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

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)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Sickle Cell Disease (SCD)
• Intervention / Treatment: Drug: Crizanlizumab (SEG101); Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1000
    • Novartis Investigative Site
  • Bruxelles, Belgium, 1070
    • Novartis Investigative Site
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Novartis Investigative Site
• Brazil
  • Porto Alegre, Brazil, 90035-003
    • Novartis Investigative Site
  • Bahia
    • Salvador, Bahia, Brazil, 41253-190
      • Novartis Investigative Site
  • PA
    • Belem, PA, Brazil, 66033 000
      • Novartis Investigative Site
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50070-170
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20.211-030
      • Novartis Investigative Site
  • SP
    • Ribeirao Preto, SP, Brazil, 14048-900
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 08270-070
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 01232-010
      • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 1R9
      • Novartis Investigative Site
• Colombia
  • Barranquilla, Colombia, 080020
    • Novartis Investigative Site
  • Monteria, Colombia, 230004
    • Novartis Investigative Site
  • Cesar
    • Valledupar, Cesar, Colombia, 5602310
      • Novartis Investigative Site
• Finland
  • Helsinki, Finland, FIN 00290
    • Novartis Investigative Site
• France
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Marseille Cedex 05, France, 13885
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Koeln, Germany, 50937
    • Novartis Investigative Site
  • Stuttgart, Germany, 70376
    • Novartis Investigative Site
• Ghana
  • Accra, Ghana, 0437-0594
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Patras, Greece, 265 00
    • Novartis Investigative Site
  • Thessaloniki, Greece, GR 54636
    • Novartis Investigative Site
• India
  • Odisha
    • Bhubaneswar, Odisha, India, 751003
      • Novartis Investigative Site
  • Telangana
    • Hyderabad, Telangana, India, 500082
      • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80138
    • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16128
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
  • VR
    • Verona, VR, Italy, 37126
      • Novartis Investigative Site
• Jordan
  • Irbid, Jordan, 22110
    • Novartis Investigative Site
• Lebanon
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
  • Tripoli, Lebanon, 1434
    • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Den Haag, Netherlands, 2545 CH
    • Novartis Investigative Site
  • Zuid Holland
    • Rotterdam, Zuid Holland, Netherlands, 3015 GD
      • Novartis Investigative Site
• Oman
  • Muscat, Oman, 123
    • Novartis Investigative Site
• Panama
  • Panama, Panama, 0801
    • Novartis Investigative Site
  • Panama City, Panama, 0801
    • Novartis Investigative Site
  • Republica De Panama
    • Panama City, Republica De Panama, Panama, 0801
      • Novartis Investigative Site
• South Africa
  • Gauteng
    • Soweto, Gauteng, South Africa, 2013
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28034
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Antakya / Hatay, Turkey, 31100
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Novartis Investigative Site
  • London, United Kingdom, SE1 9RT
    • Novartis Investigative Site
  • London, United Kingdom, SE5 9RS
    • Novartis Investigative Site
  • Sheffield, United Kingdom, S10 2TH
    • Novartis Investigative Site
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Novartis Investigative Site
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Novartis Investigative Site
  • Tennessee
    • Memphis, Tennessee, United States, 38163
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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. Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years
3. 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

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) analgesia 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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Crizanlizumab (SEG101) at 5.0 mg/kg; Participants received Crizanlizumab (SEG101) at 5.0 mg/kg	Drug: Crizanlizumab (SEG101); 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.; Other Names: SEG101
Experimental: Crizanlizumab (SEG101) at 7.5 mg/kg; Participants received Crizanlizumab (SEG101) at 7.5 mg/kg	Drug: Crizanlizumab (SEG101); 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.; Other Names: SEG101
Placebo Comparator: Placebo; Participants received the placebo drug.	Drug: Placebo; 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.

What is the study measuring?

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
Evolution of albuminuria and albumin creatinine ratio (ACR)	To assess (sickle cell disease) SCD-related renal damage in each group.	1 year
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
Absolute change from baseline in hemoglobin	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
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
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
Growth and sexual maturity assessment in adolescents (Tanner stage)	To assess safety of crizanlizumab over the study period.	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
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
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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2019
• Primary Completion (Actual): August 31, 2022
• Study Completion (Estimated): December 14, 2026

Study Registration Dates

• First Submitted: January 21, 2019
• First Submitted That Met QC Criteria: January 21, 2019
• First Posted (Actual): January 24, 2019

Study Record Updates

• Last Update Posted (Actual): September 1, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: hemoglobin; Sickle Cell Disease; SCD; SEG101; blood disorders; red blood cells; sickle-like shape; mutation in hemoglobin gene; sickle-cell trait; sickle-cell crisis; SCA; Crizanlizumab; Hydroxyurea/ Hydroxycarbamide Therapy; Vaso-Occlusive Crises
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell
• Other Study ID Numbers: CSEG101A2301; 2017-001746-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No