Clinical trial NCT03814746: Study of Two Doses of Crizanlizumab Versus Placebo in Adolescent and Adult Sickle Cell Disease Patients
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Sickle Cell Disease (SCD)
Keywords: 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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-01-24
Enrollment: 259
Sex: ALL
Minimum age (years): 12
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to a Healthcare Visit
timeFrame: 1 year
Secondary outcomes:
measure: Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over the First-year Post Randomization (Key Secondary)
timeFrame: 1 year
measure: Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home Over 5 Years Post Randomization (Key Secondary)
timeFrame: 5 years
measure: Mean Duration of VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
timeFrame: 1 year
measure: Number of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
timeFrame: 1 year
measure: Percentage of Participants Free From VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
timeFrame: 1 year
measure: Time to First and Second VOCs Leading to a Healthcare Visit Over the First-year Post Randomization
timeFrame: 1 year
measure: Annualized Rate of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization
timeFrame: 1 year
measure: Annualized Days of Visits to Clinic, Emergency Room (ER) and Hospitalizations, Both Overall and VOC-related Over the First-year Post-randomization
timeFrame: 1 year
measure: Evolution of Albumin Creatinine Ratio (ACR) Over the First-year Post-randomization (Change From Baseline)
timeFrame: Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
measure: Evolution of Albuminuria (Urine Microalbumin) Over the First-year Post-randomization (Change From Baseline)
timeFrame: Over first year post-randomization (Baseline, Week 27 Day 1, Week 51 Day 1)
measure: Pharmacokinetic (PK) Profile of Crizanlizumab: AUCd15, AUCtau
timeFrame: 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
measure: PK Profile of Crizanlizumab: Cmax
timeFrame: 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
measure: PK Profile of Crizanlizumab: Tmax
timeFrame: 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
measure: PK Profile of Crizanlizumab: Half-life
timeFrame: steady-state was assessed at W15D1 (pre-dose, 0.5 hr, 2 hrs and 4 hrs post-dose), W15D2, W15D4, W16D1, W17D1, W18D1, W19D1
measure: PD Parameter (P-selectin Inhibition)
timeFrame: AUCd15 (first dose): W1D1, W1D2, W1D4, W2D1 and W3D1; steady state: W15D1, W15D2, W15D4, W16D1, W17D1 W18D1 and W19D1
measure: Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 1 Year
timeFrame: 1 year
measure: Annualized Rate of Various Subtypes of VOCs Leading to a Healthcare Visit at 5 Years
timeFrame: 5 years
measure: Annualized Rate of All VOCs Leading to a Healthcare Visit and Treated at Home at 5 Years
timeFrame: 5 years
measure: Number of VOCs Managed at Home at Year 1
timeFrame: 1 year
measure: Number of VOCs Managed at Home at 5 Years
timeFrame: 5 years
measure: Absolute Change From Baseline in Hemoglobin
timeFrame: 5 years
measure: Growth and Sexual Maturity Assessment in Adolescents (Tanner Stage)
timeFrame: 5 years
measure: Immunogenicity: Measurement of Anti-drug Antibodies (ADA) to Crizanlizumab
timeFrame: 5 years
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Childrens Healthcare of Atlanta
state: Georgia
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Charlotte
country: United States
facility: Levine Cancer Insitute Carolinas Healthcare System
state: North Carolina
city: Memphis
country: United States
facility: Univ of Tenn Health Sciences Ctr
state: Tennessee
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Brussel
country: Belgium
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Belem
country: Brazil
facility: Novartis Investigative Site
state: PA
city: Recife
country: Brazil
facility: Novartis Investigative Site
state: Pernambuco
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Ribeirao Preto
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Valledupar
country: Colombia
facility: Novartis Investigative Site
state: Cesar
city: Barranquilla
country: Colombia
facility: Novartis Investigative Site
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Helsinki
country: Finland
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Stuttgart
country: Germany
facility: Novartis Investigative Site
city: Accra
country: Ghana
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Patras
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Bhubaneswar
country: India
facility: Novartis Investigative Site
state: Odisha
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Telangana
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Verona
country: Italy
facility: Novartis Investigative Site
state: VR
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Irbid
country: Jordan
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Tripoli
country: Lebanon
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Den Haag
country: Netherlands
facility: Novartis Investigative Site
city: Muscat
country: Oman
facility: Novartis Investigative Site
city: Panama City
country: Panama
facility: Novartis Investigative Site
state: Republica De Panama
city: Panama City
country: Panama
facility: Novartis Investigative Site
city: Panama
country: Panama
facility: Novartis Investigative Site
city: Soweto
country: South Africa
facility: Novartis Investigative Site
state: Gauteng
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
state: South Yorkshire
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: