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NCT03264989

Pharmacokinetics and Pharmacodynamics Study of SEG101 (Crizanlizumab) in Sickle Cell Disease (SCD) Patients With Vaso- Occlusive Crisis (VOC)

Completed Phase 2 Results posted Last updated 9 October 2024
What this trial tests

Phase 2 trial testing crizanlizumab in Sickle Cell Disease (SCD) in 57 participants. Completed in 26 June 2023.

Timeline
19 December 2017
Primary endpoint
26 June 2023
26 June 2023

Quick facts

Lead sponsorNovartis Pharmaceuticals
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment57
Start date19 December 2017
Primary completion26 June 2023
Estimated completion26 June 2023
Sites12 locations across United States

Drugs / interventions tested

Conditions studied

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 16 to 70, any sex, with Sickle Cell Disease (SCD). Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Pharmacokinetic (PK): AUCd15 and AUCtau of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients Primary · 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8 & 15; 5th dose: Day 1 (pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29

To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. AUCd15: The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1) after single dose AUCtau: The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)

Starting dose (Week 1): AUCd15
GroupValue95% CI
Crizanlizumab 5.0 mg/kg13100± 2810
Steady State (Week 15): AUCtau
GroupValue95% CI
Crizanlizumab 5.0 mg/kg20800± 5030
PK: Cmax of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients Primary · After the starting dose (Week 1) and after multiple doses (steady state, Week 15)

To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. Cmax: The maximum (peak) observed serum drug concentration after dose administration (mass x volume-1).

Starting dose (Week 1)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg102± 29.8
Steady State (Week 15)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg123± 36.4
Pre-dose Concentrations Prior to Each Study Drug Dose Primary · Pre-dose at Day 1 on Weeks 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51

To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients, by serum concentrations by treatment group. Data was collected prior to each study drug dose; From Week 3 (loading dose), pre-dose (trough) concentrations were obtained every 4 weeks.

Week (W) 3 Day 1 (D)1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg18.0± 6.42
W7 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg10.8± 5.21
W11 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.04± 5.04
W15 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg10.0± 5.39
W19 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.37± 4.95
W23 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.91± 5.09
W27 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.65± 4.03
W31 D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.75± 4.66
Percentage of P-selectin Inhibition After the Starting Dose (PD-AUCd15), After Multiple Doses (PD-AUCd29) of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients Primary · 1st dose: Day 1: (pre-dose, 0.5, 1, 2, 4, 6 & 24 hours post dose, Days 4, 8, 15; 5th dose: Day 1(pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post dose), Days 4, 8, 15, 22 & 29

PD-AUCd15 and PD-AUCd29 were derived from the P-selectin inhibition data of week 1 and week 15, respectively. To characterize PD of crizanlizumab at 5.0 mg/kg in SCD patients The area under the curve (AUC) of percentage of P-selectin inhibition versus time profile after the starting dose (PD-AUCd15) and after multiple doses (PD-AUCd29) is being reported.

Starting dose (Week 1): PD-AUCd15
GroupValue95% CI
Crizanlizumab 5.0 mg/kg33200± 1830
Steady state (Week 15): PD-AUCd29
GroupValue95% CI
Crizanlizumab 5.0 mg/kg66900± 5540
Annualized Rate of Vaso-occlusive Crisis (VOC) Events Leading to Healthcare Visit in Clinic/Emergency Room (ER)/Hospital Secondary · Baseline (Week 1) through approx. 45 months (median exposure to treatment)

To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in Sickle cell disease (SCD) patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

Baseline annualized rate of VOC
GroupValue95% CI
Crizanlizumab 5.0 mg/kg4.001.0 – 25.0
Crizanlizumab 7.5 mg/kg2.001.0 – 9.0
Annualized rate of VOC on treatment
GroupValue95% CI
Crizanlizumab 5.0 mg/kg2.750.0 – 17.3
Crizanlizumab 7.5 mg/kg0.970.0 – 7.9
Annualized Rate of VOC Events Treated at Home (Based on Documentation by Health Care Provider Following Phone Contact With Patient) Secondary · Baseline (Week 1) through approx. 45 months (median exposure to treatment)

To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

GroupValue95% CI
Crizanlizumab 5.0 mg/kg0.680.21 – 2.17
Crizanlizumab 7.5 mg/kg0.710.35 – 1.74
Annualized Rate of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits Secondary · Baseine (Week 1) through approx. 45 months (median exposure to treatment)

To assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of hospitalizations and ER visits = number of hospitalizations and ER visits reported until end date × 365.25/(End date - treatment start date + 1). End date is defined as the 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

Annualized rate (total)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg3.420.0 – 57.8
Crizanlizumab 7.5 mg/kg2.470.0 – 8.1
Annualized rate (VOC related)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg3.340.0 – 57.8
Crizanlizumab 7.5 mg/kg0.860.0 – 7.9
Hospitalizations/ER Annualized rate (total)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg2.460.0 – 22.1
Crizanlizumab 7.5 mg/kg1.440.0 – 7.9
Hospitalizations/ER Annualized rate (VOC related)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg2.270.0 – 22.1
Crizanlizumab 7.5 mg/kg0.480.0 – 7.9
Annualized Days of Total and VOC-related Hospitalizations and Emergency Room (ER) Visits Secondary · Baseline (Week 1) through approx. 45 months (median exposure to treatment)

Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients for hospitalizations and ER visits. Annualized days of all hospitalizations and ER visits = Number of days of all hospitalizations and ER visits × 365.25/(End date - treatment start date + 1). End date is defined as the 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

Annualized days (total)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg11.950.0 – 86.2
Crizanlizumab 7.5 mg/kg3.170.0 – 36.8
Annualized days (VOC related)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg9.030.0 – 86.2
Crizanlizumab 7.5 mg/kg1.570.0 – 36.8
Hospitalizations/ER Annualized days (total)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg10.310.0 – 69.4
Crizanlizumab 7.5 mg/kg2.570.0 – 36.8
Hospitalizations/ER Annualized days (VOC related)
GroupValue95% CI
Crizanlizumab 5.0 mg/kg7.270.0 – 69.4
Crizanlizumab 7.5 mg/kg0.600.0 – 36.8
Annualized Rate of Each Subcategory of All VOC Events (Acute Chest Syndrome (ACS), Priapism, Uncomplicated Sickle Cell-vaso-occlusive Cisis (Uncomplicated SC-VOCs)) Secondary · Baseline (Week 1) through approx. 45 months (median exposure to treatment)

Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. The baseline (BL) annualized rate of VOC is defined as the number of VOCs reported in the last 12 months in the eCRF. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date - date of first dose of study treatment+1). End date is defined as the 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

BL annualized rate of VOC: ACS
GroupValue95% CI
Crizanlizumab 5.0 mg/kg0.000.0 – 2.0
Crizanlizumab 7.5 mg/kg0.000.0 – 2.0
Annualized rate of VOC on treatment: ACS
GroupValue95% CI
Crizanlizumab 5.0 mg/kg0.620.0 – 2.7
Crizanlizumab 7.5 mg/kg0.250.0 – 0.6
BL annualized rate of VOC: Priapism
GroupValue95% CI
Crizanlizumab 5.0 mg/kg1.000.0 – 4.0
Annualized rate of VOC on treatment: Priapism
GroupValue95% CI
Crizanlizumab 5.0 mg/kg1.580.0 – 3.8
BL annualized rate of VOC: Uncomplicated SC-VOCs
GroupValue95% CI
Crizanlizumab 5.0 mg/kg3.001.0 – 25.0
Crizanlizumab 7.5 mg/kg2.001.0 – 9.0
Annualized rate of VOC on treatment: Uncomplicated SC-VOCs
GroupValue95% CI
Crizanlizumab 5.0 mg/kg2.580.0 – 17.3
Crizanlizumab 7.5 mg/kg1.040.0 – 7.9
Annualized Rate of VOC Events (Including Both Healthcare Visit and Home Treatment) Secondary · Baseline (Week 1) through approx. 45 months (median exposure to treatment)

Assess the efficacy of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. Annualized rate of VOC=(Number of VOC reported until End date ×365.25)/(End date -date of first dose of study treatment+1). End date is defined as th e 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 to treat SCD and or to prevent/reduce VOCs, cut-off date).

