Infusion-Related Reactions
In the SUSTAIN clinical trial, infusion-related reactions (defined as occurring within 24 hours of infusion) were observed in 2 (3%) patients treated
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Efficacy
Reduction in Frequency of VOCs
In the 52-week SUSTAIN study, ADAKVEO was proven to reduce the frequency of VOCs1
Significant 45% (1.63 vs 2.98) reduction in the median annual rate of VOCs vs placebo1,2*
In a prespecified analysis of the per-protocol population2,3
- Patients on ADAKVEO® (crizanlizumab-tmca) experienced a 52% reduction in vaso-occlusive crises (VOCs) vs placebo (1.04 vs 2.18; HL=-1.02; 95% CI: -2.00, -0.03)
- Per-protocol population is a subset of the ITT patient population who received at least 12 of the 14 planned doses of ADAKVEO (n=40) or placebo (n=41), completed a visit at least 14 days after final dose of study drug, and had no major protocol violations. The per-protocol population was analyzed according to the randomized treatment arm and not powered to show statistical significance.2
In a prespecified, noncomparative subgroup analysis, reduction in the frequency of VOCs was observed with ADAKVEO regardless of hydroxyurea use1-3
The subgroup analyses should be interpreted with caution because the data are from a prespecified, noncomparative subgroup analysis of the primary end point and are not powered to detect statistical significance or superiority of ADAKVEO over placebo.3
ITT, intent to treat; HL, Hodges-Lehmann; CI, confidence interval; ER, emergency room.
*Annual rate of VOCs leading to a health care visit (ER, clinic, hospital, or local physician visit).1,4
Reduction in Days Hospitalized
Patients treated with ADAKVEO were hospitalized for fewer days1
42% (4.00 vs 6.87) reduction with ADAKVEO in the median annual rate of days hospitalized vs placebo1,2
The key secondary end point in the SUSTAIN study was defined as the annual rate of days a patient was hospitalized, including those related to VOCs. The range of days hospitalized for the ADAKVEO and placebo population was 0 to 131 days and 0 to 307 days, respectively.3
Patients Who Did Not Experience a VOC
>2 times more patients did not experience a VOC with ADAKVEO1
36% of patients treated with ADAKVEO did not experience a VOC vs 17% with placebo1
A patient was considered to not have experienced a VOC if the annualized VOC rate was zero, whether or not the patient completed the 12-month treatment period.2,3
In a post hoc analysis5
- 22% of patients who completed the 12-month treatment period did not experience a VOC with ADAKVEO vs 8% with placebo (15 of 67 patients vs 5 of 65 patients; OR=3.57; 95% CI: 1.20, 10.63)
- Results are based on a noncomparative post hoc analysis and are observational in nature; as such, they are not powered to show statistical significance.
Delayed Time to First VOC
Time to first VOC was delayed with ADAKVEO1
>3 times delay in the median time to first VOC from randomization with ADAKVEO—4.1 months vs 1.4 months with placebo1
An early separation of the time to first VOC was observed at Week 2 with ADAKVEO.
- Results reported at 2 weeks were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error
In a post hoc analysis, median time to first VOC from randomization in patients with or without hydroxyurea who still experienced VOCs6
Time to first VOC
- In patients on ADAKVEO with hydroxyurea time to first VOC was 2.4 months vs 1.2 months in those on placebo with hydroxyurea (HR=0.58; 95% CI: 0.35, 0.96)
- In patients on ADAKVEO without hydroxyurea time to first VOC was 5.7 months vs 2.9 months in those on placebo without hydroxyurea (HR=0.39; 95% CI: 0.20, 0.76)
These analyses should be interpreted with caution as the data are from a noncomparative post hoc subgroup analysis and not powered to detect statistical significance or superiority of ADAKVEO over placebo.
HR, harzard ratio.
