Study of Efficacy, Safety and Tolerability of ACZ885 (Canakinumab) in Pediatric and Young Adult Patients With Sickle Cell Anemia

Study Overview
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Brief Summary
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The study assesses the efficacy, safety and tolerability of ACZ885 (canakinumab) in pediatric and young adult patients with sickle cell anemia (SCA).

Detailed Description
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This was an ambulatory-based 24-week study followed by an additional 24-week open label phase. It was a subject- and investigator-blinded, randomized, placebo-controlled, parallel group, non-confirmatory study to assess the clinical efficacy of ACZ885 administered s.c. in six injections given 28 days apart (in each phase of the study). Pediatric and young adult subjects diagnosed with sickle cell anemia (SCA) were planned to be randomized to either ACZ885 treatment or placebo treatment in a 1:1 ratio,. For each subject, there was a maximum 28-day screening period that included recording of daily pain frequency and intensity by e-diary for at least 1 week. Subjects who met the eligibility criteria at screening underwent evaluation of baseline clinical and biomarker assessments prior to first dose administration. On Day 1, monthly s.c. dosing with ACZ885 started at 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects. Subjects in the placebo treatment arm were injected with placebo in a like manner. All subjects returned to the study centers for safety checks on a monthly basis when they received treatment with either ACZ885 or placebo. The final blinded dosing was given on Week 20, followed by blinded clinical assessments at Week 24. Subjects from both study arms were then offered optional, open label monthly dosing of ACZ885 for an additional 24 weeks (Weeks 24-48) with clinical outcome assessment. Subjects returned for the end of study (EOS) visit at Week 56. For subjects who chose not to participate in the optional, open label portion of the study, or for those stopping treatment early for any other reason, an EOS visit occurred approximately 8 weeks after last dose received. After enrollment of 49 subjects, Novartis decided to terminate the study early due to strategic reasons not related to safety and decided that no additional enrollment was needed in order to interpret the study objectives.

Official Title
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A Multiple-dose, Subject- and Investigator-blinded, Placebo-controlled, Parallel Design Study to Assess the Efficacy, Safety and Tolerability of ACZ885 (Canakinumab) in Pediatric and Young Adult Patients With Sickle Cell Anemia

Conditions
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Sickle Cell Anemia

Intervention / Treatment
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* Drug: ACZ885
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects ages 8-20 years of age (both inclusive) diagnosed with sickle cell anemia (HbSS) or sickle beta0 thalassemia (documented by family studies, or analysis of either hemoglobin or DNA). Patient's written informed consent from those ≥18 years of age must be obtained before any assessment is performed. Parent or legal guardian's written informed consent and child's assent, if appropriate, are required before any assessment is performed for patients < 18 years of age. Detectable baseline of background or episodic pain measured by daily e-diary over 1 to 2 weeks during screening period as defined below: Average daily pain score ≥ 1 cm without analgesic use over a period of at least 7 days and/or, At least one episode of pain requiring analgesic use during a period of up to 14 days. History of ≥2 vaso-occlusive pain episodes in the past year, as defined as pain with no other, non-sickle cell identifiable cause that requires analgesia and interferes with the patient's normal daily routine. Exclusion Criteria: History of known hypersensitivity to canakinumab. Ongoing or treatment with the past 3 months with red blood cell transfusion therapy, or have evidence of iron overload requiring chelation therapy. Transcranial Doppler ultrasound in the past year or at screening in patients with an accessible transtemporal window, demonstrating velocity in middle or anterior cerebral or internal carotid artery ≥200 cm/sec. Administration of any other blood products within 3 weeks of screening visit. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects | Drug: Placebo<br>* Monthly doses of placebo to match the administered dose of canakinumab s.c.<br>|
| Experimental: ACZ885<br>Monthly doses of 300 mg (4 mg/kg for patients ≤ 40 kg) canakinumab s.c. | Drug: ACZ885<br>* Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects<br>* Other names: Canakinumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of 4- Week Average Daily Pain Measured by Visual Analog Score (VAS) Over the Period of Week 8 to 12 | Visual analog scale (VAS) was used to record severity. Pediatric and young adult participants rated their daily sickle cell associated pain intensity once each day in the evening using an 11-point numerical rating scale from 0 to 10 with higher ratings associated with more intense pain (0 = no pain, 10 = worst pain). For each subject, there was a maximum 28-day screening period that included recording of daily pain intensity by e-diary for at least 1 week. The average daily pain results in the screening period were used to derive the baseline value. The average over week 8 to 12 was calculated and the change from baseline in the average daily pain VAS was analyzed using a Bayesian model for repeated measures. | Baseline (upto 28 days prior to start of treatment), Week 8 to 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline of Average Daily Pain VAS Over 4 Weeks Intervals up to Week 24 | Visual analog scale (VAS) was used to record severity. Pediatric and young adult participants rated their daily sickle cell associated pain intensity once each day in the evening using an 11-point numerical rating scale from 0 to 10 with higher ratings associated with more intense pain (0 = no pain, 10 = worst pain). The average of 4 weeks interval up to week 24 was calculated. | Baseline (upto 28 days prior to start of treatment), Week 0 to 4, Week 4 to 8, Week 8 to 12, Week 12 to 16, Week 16 to 20 and Week 20 to 24 | 
| Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) From Baseline to Week 12 | hs-CRP is a biomarker that represents the inflammation process. | Baseline, Week 12 | 
| Change in the Concentration of White Blood Cell (WBC) Count From Baseline to Week 12 | WBC count was used as a laboratory marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Absolute Count of Neutrophils From Baseline to Week 12 | Absolute count of neutrophils was measured as a laboratory marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Absolute Count of Blood Monocytes From Baseline to Week 12 | Absolute count of blood monocytes was measured as a laboratory marker to determine the effect of the drug. | Baseline, Week 12 | 
| Change in the Concentration of Hemoglobin From Baseline to Week 12 | Hemoglobin was used as a hemolysis marker to determine the effect of the drug. | Baseline, Week 12 | 
| Change in the Reticulocyte Count From Baseline to Week 12 | Reticulocyte count was used as a hemolysis marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Bilirubin From Baseline to Week 12 | Bilirubin was used as a hemolysis marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Lactate Dehydrogenase (LDH) From Baseline to Week 12 | LDH was used as a hemolysis marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Haptoglobin From Baseline to Week 12 | Haptoglobin was used as a hemolysis marker to determine the effect of the drug | Baseline, Week 12 | 
| Change in the Concentration of Oxygen Percent Saturation (SAO2) From Baseline to Week 12 | SAO2 was used as a hemolysis marker to determine the effect of the drug | Baseline, Week 12 | 
| Number of Days Absent From School or Work Due to Pain as Recorded by E-diary | The number of SCA-related days absent from school or work were derived from eDiary records. | up to Week 24 | 
| Number of Acute Blood Transfusions Per Patient by Study Period - Double-blind Period | The occurrence of acute blood transfusions was summarized as the proportion of subjects who received at least one acute blood transfusion and the event rate of acute blood transfusions per subject, by study period, group and reason of transfusion. | 12 weeks | 
| Mean Serum Concentration After Repeated Dosing of ACZ885 | PK samples were collected at Baseline, Week 4, 12, 20 and 24. Mean and standard deviation of the ACZ885 concentration was reported. Only those participants available at the specified time points were analyzed | Baseline, Week 4, 12, 20 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle cell disease, hemoglobinopathy, pediatric