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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
First received
Last updated
Start date July 26, 2019
Est. completion date December 14, 2026

Study information

Verified date May 2024
Source Novartis
Contact n/a
Is FDA regulated No
Health authority
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

Study Design


Related Conditions & MeSH terms


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
See also
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Completed NCT03478917 - Early Diagnosis of Sickle Acute Chest Syndrome Using a Combination of Plasma Bimarkers and Chest Imaging
Active, not recruiting NCT05565092 - Safety, Efficacy, Pharmacokinetic, and Pharmacodynamic Study of ALXN1820 in Adult Participants With Sickle Cell Disease Phase 2
Completed NCT03264989 - Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC) Phase 2
Completed NCT04053764 - Study Exploring the Effect of Crizanlizumab on Kidney Function in Patients With Chronic Kidney Disease Caused by Sickle Cell Disease Phase 2