or VOC is permitted
3. Contraindication or hypersensitivity to any drug or metabolites from similar class as study drug or to any excipients of the study drug formulation. 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.
4. Received active treatment on another investigational trial within 30 days (or 5 half-lives of that agent, whichever is greater) prior to Screening visit or plans to participate in another investigational drug trial.
5. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant unless they are using highly effective methods of contraception during dosing and for 15 weeks after stopping treatment.
6. 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.
7. History or current diagnosis of ECG abnormalities indicating significant risk of safety such as: • Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), and clinically significant second or third degree AV block without a pacemaker • History of familial long QT syndrome or know family history of Torsades de Pointes
8. Not able to understand and to comply with study instructions and requirements.
9. Received prior treatment with crizanlizumab or other selectin targeting agent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Annualized rate of VOC events leading to healthcare visit in each treatment group over the first year post randomization

Secondary endpoints 16

1. Annualized rate of all VOCs leading to healthcare visit and treated at home (based on documentation by health care provider following contact with participant) over the first year post randomization
2. Annualized rate of VOCs managed at home over the first year post randomization
3. Duration of VOCs leading to healthcare visit over the first year post randomization
4. Number and percentage of participants free from VOCs leading to healthcare visit in each group over the first year post randomization
5. The time to first and second VOC calculated respectively as the time from date of randomization until the first and the second VOC leading to healthcare visit over the first year post randomization
6. Annualized rate of visits to clinic, Emergency room (ER) and hospitalizations, both overall and VOC-related over the first year post randomization
7. Evolution of albuminuria and ACR over the first year post randomization
8. PK parameters after the first and fifth dose (e.g., AUC, Cmax, Tmax, half-life)
9. PD parameter (P-selectin inhibition) after the first and fifth dose
10. Annualized rate of VOCs leading to healthcare visit
11. Annualized rate of all VOCs leading to healthcare visit and treated at home
12. Annualized rate of VOCs managed at home
13. Number, seriousness, severity, and causality assessments of treatment-emergent adverse events, including infections (serious, non-serious and opportunistic infections) and other safety data as considered appropriate
14. Absolute change from baseline in hemoglobin
15. Growth and sexual maturity assessment in adolescents (Tanner stage)
16. Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 17

Locations

5 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 37 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications