Prescribing information

 

Study design

The SUSTAIN study assessed the safety and efficacy of ADAKVEO® (crizanlizumab) as a preventative therapy for VOCs in patients (16 to 65 years of age) with sickle cell disease (SCD)1

  • A pivotal Phase II, 52-week, randomised, multicentre, placebo-controlled, double-blind study*
  • Included 198 patients at 69 study centres in 3 countries

 

Diagram showing the study design for 'The SUSTAIN study' image is showing  the safety and efficacy of ADAKVEO® (crizanlizumab) as a preventative therapy for VOCs in patients (16 to 65 years of age) with sickle cell disease (SCD).

VOCs as defined by the SUSTAIN study protocol

VOCs were defined as acute episodes of pain, with no medically determined cause other than a vaso-occlusive event, that resulted in a medical facility visit and treatment with oral or parenteral narcotic agents or with a parenteral nonsteroidal anti-inflammatory drug (NSAIDs). Acute chest syndrome (ACS), hepatic sequestration, splenic sequestration, and priapism were also considered to be crisis events1

 

Study endpoints

Clinically meaningful primary endpoint1

  • Annual rate of VOCs
    VOCs were defined as acute episodes of pain with no other cause than a vaso-occlusive event that required a medical facility visit (accident & emergency [A&E], clinic, hospital, or local physician visit) and treatment with oral or parenteral opioids or parenteral NSAIDs, and which included events such as ACS, hepatic sequestration, splenic sequestration, and priapism
  • Pre-specified, non-comparative subgroup analysis
    Subgroup evaluation of the annual rate of VOCs in the intention-to-treat population according to: concomitant HC use, VOC frequency in the previous year and SCD genotype

 

Key secondary endpoints

  • Annual rate of days hospitalised
  • Time to first and second VOC

Only the primary endpoint (annual rate of VOC leading to healthcare visit) and secondary endpoints (annual rate of days hospitalised; time to first sickle cell-related pain crises; time to second sickle cell-related pain crises; ACS) were formally tested for statistical significance

Post-hoc analysis 

Study design1,2

A sample of at least 50 patients per group would provide the trial with a statistical power of greater than 90%, at an alpha level of 0.05, to detect a 40% lower annual rate of crises with ADAKVEO® than with placebo, with the use of a stratified Wilcoxon rank-sum test, assuming a median rate of crises per year in the placebo group of 3.0 with a predicted standard deviation of 1.7

Study endpoints1,2

For the primary end point, the analysis included all 198 patients who underwent randomisation, according to the intention-to-treat principle. The crisis rate for every patient was annualised to 12 months. The annual crisis rate was imputed for patients who did not complete the trial. The difference in the annual crisis rate between the high-dose crizanlizumab group and the placebo group was analysed with the use of the stratified Wilcoxon rank-sum test, with the use of categorised history of crises in the previous year (2 to 4 or 5 to 10 crises) and concomitant HU/HC use (yes or no) as strata. A hierarchical testing procedure was used (alpha level of 0.05 for high-dose ADAKVEO® vs. placebo, and if significant, low-dose ADAKVEO® vs. placebo)

 

ADAKVEO® is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Reporting suspected adverse reactions after authorisation of ADAKVEO® is important to understand the safety profile of the treatment for SCD patients.

Indication: ADAKVEO® (crizanlizumab) is indicated for the prevention of recurrent VOCs in patients with SCD who are aged 16 years and over. It can be given as an add-on therapy to HU/HC or as monotherapy in patients for whom HU/HC is inappropriate or inadequate.3

ADAKVEO® has a conditional marketing authorisation and further evidence is awaited.

*All efficacy analyses were conducted using the ITT population which included all patients randomised to ADAKVEO® 5 mg/kg (n=67), ADAKVEO® 2.5 mg/kg (n=66), or placebo (n=65). An additional sensitivity analysis was performed using the per-protocol population which included all patients who underwent randomisation, received 12 to 14 planned doses of ADAKVEO® (n=40) or placebo (n=41), and had no major violations of protocol.1

Study sites included: 60 in United States (n=151); 8 in Brazil (n=40); 1 in Jamaica (n=7).1

With or without HU/HC.1

Abbreviations: A&E, accident and emergency; ACS, acute chest syndrome; HC, hydroxycarbamide; HR, hazard ratio; HU, hydroxyurea; NSAIDs, non-steroidal anti-inflammatory drugs; SCD, sickle cell disease; VOC, vaso-occlusive crisis.

References

  1. Ataga KI, et al. N Engl J Med. 2017;376(5):429–439
  2. Kutlar A, et al. Am J Hematol. [Suppl appendix]. 2019;94(1):55–61.
  3. ADAKVEO® Summary of Product Characteristics.

 

 

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UK | May 2021 | 104658
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ADAKVEO® has a conditional marketing authorisation and further evidence is awaited.

For more information, refer to the ADAKVEO® ▼ (crizanlizumab) prescribing information available here:  https://www.health.novartis.co.uk/sites/health.novartis.co.uk/files/adak...

Legal Category: POM.

Marketing Authorisation (MA) number, quantities and price: EU/1/20/1476/001  £1,038.00 per 10ml vial

 

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Novartis via [email protected] or online through the pharmacovigilance intake (PVI) tool at www.report.novartis.com
If you have a question about the product, please contact Medical Information on 01276 698370 or by email at [email protected]