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

Sickle Cell Disease (SCD) Clinical Trial

— STAND  

Official title:

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03814746
• Other study ID #: CSEG101A2301
• Secondary ID: 2017-001746-10
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: July 26, 2019
• Est. completion date: December 14, 2026

Study information

• Verified date: March 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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. This is a multicenter clinical trial comparing 2 doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo in addition to standard of care participants might be taking at the time of study start, in adolescent and adult participants with confirmed diagnosis of sickle cell disease (SCD) and history of vaso-occlusive crisis (VOC) leading to a 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 252
• Est. completion date: December 14, 2026
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Key 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

Key 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

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease (SCD)

Intervention

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.
• 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.

Locations

Country	Name	City	State
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Brazil	Novartis Investigative Site	Belem	PA
Brazil	Novartis Investigative Site	Porto Alegre
Brazil	Novartis Investigative Site	Recife	Pernambuco
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Salvador	Bahia
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Colombia	Novartis Investigative Site	Barranquilla
Colombia	Novartis Investigative Site	Monteria
Colombia	Novartis Investigative Site	Valledupar	Cesar
Finland	Novartis Investigative Site	Helsinki
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Stuttgart
Ghana	Novartis Investigative Site	Accra
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Patras
Greece	Novartis Investigative Site	Thessaloniki
India	Novartis Investigative Site	Bhubaneswar	Odisha
India	Novartis Investigative Site	Hyderabad	Telangana
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Verona	VR
Jordan	Novartis Investigative Site	Irbid
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Tripoli
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Rotterdam	Zuid Holland
Oman	Novartis Investigative Site	Muscat
Panama	Novartis Investigative Site	Panama
Panama	Novartis Investigative Site	Panama City	Republica De Panama
Panama	Novartis Investigative Site	Panama City
South Africa	Novartis Investigative Site	Soweto	Gauteng
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Antakya / Hatay
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Sheffield
United Kingdom	Novartis Investigative Site	Sheffield	South Yorkshire
United States	Childrens Healthcare of Atlanta .	Atlanta	Georgia
United States	Boston Medical Center	Boston	Massachusetts
United States	Levine Cancer Insitute Carolinas Healthcare System	Charlotte	North Carolina
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Univ of Tenn Health Sciences Ctr	Memphis	Tennessee

