Crizanlizumab for Sickle Cell Disease

(CRIZ Trial)

Not currently recruiting at 1 trial location

Overseen By Andria Ford, MD

Age: Any Age

Sex: Any

Trial Phase: Academic

Sponsor: Andria Ford

Must not be taking: Investigational drugs, Monoclonal antibodies, Anticoagulants

Disqualifiers: Chronic transfusion, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 30 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called crizanlizumab, a monoclonal antibody, to determine if it can prevent silent cerebral infarcts, or small strokes, in people with sickle cell disease. Participants will undergo brain scans before and after starting the treatment to monitor changes. As a single-arm study, all participants will receive crizanlizumab. Individuals with sickle cell disease who have experienced frequent pain crises or have been identified as having a higher risk of small strokes may be suitable for this trial. As an unphased trial, this study provides a unique opportunity for participants to contribute to groundbreaking research that could lead to new treatment options for sickle cell disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic transfusion therapy, have used other investigational drugs recently, or have taken certain medications like monoclonal antibodies or anticoagulants in the last 30 days.

Is there any evidence suggesting that crizanlizumab is likely to be safe for humans?

Research has shown that crizanlizumab is generally well-tolerated by patients. In studies, people with sickle cell disease who took crizanlizumab found it manageable. The treatment blocks a molecule called P-selectin, which can cause blood cells to stick together, thereby reducing complications from sickle cell disease.

A combined analysis examined the safety of crizanlizumab at a dose of 5.0 mg/kg and found it safe for patients. The studies indicated that side effects were not severe for most people. Common side effects included mild headaches and joint pain, which were not serious and could be managed.

Overall, crizanlizumab has demonstrated a good safety record in earlier studies, helping many patients without causing major problems. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about crizanlizumab for sickle cell disease because it offers a unique approach compared to standard treatments like hydroxyurea and blood transfusions. Unlike these existing options, crizanlizumab targets P-selectin, a molecule that plays a key role in the formation of blood clots and inflammation, which are central to sickle cell crises. This mechanism of action is promising because it could potentially reduce the frequency of painful episodes and prevent silent cerebral infarcts, which are mini-strokes common in sickle cell patients. By directly addressing the underlying processes that lead to these complications, crizanlizumab might offer improved outcomes for those living with this challenging condition.

What evidence suggests that crizanlizumab might be an effective treatment for sickle cell disease?

Research has shown that crizanlizumab, the treatment under study in this trial, may help people with sickle cell disease. One study found it reduced hospital visits for those frequently needing urgent care. Crizanlizumab blocks a molecule called P-selectin, which causes blood cells to stick together and form blockages. While some studies did not find a decrease in pain episodes, others reported that it is safe and well-tolerated. Overall, crizanlizumab has demonstrated potential benefits in managing symptoms of sickle cell disease. ^{1 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for individuals with sickle cell disease at risk of silent cerebral infarcts. They should have had multiple pain crises in the past year and be over 16 years old. Participants must not be on chronic transfusion therapy, planning major treatments like stem cell transplants, or have used investigational drugs recently. Women who can bear children must use contraception and avoid pregnancy during and after the study.

Inclusion Criteria

Your doctor thinks you have a high chance of having silent strokes in your brain based on certain criteria.

I have sickle cell disease with a confirmed specific genotype.

I've had 2 to 10 pain crises due to sickle cell disease in the last year.

Exclusion Criteria

I cannot come back for follow-up visits.

I am currently on a long-term blood transfusion plan.

I currently have an acute infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive crizanlizumab infusions to prevent progression of silent cerebral infarcts

30 months

Regular infusions with MRI at baseline, 6 months, and 30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Crizanlizumab

Trial Overview The study is testing Crizanlizumab's effectiveness in preventing silent brain injuries in sickle cell patients by comparing brain MRIs before treatment and at two intervals (6 and 30 months) after starting Crizanlizumab infusions against a group not receiving it.

How Is the Trial Designed?

