Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of 2 doses of crizanlizumab (5.0 mg/kg and 7.5 mg/kg) versus placebo in adolescent and adult sickle cell disease (SCD) patients with history of vaso-occlusive crisis (VOC) leading to healthcare visit.

Detailed Description
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Study CSEG101A2301 (STAND) is an ongoing Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in adolescent and adult patients with SCD and history of VOC leading to healthcare visit. 240 participants (including 48 adolescents) were planned to be randomized in a 1:1:1 ratio to either 5 mg/kg, 7.5 mg/kg of crizanlizumab or placebo. Randomized participants were stratified by concomitant HU/HC usage (yes/no) and baseline rate of VOCs leading to a healthcare visit in 12 months prior to screening visit (2-4 vs. ≥ 5 VOCs) at the time of enrollment. In November 2020, a capping of 90 adult participants per strata was implemented to ensure adequate opportunity for enrollment into each of the 4 strata.

Official Title
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A Phase III, Multicenter, Randomized, Double-blind Study to Assess Efficacy and Safety of Two Doses of Crizanlizumab Versus Placebo, With or Without Hydroxyurea/ Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Vaso-Occlusive Crises (STAND)

Conditions
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Sickle Cell Disease (SCD)

Intervention / Treatment
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* Drug: Crizanlizumab (SEG101)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained prior to any screening procedures Male or female patients aged 12 years and older on the day of signing informed consent. Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid chromatography (HPLC) [performed locally]. All SCD genotypes are eligible, genotyping is not required for study entry 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: Pain crisis defined as an acute onset of pain for which there is no other medically determined explanation other than vaso- occlusion - which requires a visit to a medical facility and/or healthcare professional, and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory drug (NSAID) analgesia Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be considered VOC in this study 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 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 ECOG performance status ≤2.0 for adults and Karnofsky ≥ 50% for adolescents Exclusion Criteria: History of stem cell transplant. 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. 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. 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. 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. 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. 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 Not able to understand and to comply with study instructions and requirements. Received prior treatment with crizanlizumab or other selectin targeting agent

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crizanlizumab (SEG101) at 5.0 mg/kg<br>Participants received Crizanlizumab (SEG101) at 5.0 mg/kg | Drug: Crizanlizumab (SEG101)<br>* Crizanlizumab was supplied in single use 10 mL glass vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab. This is a concentrate for solution for infusion. IV.<br>* Other names: SEG101;|
| Experimental: Crizanlizumab (SEG101) at 7.5 mg/kg<br>Participants received Crizanlizumab (SEG101) at 7.5 mg/kg | Drug: Crizanlizumab (SEG101)<br>* Crizanlizumab was supplied in single use 10 mL glass vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab. This is a concentrate for solution for infusion. IV.<br>* Other names: SEG101;|
| Placebo Comparator: Placebo<br>Participants received the placebo drug. | Drug: Placebo<br>* Placebo was supplied in single use 10 mL glass vials at a concentration of 0 mg/mL. This is a concentrate for solution for infusion IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of vaso-occlusive crisis (VOC) events leading to healthcare visit | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo in addition to standard of care. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized rate of all VOCs leading to healthcare visit and treated at home (Key Secondary) | 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), based on documentation by health care provider following contact with participant. | 1 year, 5 years | 
| Duration of VOCs leading to healthcare visit | To assess the duration of VOCs leading to a healthcare visit in each group | 1 year | 
| Number of subjects free from VOCs leading to healthcare visit | To assess number of participants free from VOC leading to a healthcare visit in each group | 1 year | 
| Percentage of subjects free from VOCs leading to healthcare visit | To assess rate of participants free from VOC leading to a healthcare visit in each group | 1 year | 
| Time to first and second VOC leading to healthcare visit | To assess the time to first and second VOC leading to healthcare visit in each group | 1 year | 
| Annualized rate of visits to clinic, Emergency room (ER) and hospitalizations, both overall and VOC-related | To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC- related | 1 year | 
| Evolution of albuminuria and albumin creatinine ratio (ACR) | To assess (sickle cell disease) SCD-related renal damage in each group. | 1 year | 
| Pharmacokinetic (PK) profile of crizanlizumab: AUC | To characterize the Pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg using AUC | after the first and fifth dose | 
| PK profile of crizanlizumab: Cmax | To characterize the PK profile of crizanlizumab at 5.0 and 7.5 mg/kg using Cmax | after the first and fifth dose | 
| PK profile of crizanlizumab: Tmax | To characterize the PK profile of crizanlizumab at 5.0 and 7.5 mg/kg using Tmax | after the first and fifth dose | 
| PK profile of crizanlizumab: half-life | To characterize the PK profile of crizanlizumab at 5.0 and 7.5 mg/kg using half-life | after the first and fifth dose | 
| PD parameter (P-selectin inhibition) | To characterize the pharmacodynamic (PD) (P-selectin inhibition) of crizanlizumab at 5.0 and 7.5 mg/kg | after the first and fifth dose | 
| Annualized rate of subtypes of VOCs leading to a healthcare visit | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs leading to healthcare visit by subtypes. | 1 year, 5 years | 
| Annualized rate of all VOCs leading to a healthcare visit and treated at home | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of all VOCs (managed at home + leading to healthcare visit). | 1 year, 5 years | 
| Annualized rate of VOCs managed at home | To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the annualized rate of VOCs managed at home. | 1 year, 5 years | 
| Absolute change from baseline in hemoglobin | To assess safety of crizanlizumab over the study period. | 5 years | 
| Growth and sexual maturity assessment in adolescents (Tanner stage) | To assess safety of crizanlizumab over the study period. | 5 years | 
| Measurement of anti-drug antibodies (ADA) to crizanlizumab | To assess immunogenicity of crizanlizumab over the study period. | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, SCD, SEG101, Crizanlizumab, Hydroxyurea/ Hydroxycarbamide Therapy, Vaso-Occlusive Crises, SCA, blood disorders, hemoglobin, red blood cells, sickle-like shape, mutation in hemoglobin gene, sickle-cell trait, sickle-cell crisis