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  Brazil,  Canada,  Colombia,  Finland,  France,  Germany,  Ghana,  Greece,  India,  Italy,  Jordan,  Lebanon,  Netherlands,  Oman,  Panama,  South Africa,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit	VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration.; Healthcare visit is defined as any visit to a medical facility such as emergency room (ER), hospital and/or office visit, which includes pain management of VOC in situ.; Annualized rate of corresponding VOC events = (Number of corresponding VOC events * 365)/(number of days in the observation period).; Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor and erythropoietin therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).	1 year
Secondary	Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary)	VOCs are based on documentation by provider following contact with participant. VOC:pain crisis requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit:a visit to a medical facility (ER, hospital &/or office visit resulting in pain management of VOC. Managed at home: no visit to any medical facility &/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. Annualized rate of corresponding VOC events = (# of corresponding VOC events * 365)/(# of days in observation period). Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor & erythropoietin therapies to treat SCD &/or to prevent/reduce VOCs), date of randomization + 365 days)	1 year
Secondary	Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over 5 Years Post Randomization (Key Secondary)	To compare the efficacy of 5.0 mg/kg vs placebo & 7.5 mg/kg vs placebo on the annualized rate of all VOCs based on documentation by provider following contact with participant. VOC is defined as pain crisis (an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) requiring therapy with oral/parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome, priapism and hepatic or splenic sequestration. Healthcare visit is defined as a visit to a medical facility (emergency room, hospital and/or office visit resulting in pain management of VOC. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is allowed. The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 & divided by the number of days in observation period.	5 years
Secondary	Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization	To assess the duration of VOCs leading to healthcare visit in each group. Mean duration of VOC per participant is defined as the average duration of all individual episodes of VOCs leading to healthcare visits of a given participant (a VOC duration is defined as end date of the VOC - start date of the VOC + 1). Participants with no VOC leading to healthcare visits have been excluded.	1 year
Secondary	Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization	To assess the number of participants free from VOCs leading to healthcare visit.; VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis.	1 year
Secondary	Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization	To assess the percentage of participants free from VOCs leading to healthcare visit. VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. A participant is free from VOC if they do not have a VOC crisis.	1 year
Secondary	Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization	To assess the time to first and second VOC leading to healthcare visit in each group.; Time to first occurrence of VOC leading to a healthcare visit is defined as the time from the date of randomization to the date of the first occurrence of the VOC.; Time to second occurrence of VOC leading to a healthcare visit is defined as the time from date of randomization to the date of the second occurrence of VOC.	1 year
Secondary	Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization	To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group.; Annualized rate of corresponding healthcare visits =(Number of corresponding healthcare visits * 365)/(number of days in the observation period).; Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor and erythropoietin therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days)	1 year
Secondary	Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization	To assess Healthcare resource utilization (visits to clinic, Emergency room (ER) and hospitalizations) both overall and VOC-related in each group.; Annualized days of corresponding healthcare visits =(Number of days =(Number of days of corresponding healthcare visits * 365)/(number of days in the observation period).; Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor and erythropoietin therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).	1 year
Secondary	Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline)	Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline.	Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
Secondary	Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline)	Laboratory values for parameters related to renal function (creatinine, estimated glomerular filtration rate, urine microalbumin, and urine albumin/creatinine ratio) were measured at 6-month intervals over time from baseline.	Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
Secondary	Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau	To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Area under the (concentration-time profile) curve.	AUCd15 (first-dose) was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) to W3D1; AUCtau (steady-state) was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Secondary	PK Profile of Crizanlizumab: Cmax	To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Maximum concentration.	first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Secondary	PK Profile of Crizanlizumab: Tmax	To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: Time to maximum concentration.	first-dose was assessed at W1D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose) through to W3D1; steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Secondary	PK Profile of Crizanlizumab: Half-life	To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 7.5 mg/kg: half life.	steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
Secondary	PD Parameter (P-selectin Inhibition)	To characterize the pharmacodynamic (PD) of crizanlizumab at 5.0 and 7.5 mg/kg: P-selectin inhibition (% inhibition multipled by hr)	AUCd15 (first dose): W1D1, W1D2, W1D4, W2D1 and W3D1; steady state: W15D1, W15D2, W15D4, W16D1, W17D1 W18D1 and W19D1
Secondary	Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year	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. VOC is defined as pain crisis which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Healthcare visit: any visit to a medical facility such as ER, hospital and/or office visit, which includes pain management of VOC in situ.; Annualized rate of corresponding VOC events = (Number of corresponding VOC events * 365)/(number of days in the observation period).; Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor and erythropoietin therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).	1 year
Secondary	Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 5 Years	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.; VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration.; Healthcare visit is defined as any visit to a medical facility such as emergency room, hospital and/or office visit, which includes pain management of VOC in situ.; The annualized rate of VOC leading to healthcare visit is the number of VOC leading to healthcare visit multiplied by 365 and divided by the number of days in the observation period.	5 years
Secondary	Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home at 5 Years	To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the rates of all VOCs (managed at home + leading to healthcare visit).	5 years
Secondary	Number of VOCs Managed at Home at Year 1	To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home.; VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed.	1 year
Secondary	Number of VOCs Managed at Home at 5 Years	To compare the efficacy of 5.0 mg/kg versus placebo and 7.5 mg/kg of crizanlizumab versus placebo on the number of VOC events that were managed at home.; VOC is defined as pain crisis (defined as an acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) which requires therapy with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as acute chest syndrome (ACS), priapism and hepatic or splenic sequestration. Managed at home is defined as no visit to any medical facility and/or healthcare professional to receive treatment for VOC. Healthcare contact for medical advice was allowed.	5 years
Secondary	Absolute Change From Baseline in Hemoglobin	To assess safety of crizanlizumab over the study period.	5 years
Secondary	Growth and Sexual Maturity Assessment in Adolescents (Tanner Stage)	To assess safety of crizanlizumab over the study period.	5 years
Secondary	Immunogenicity: Measurement of Anti-drug Antibodies (ADA) to Crizanlizumab	To assess immunogenicity of crizanlizumab over the study period.	5 years