Group I: Single Arm: Crizanlizumab Experimental Treatment 1 Intervention

Single-arm: Patients with sickle cell disease and increased risk of silent cerebral infarcts

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

Who Is Running the Clinical Trial?

Andria Ford

Lead Sponsor

Trials

1

Recruited

30+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Imatinib, a first-line treatment for chronic myeloid leukemia (CML), often leads to intolerance in patients, prompting the need for second- and third-generation tyrosine kinase inhibitors (TKIs) like ponatinib, which is effective against all BCR-ABL1 mutants, including those resistant to other TKIs.

There is a lack of consistent definitions of intolerance across clinical trials, which complicates the assessment of adverse events and their impact on patient quality of life, highlighting the need for better evaluation methods and consideration of ponatinib for patients who cannot tolerate other TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. Breccia, M., Efficace, F., Iurlo, A., et al.[2019]

A patient with chronic myeloid leukemia (CML) carrying the T315I mutation, which is resistant to other treatments, showed a complete response to ponatinib therapy, with the mutation burden dropping to undetectable levels.

Before treatment with ponatinib, the patient had a high level of BCR-ABL1 transcripts (18%), but after therapy, this level significantly decreased to just 0.011%, indicating the drug's efficacy in overcoming resistance to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity of ponatinib in one patient with chronic myeloid leukemia in chronic phase with e19a2 transcript and T315I mutation. Ferri, CA., Bianchini, M., Bengió, RM., et al.[2015]

Dasatinib has been approved by the FDA as a treatment for pediatric chronic myeloid leukemia, providing a new therapeutic option for young patients.

As the second tyrosine kinase inhibitor approved for this condition, dasatinib can be used in both first- and second-line treatment, expanding the choices available for managing this type of leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib Approved for Pediatric CML. [2019]

Crizanlizumab is the first monoclonal antibody approved for sickle cell disease, specifically designed to reduce the frequency of vaso-occlusive pain crises, based on data from a phase 2 clinical trial.

This medication is administered as a monthly intravenous infusion for patients aged 16 and older, showing efficacy in crisis prevention, although concerns about cost and long-term safety remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease. Stevens, DL., Hix, M., Gildon, BL.[2022]

Imatinib, the first tyrosine-kinase inhibitor (TKI) for chronic myeloid leukemia (CML), has significantly improved patient outcomes since its introduction 10 years ago.

Second generation TKIs like dasatinib and nilotinib are more effective and better tolerated than imatinib, suggesting they may soon become the standard first-line treatment for CML, with a future goal of achieving curative therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current therapy of chronic myeloid leukemia]. Koskela, H., Koskenvesa, P., Mustjoki, S., et al.[2022]

Imatinib (Gleevec) has significantly improved survival rates for patients with chronic myeloid leukemia in chronic phase (CML-CP), transforming a previously poor prognosis into one comparable to that of healthy individuals of similar age.

While newer TKIs like nilotinib (Tasigna) and dasatinib (Sprycel) offer faster responses and are effective for patients who cannot tolerate or are resistant to imatinib, they have not demonstrated a survival advantage over long-term imatinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is imatinib still an acceptable first-line treatment for CML in chronic phase? Goldman, JM., Marin, D.[2017]

Crizanlizumab is a monoclonal antibody that effectively reduces the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease by blocking P-selectin, which is crucial for cell adhesion and inflammation.

Approved in the USA in November 2019 for adults and pediatric patients aged 16 and older, crizanlizumab is also under review in the EU and being studied for use in myelofibrosis, indicating its potential versatility in treating blood-related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crizanlizumab: First Approval. Blair, HA.[2020]

Crizanlizumab, a monoclonal antibody targeting P-selectin, received conditional marketing authorization in the EU for preventing recurrent vaso-occlusive crises in sickle cell disease patients aged 16 and older, showing a 45.3% reduction in annual pain crises at a high dose compared to placebo.

