Crizanlizumab for Sickle Cell Disease
(SPARKLE Trial)
Recruiting in Palo Alto (17 mi)
+7 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Novartis Pharmaceuticals
Disqualifiers: Stroke, Intracranial hemorrhage, Transfusion, others
Pivotal Trial (Near Approval)
Prior Safety Data
Approved in 1 Jurisdiction
Trial Summary
What is the purpose of this trial?
A phase III, multi-center, randomized, placebo-controlled, double-blind study to assess efficacy and safety of crizanlizumab (5 mg/kg) versus placebo, with or without hydroxyurea/hydroxycarbamide therapy, in adolescent and adult Sickle Cell Disease patients with frequent vaso-occlusive crises.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, if you are on hydroxyurea/hydroxycarbamide or an erythropoietin stimulating agent, you must have been on a stable dose for at least 3 months and plan to continue it during the study.
What data supports the effectiveness of the drug crizanlizumab for sickle cell disease?
Is crizanlizumab safe for humans?
What makes the drug Crizanlizumab unique for treating Sickle Cell Disease?
Crizanlizumab is unique because it targets P-selectin, a protein that plays a key role in the inflammation and blockage of blood vessels in Sickle Cell Disease, helping to reduce pain crises. This mechanism is different from other treatments that primarily focus on managing symptoms or increasing fetal hemoglobin levels.7891011
Eligibility Criteria
This trial is for adolescents and adults aged 12 years and older with confirmed Sickle Cell Disease (SCD). They must have experienced 4 to 12 vaso-occlusive crises (VOCs) in the past year. If they're on hydroxyurea/hydroxycarbamide, it should be a stable dose for at least 3 months before the study.Inclusion Criteria
I am 12 years old or older.
I have been diagnosed with sickle cell disease through a blood test.
I've had 4 to 12 severe pain crises managed by a doctor in the last year.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive Crizanlizumab 5 mg/kg or placebo, with or without hydroxyurea/hydroxycarbamide therapy, for the management of vaso-occlusive crises
52 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Long-term follow-up
Participants are monitored for long-term safety and efficacy outcomes, including adverse events and immunogenicity
2 years
Treatment Details
Interventions
- Crizanlizumab (Monoclonal Antibodies)
Trial OverviewThe SPARKLE study is testing Crizanlizumab (5 mg/kg) against a placebo to see if it's effective and safe in reducing VOCs in SCD patients. This includes those taking hydroxyurea/hydroxycarbamide, with participants randomly assigned to either group.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Crizanlizumab (SEG101) at 5.0 mg/kgExperimental Treatment1 Intervention
Participants receive Crizanlizumab (SEG101) at 5.0 mg/kg and standard of care.
Group II: PlaceboPlacebo Group1 Intervention
Participants receive the placebo drug and standard of care.
Crizanlizumab is already approved in United States for the following indications:
🇺🇸 Approved in United States as Adakveo for:
- Prevention of recurrent vaso-occlusive crises in sickle cell disease patients aged 16 years and older
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
WCG Sonar Clinical ResearchRiverdale, GA
University of FloridaJacksonville, FL
Augusta University GeorgiaAugusta, GA
Childrens Hospital at MontefioreBronx, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
References
Crizanlizumab: First Approval. [2020]Crizanlizumab (Adakveo®; crizanlizumab-tmca) is an intravenously administered monoclonal antibody developed by Novartis Pharmaceuticals for the prevention of vaso-occlusive crises (VOCs) in patients with sickle cell disease. Crizanlizumab binds to P-selectin, thereby blocking its interaction with P-selectin glycoprotein ligand-1. In November 2019, crizanlizumab received its first global approval in the USA, where it is indicated to reduce the frequency of VOCs in adults and paediatric patients aged ≥ 16 years with sickle cell disease. The drug is also under regulatory review in the EU for the prevention of VOCs in patients with sickle cell disease. The use of crizanlizumab (in combination with ruxolitinib) in myelofibrosis is also being evaluated in Australia, Spain, Germany and Hungary. This article summarizes the milestones in the development of crizanlizumab leading to this first approval for the reduction of VOCs in patients with sickle cell disease.
Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. [2022]Objective: To review the efficacy and safety of crizanlizumab (Adakveo) in the prevention of vaso-occlusive pain crises in sickle cell disease. Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to January 2021) was completed using the terms crizanlizumab, SEG101, SelG1, and sickle cell disease. Manufacturer prescribing information, article bibliographies, and data from clinicaltrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on clinicaltrials.gov were incorporated in the reviewed data. Data Synthesis: Crizanlizumab is the first monoclonal antibody approved for sickle cell disease to reduce the frequency of vaso-occlusive crises. One phase 2 clinical trial and a post hoc analysis of the trial have been published. Relevance to Patient Care and Clinical Practice: Crizanlizumab is a monthly intravenous infusion approved by the Food and Drug Administration for patients with sickle cell disease 16 years of age and older to reduce the frequency of vaso-occlusive crises. Conclusion: Crizanlizumab appears to be an efficacious therapy for patients with sickle cell disease to reduce the frequency of vaso-occlusive crises. Concerns include drug cost and administration. Long-term benefits and risks have not been determined.
Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis. [2023]Crizanlizumab was approved by the United States Food and Drug Administration agency in 2019 for decreasing vaso-occlusive events (VOEs) in sickle cell disease (SCD). Data regarding the use of crizanlizumab in the real-world setting are limited. Our goal was to identify patterns of crizanlizumab prescriptions in our SCD program and evaluate the benefits and identify barriers to its use in our SCD clinic.
The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease. [2021]Crizanlizumab is a monoclonal antibody that binds to P-selectin. On October 28, 2020, a conditional marketing authorization valid through the European Union (EU) was issued for crizanlizumab for the prevention of recurrent vaso-occlusive crises (VOCs) in patients with sickle cell disease aged 16 years or older. Crizanlizumab was evaluated in a phase 2, double-blind, placebo-controlled randomized multicenter trial comparing high-dose (5 mg/kg) crizanlizumab, low-dose (2.5 mg/kg) crizanlizumab and placebo in patients with a history of 2-10 VOCs in the previous year. Patients who were receiving concomitant hydroxycarbamide (HC) as well as those not receiving HC were included in the study. The primary endpoint of the trial was the annual rate of sickle cell-related pain crises as adjudicated by a central review committee. High-dose crizanlizumab led to a 45.3% lower median annual rate of sickle cell-related pain crises compared to placebo (P = 0.010), with no statistically significant difference for the low dose. Treatment with high-dose crizanlizumab led to similar incidences of adverse events (AEs), grade 3 AEs, and serious AEs compared to placebo. Most frequently observed AEs that occurred more often in the crizanlizumab arm compared to placebo were infusion related reactions (34.8% versus 21%), arthralgia (18.2% versus 8.1%), diarrhea (10.6% versus 3.2%), and nausea (18.2% versus 11.3%). The aim of this article is to summarize the scientific review of the application leading to regulatory approval in the EU.
Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. [2020]Sickle cell disease (SCD) is one of the most common inherited blood disorders globally. It is a grouping of autosomal recessive genetic disorders identified by a genetic mutation that replaces glutamic acid with valine at the sixth amino acid on the hemoglobin β-globin chain. Millions of people around the world live with a severe genotype of SCD that is often associated with occlusion of the microvasculature resulting in episodes of severe pain and multiple organ system dysfunction. These episodes, commonly categorized as vaso-occlusive crises (VOC), are a distinctive clinical presentation of SCD which represents the majority of SCD morbidity and associated hospitalizations. Though the complete process by which these crises occur is complex and not fully outlined, evidence reveals this process to be multifactorial and heterocellular. For nearly two decades, hydroxyurea was the only FDA-approved therapy for SCD. Evidence to date shows that hydroxyurea treatment significantly reduces the rate of VOC, hospitalizations, and mortality. Despite these benefits, adherence remains problematic due to a variety of adverse effects and interpatient variability connected with hydroxyurea therapy. Crizanlizumab, an adhesion inhibitor of sickled red blood cells, was recently granted breakthrough therapy designation. Results of a phase 2 study have reported a successful reduction in annual rates of vaso-occlusive crisis with a favorable safety profile. This paper reviews the available literature concerning crizanlizumab use in patients with SCD.
Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. [2023]Crizanlizumab is an anti-P-selectin monoclonal antibody indicated to reduce the frequency/prevent recurrence of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD) aged ≥16 years. This analysis of an ongoing phase 2, nonrandomized, open-label study reports the pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy of crizanlizumab 5.0 mg/kg (N = 45) and 7.5 mg/kg (N = 12) in patients with SCD with a history of VOCs. The median treatment duration was 104.7 and 85.7 weeks in the 5.0 and 7.5 mg/kg groups, respectively. For both doses, serum crizanlizumab concentrations rose to near maximum levels shortly after infusion, and near complete and sustained ex vivo P-selectin inhibition was observed. Grade ≥3 adverse events (AEs) occurred in 48.9% and 33.3% of patients in the 5.0 and 7.5 mg/kg groups, respectively; only 1 event was deemed treatment-related (7.5 mg/kg group). No treatment-related serious AEs occurred. One infusion-related reaction was recorded (5.0 mg/kg, grade 2 "pain during infusion"), which resolved without treatment withdrawal. Infections occurred in 57.8% and 41.7% of patients in the 5.0 and 7.5 mg/kg groups, respectively; none were drug-related. No treatment-related bleeding events were reported. No patients developed immunogenicity. The median (range) absolute reduction from baseline in the annualized rate of VOCs leading to a health care visit was -0.88 (-14.7 to 13.3) and -0.93 (-2.0 to 0.4) in the 5.0 and 7.5 mg/kg groups, respectively. Results here demonstrate the PK/PD properties of crizanlizumab in patients with SCD and the potential sustained efficacy and long-term safety of the drug after >12 months' treatment. This trial was registered at www.clinicaltrials.gov as #NCT03264989.
[Current therapy of chronic myeloid leukemia]. [2022]Chronic myeloid leukemia (CML) originates from a hematopoietic stem cell carrying the Philadelphia (Ph) chromosome and oncogenic BCR-ABL1 fusion gene. The first tyrosine-kinase inhibitor (TKI) imatinib was introduced to clinical practice 10 years ago, and it radically improved the outcome of CML patients. The rare patients that are imatinib resistant or intolerant can be treated with second generation TKIs such as dasatinib or nilotinib. As second generation TKIs appear to be more effective than imatinib and well tolerated, they may become standard first-line treatment for CML. The major future aim in CML is curative drug therapy.
Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. [2019]In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment.
Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation. [2015]Chronic myeloid leukemia (CML) is a hematological disorder that in rare cases, mainly in CML neutrophilic, presents the e19a2 rearrangement. The encoded product is a 230-KDa protein. Despite the remarkable responses to treatment of most patients, a small but significant fraction of them develop clinical resistance to the tyrosine kinase inhibitors (TKIs). The most common mechanism of resistance is point mutations in the ABL1 kinase domain. The recently approved third-generation TKI ponatinib demonstrated remarkable activity in patients with multi-TKI-resistant disease. Particularly impressive was its efficacy in patients with T315I mutation that is resistant to all other TKIs.
Is imatinib still an acceptable first-line treatment for CML in chronic phase? [2017]The introduction of the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all, patients with chronic myeloid leukemia in chronic phase (CML-CP). A leukemia with a median survival of about 5 years was transformed into one for which the survival in many cases promises to be comparable to that of normal persons of similar age. The more recently available TKIs, namely nilotinib (Tasigna) and dasatinib (Sprycel), produce more rapid responses but have not yet shown any overall survival advantage compared with long-term administration of imatinib. They are, however, useful in treating imatinib intolerance or resistance. There are currently two choices for initial treatment of CML-CP: (1) starting all new patients on imatinib and changing to a second-generation TKI in those who fail or who are predicted to fare badly, or (2) starting all new patients on a second-generation TKI. This choice may be based primarily on considerations of cost or possible side effects.
Dasatinib Approved for Pediatric CML. [2019]The FDA approved dasatinib to treat pediatric chronic myeloid leukemia. This drug is the second tyrosine kinase inhibitor, alongside imatinib, approved for this indication and represents an important new option for first- and second-line treatment.