Study Design
SUSTAIN was a 52-week pivotal SCD study that evaluated clinically meaningful end points1,2
Study description
The efficacy of ADAKVEO® (crizanlizumab-tmca) was evaluated based on the annual rate of VOCs in patients (16 to 63 years of age) with SCD in a pivotal, phase 2, 52-week, randomized, multicenter, placebo-controlled, double-blind study.* The study included 198 patients evaluated at 60 study centers, the majority of which were located in the United States (51 centers with 151 study patients)1-3†
Primary end point2-4
- Annual rate of VOCs
- VOCs were defined as episodes that:
- Led to a health care visit, which captured all acute episodes of pain with no other cause than a vaso-occlusive event that required a medical facility visit (ER, clinic, hospital, or local physician visit)
- Required treatment with oral or parenteral opioids or parenteral NSAIDs
- Included events such as acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism
- Were adjudicated by a third-party committee
Prespecified, noncomparative subgroup analysis evaluated the annual rate of VOCs with or without hydroxyurea
Secondary and other end points2
- Annual rate of days hospitalized
- Time to first VOC
- Number of patients who did not experience a VOC
NSAIDs, non-steroidal anti-inflammatory drugs.
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*All efficacy analyses were conducted using the ITT population, which included all patients randomized to ADAKVEO 5 mg/kg (n=67) or placebo (n=65). An additional sensitivity analysis was performed using the per-protocol population, which included all patients who underwent randomization, received 12 to 14 planned doses of ADAKVEO (n=40) or placebo (n=41), and had no major violations of protocol.2
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†Other study sites included: 8 in Brazil (n=40); 1 in Jamaica (n=7).2
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‡Stratified by HU use (Y/N) and number of VOCs in the previous 12 months (2 to 4, 5 to 10).1
ADAKVEO was evaluated in a clinically diverse patient population1
Studied across all major SCD patient types1,2§
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Genotypes |
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VOC Frequency |
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(during previous 12 months)¶
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Hydroxyurea Use|| |
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Baseline characteristics1,3
- SCD, sickle cell disease.
- §Baseline characteristics of patients were balanced across study arms.1
- ¶With or without hydroxyurea.1
- ‖Patients who were receiving hydroxyurea must have been receiving the drug for ≥6 months, including an optimized dose for the most recent ≤3 months prior to Day 1 of the study; no dose adjustments were permitted during the 52-week treatment phase of the study, except for safety reasons.2
References: 1. Adakveo [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2019. 2. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429-439. 3. Data on file. Study NCT01895361. Novartis Pharmaceuticals Corp; 2016. 4. Bailey M, Thompson M, Brown S. The impact of crizanlizumab on VOC-related medical facility visits. Presented at: EHA Annual Congress; June 13-16, 2019; Amsterdam, Netherlands. Poster PF715. 5. Data on file. Novartis Pharmaceuticals Corp; November 2019. 6. Kutlar A, Kanter J, Liles DK, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: a SUSTAIN study analysis. Am J Hematol. 2019;94(1):55-61.
Indication
ADAKVEO® (crizanlizumab-tmca) is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients, aged 16 years and older, with sickle cell disease.
Important Safety Information
Infusion-Related Reactions
In the SUSTAIN clinical trial, infusion-related reactions (defined as occurring within 24 hours of infusion) were observed in 2 (3%) patients treated with ADAKVEO 5 mg/kg. Monitor patients for signs and symptoms of infusion-related reactions, which may include fever, chills, nausea, vomiting, fatigue, dizziness, pruritus, urticaria, sweating, or shortness of breath or wheezing. Discontinue ADAKVEO infusion for severe reactions and institute appropriate medical care.
Laboratory Test Interference: Platelet Counts
Interference with automated platelet counts (platelet clumping) has been observed following administration of ADAKVEO, in particular, when blood samples were collected in tubes containing EDTA.
Run blood samples within 4 hours of blood collection or collect blood samples in tubes containing citrate. When needed, estimate platelet count via peripheral blood smear.
Pregnancy
Based on animal data ADAKVEO has the potential to cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. ADAKVEO should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.
Most Common Adverse Reactions
The most frequently reported adverse reactions (≥10%) in patients treated with ADAKVEO were nausea (18%), arthralgia (18%), back pain (15%), and pyrexia (11%).
Other Clinically Important Adverse Reactions
Clinically relevant adverse reactions (all grades) that were reported in <10% of patients treated with ADAKVEO included: oropharyngeal pain, abdominal pain (abdominal pain, upper abdominal pain, lower abdominal pain, abdominal discomfort, and abdominal tenderness), diarrhea, vomiting, pruritus (pruritus and vulvovaginal pruritus), musculoskeletal chest pain, myalgia, infusion-site reaction (infusion-site extravasation, infusion-site pain, and infusion-site swelling), and infusion-related reaction.
Please see full Prescribing Information.