The treatment was found to have a similar safety profile to placebo, with common side effects including infusion-related reactions and arthralgia, indicating that crizanlizumab is both effective and relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Crizanlizumab for the Prevention of Recurrent Vaso-Occlusive Crises in Patients With Sickle Cell Disease. Delgado, J., Voltz, C., Stain, M., et al.[2021]

Crizanlizumab may help reduce acute care visits for patients with sickle cell disease, especially among those who frequently use hospital services, with a significant decrease from an average of 40 visits to 16 after starting treatment.

Despite its potential benefits, the study found a high discontinuation rate, with only five out of fifteen patients remaining on crizanlizumab six months after starting, indicating a need for further research into the reasons for discontinuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Data of Crizanlizumab in Sickle Cell Disease: A Single-Center Analysis. Cheplowitz, H., Block, S., Groesbeck, J., et al.[2023]

Crizanlizumab effectively reduces the frequency of vaso-occlusive crises (VOCs) in patients with sickle cell disease, showing a significant reduction in the annualized rate of VOCs after more than 12 months of treatment, with a median reduction of -0.88 and -0.93 for the 5.0 mg/kg and 7.5 mg/kg doses, respectively.

The treatment demonstrated a favorable safety profile, with only one treatment-related adverse event reported and no serious treatment-related adverse events, indicating that crizanlizumab can be safely administered over long periods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. Kanter, J., Brown, RC., Norris, C., et al.[2023]

Crizanlizumab, a new treatment for sickle cell disease (SCD), has shown promise in reducing the annual rates of vaso-occlusive crises (VOC) with a favorable safety profile, marking a significant advancement in therapy options beyond hydroxyurea.

While hydroxyurea has been effective in decreasing VOC and hospitalizations, adherence to this treatment can be challenging due to side effects; crizanlizumab offers a new approach that may improve patient compliance and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of crizanlizumab and its potential in the prevention of pain crises in sickle cell disease: evidence to date. Riley, TR., Riley, TT.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11533247/

final results from the phase II SOLACE-adults study In conclusion, crizanlizumab at both doses reached levels of exposure that caused sustained inhibition of P-selectin, had tolerable safety, and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10332863/

Real-World Data of Crizanlizumab in Sickle Cell Disease Our study suggests that crizanlizumab use may be helpful in decreasing acute care visits in SCD, particularly among high utilizers of hospital-based acute care ...

3. hematologyadvisor.com hematologyadvisor.com/news/sickle-cell-disease-scd-crizanlizumab-stand-trial-efficacy-benefit/

No Efficacy Benefit With Crizanlizumab in the STAND Trial ... The primary analysis of the phase 3 STAND trial showed no significant improvement in the rate of vaso-occlusive crisis or associated health care visits.

4. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00384-3/abstract

Crizanlizumab with or without hydroxyurea in patients ... Crizanlizumab 5·0 mg/kg exhibits a favorable safety profile in patients with sickle cell disease: pooled data from two phase II studies.

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03264989

Study Details | NCT03264989 | Pharmacokinetics and ... This study provides five years follow up data that fully characterizes the safety, tolerability and treatment effect of the 5.0 mg/kg and 7.5 mg/kg doses of ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01895361

NCT01895361 | Study to Assess Safety and Impact of ... Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease. Blood Adv. 2023 Mar 28;7(6):943-952. doi ...

7. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/1139/505806/Safety-Profile-of-Crizanlizumab-5-0-Mg-Kg-in

Safety Profile of Crizanlizumab 5.0 Mg/Kg in Sickle Cell Disease This pooled analysis assesses the safety of the recommended dosage of crizanlizumab (5.0 mg/kg monthly) in treated patients. Methods: Safety was ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40088922/

Crizanlizumab with or without hydroxyurea in patients ... The STAND study aimed to evaluate the efficacy and safety of two doses (5·0 mg/kg and 7·5 mg/kg) of crizanlizumab in sickle cell disease. Herein, we report the ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S0268960X25000438

Review Evidence and gaps in clinical outcomes of novel ... This systematic review aims to summarise the clinical outcomes of l-glutamine, crizanlizumab, and voxelotor in the treatment of sickle cell disease (SCD)