GroupValue95% CI
Crizanlizumab 5.0 mg/kg3.420.0 – 17.3
Crizanlizumab 7.5 mg/kg1.650.0 – 9.3
Number of Participants With Immunogenicity (IG) by Any Positive Status Secondary · Baseline (Week 1), post-baseline (approx. 45 months (median exposure))

Assess safety and tolerability of crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients by the percentage of participants with any positive status. Immunogenicity is the measurement of anti-drug antibodies (ADA) to crizanlizumab.

Baseline: Positive
GroupValue95% CI
Crizanlizumab 5.0 mg/kg0
Crizanlizumab 7.5 mg/kg0
All Participants0
Post-Baseline: Any Positive
GroupValue95% CI
Crizanlizumab 5.0 mg/kg0
Crizanlizumab 7.5 mg/kg0
All Participants0
Percentage of P-selectin Inhibition Prior to Each Study Drug Dose of Crizanlizumab at 5.0 mg/kg in Sickle Cell Disease (SCD) Patients Primary · Pre-dose on Day 1 for Weeks 3, 7, 11, 15, 19, 23, 27, 31,35, 39, 43, 47, 51 (at 0 hr or pre-dose)

To characterize the PD effect of crizanlizumab in terms of Percentage of P-selectin inhibition prior to study drug dose at 5 mg/kg in CSD patients.

Week (W) 3 Day (D) 1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg97.3± 7.49
W7D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg93.0± 17.1
W11D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg87.8± 22.6
W15D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg94.1± 12.8
WD19: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg91.7± 18.5
W23D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg93.2± 14.9
W27D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg94.3± 13.0
W31D1: 0 hrs pre-dose
GroupValue95% CI
Crizanlizumab 5.0 mg/kg92.4± 18.9

Adverse events — posted to ClinicalTrials.gov

Time frame: All deaths, Serious Adverse Events, and Other Adverse Events for both 'Treatment phase' and 'Post-treatment follow-up phase' (up to 105 days after the last dose of study treatment) were reported. The median duration of exposure to crizanlizumab was 206.1 weeks in the 5.0 mg/kg dose group and 169.6 weeks in the 7.5 mg/kg dose group.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Crizanlizumab 5.0 mg/kg
Serious: 22/45 (49%)
Deaths: 1/45
Crizanlizumab 7.5 mg/kg
Serious: 6/12 (50%)
Deaths: 1/12
All Participants
Serious: 28/57 (49%)
Deaths: 2/57

Serious adverse events (59 terms)

ReactionSystemCrizanlizumab 5.0 mg/kgCrizanlizumab 7.5 mg/kgAll Participants
COVID-19Infections and infestations
PneumoniaInfections and infestations
Pulmonary embolismRespiratory, thoracic and mediastinal disorders
Chest painGeneral disorders
PyrexiaGeneral disorders
Urinary tract infectionInfections and infestations
OsteonecrosisMusculoskeletal and connective tissue disorders
Acute kidney injuryRenal and urinary disorders
AnaemiaBlood and lymphatic system disorders
CytopeniaBlood and lymphatic system disorders
Sickle cell anaemia with crisisBlood and lymphatic system disorders
Acute myocardial infarctionCardiac disorders
Cardiac arrestCardiac disorders
Vertigo positionalEar and labyrinth disorders
Abdominal painGastrointestinal disorders
DiverticulumGastrointestinal disorders
Haemorrhoidal haemorrhageGastrointestinal disorders
Mouth ulcerationGastrointestinal disorders
Small intestinal obstructionGastrointestinal disorders
StomatitisGastrointestinal disorders
Tooth erosionGastrointestinal disorders
Gait disturbanceGeneral disorders
Multiple organ dysfunction syndromeGeneral disorders
CholelithiasisHepatobiliary disorders
HypertransaminasaemiaHepatobiliary disorders
Other adverse events (76 terms — click to expand)

ReactionSystemCrizanlizumab 5.0 mg/kgCrizanlizumab 7.5 mg/kgAll Participants
PyrexiaGeneral disorders
HypokalaemiaMetabolism and nutrition disorders
HeadacheNervous system disorders
Upper respiratory tract infectionInfections and infestations
ArthralgiaMusculoskeletal and connective tissue disorders
NauseaGastrointestinal disorders
VomitingGastrointestinal disorders
Chest painGeneral disorders
COVID-19Infections and infestations
Road traffic accidentInjury, poisoning and procedural complications
Back painMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
Oedema peripheralGeneral disorders
Pain in extremityMusculoskeletal and connective tissue disorders
PruritusSkin and subcutaneous tissue disorders
ConstipationGastrointestinal disorders
FatigueGeneral disorders
PharyngitisInfections and infestations
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
ToothacheGastrointestinal disorders
GastroenteritisInfections and infestations
Urinary tract infectionInfections and infestations
Decreased appetiteMetabolism and nutrition disorders
DehydrationMetabolism and nutrition disorders
OsteonecrosisMusculoskeletal and connective tissue disorders
AnxietyPsychiatric disorders
InsomniaPsychiatric disorders
HypoxiaRespiratory, thoracic and mediastinal disorders
HypertensionVascular disorders
Deafness neurosensoryEar and labyrinth disorders
Abdominal pain upperGastrointestinal disorders
GastritisGastrointestinal disorders
PainGeneral disorders
Ocular icterusHepatobiliary disorders
Acute sinusitisInfections and infestations
CystitisInfections and infestations
PneumoniaInfections and infestations
Tooth infectionInfections and infestations
Post-traumatic painInjury, poisoning and procedural complications
Skin lacerationInjury, poisoning and procedural complications

Most-reported serious reactions: COVID-19, Pneumonia, Pulmonary embolism, Chest pain, Pyrexia, Urinary tract infection, Osteonecrosis, Acute kidney injury.

Data from ClinicalTrials.gov NCT03264989 adverse events section.

Sponsor's own description

The purpose of the CSEG101A2202 study was to characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of SEG101/crizanlizumab and to evaluate the safety and efficacy of SEG101/crizanlizumab in sickle cell disease (SCD) patients.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. The clinical impact of glycobiology: targeting selectins, Siglecs and mammalian glycans.
    Smith BAH, Bertozzi CR. · · 2021 · cited 380× · PMID 33462432 · DOI 10.1038/s41573-020-00093-1
  2. Antibodies to watch in 2018.
    Kaplon H, Reichert JM. · · 2018 · cited 179× · PMID 29300693 · DOI 10.1080/19420862.2018.1415671
  3. Recent Advances in the Treatment of Sickle Cell Disease.
    Salinas Cisneros G, Thein SL. · · 2020 · cited 110× · PMID 32508672 · DOI 10.3389/fphys.2020.00435
  4. P- and E- selectin in venous thrombosis and non-venous pathologies.
    Purdy M, Obi A, Myers D, Wakefield T. · · 2022 · cited 60× · PMID 35243742 · DOI 10.1111/jth.15689
  5. Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials.
    Ali MA, Ahmad A, Chaudry H, Aiman W, et al · · 2020 · cited 41× · PMID 32841705 · DOI 10.1016/j.exphem.2020.08.008
  6. Drug Therapies for the Management of Sickle Cell Disease.
    Rai P, Ataga KI. · · 2020 · cited 32× · PMID 32765834 · DOI 10.12688/f1000research.22433.1
  7. Targeting pain at its source in sickle cell disease.
    Gupta K, Jahagirdar O, Gupta K. · · 2018 · cited 28× · PMID 29590553 · DOI 10.1152/ajpregu.00021.2018
  8. Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing.
    Anurogo D, Yuli Prasetyo Budi N, Thi Ngo MH, Huang YH, et al · · 2021 · cited 26× · PMID 34200975 · DOI 10.3390/ijms22126275

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