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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02961218
• Collaborator: (none)
• Enrollment: 49
• Locations: 15
• Arms: 2
• Actual Duration (Months): 36.7
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia	Drug: ACZ885; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Apr 5, 2017
• Actual Primary Completion Date: Jun 27, 2019
• Actual Study Completion Date: Apr 27, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline of 4- Week Average Daily Pain Measured by Visual Analog Score (VAS) Over the Period of Week 8 to 12 [Baseline (upto 28 days prior to start of treatment), 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.

Secondary Outcome Measures

1. Change From Baseline of Average Daily Pain VAS Over 4 Weeks Intervals up to Week 24 [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]

   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.

2. Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) From Baseline to Week 12 [Baseline, Week 12]

   hs-CRP is a biomarker that represents the inflammation process.

3. Change in the Concentration of White Blood Cell (WBC) Count From Baseline to Week 12 [Baseline, Week 12]

   WBC count was used as a laboratory marker to determine the effect of the drug

4. Change in the Concentration of Absolute Count of Neutrophils From Baseline to Week 12 [Baseline, Week 12]

   Absolute count of neutrophils was measured as a laboratory marker to determine the effect of the drug

5. Change in the Concentration of Absolute Count of Blood Monocytes From Baseline to Week 12 [Baseline, Week 12]

   Absolute count of blood monocytes was measured as a laboratory marker to determine the effect of the drug.

6. Change in the Concentration of Hemoglobin From Baseline to Week 12 [Baseline, Week 12]

   Hemoglobin was used as a hemolysis marker to determine the effect of the drug.

7. Change in the Reticulocyte Count From Baseline to Week 12 [Baseline, Week 12]

   Reticulocyte count was used as a hemolysis marker to determine the effect of the drug

8. Change in the Concentration of Bilirubin From Baseline to Week 12 [Baseline, Week 12]

   Bilirubin was used as a hemolysis marker to determine the effect of the drug

9. Change in the Concentration of Lactate Dehydrogenase (LDH) From Baseline to Week 12 [Baseline, Week 12]

   LDH was used as a hemolysis marker to determine the effect of the drug

10. Change in the Concentration of Haptoglobin From Baseline to Week 12 [Baseline, Week 12]

    Haptoglobin was used as a hemolysis marker to determine the effect of the drug

11. Change in the Concentration of Oxygen Percent Saturation (SAO2) From Baseline to Week 12 [Baseline, Week 12]

    SAO2 was used as a hemolysis marker to determine the effect of the drug

12. Number of Days Absent From School or Work Due to Pain as Recorded by E-diary [up to Week 24]

    The number of SCA-related days absent from school or work were derived from eDiary records.

13. Number of Acute Blood Transfusions Per Patient by Study Period - Double-blind Period [12 weeks]

    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.

14. Mean Serum Concentration After Repeated Dosing of ACZ885 [Baseline, Week 4, 12, 20 and 24]

    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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Atlanta	Georgia	United States	30329
2	Novartis Investigative Site	Augusta	Georgia	United States	30912
3	Novartis Investigative Site	Greenville	North Carolina	United States	27834
4	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 1X8
5	Novartis Investigative Site	Hamburg		Germany	20246
6	Novartis Investigative Site	Afula		Israel	1834111
7	Novartis Investigative Site	Johannesburg	Guateng	South Africa	2193
8	Novartis Investigative Site	Adana		Turkey	01330
9	Novartis Investigative Site	Ankara		Turkey	06100
10	Novartis Investigative Site	Mersin		Turkey	33343
11	Novartis Investigative Site	Wolverhampton	Staffordshire	United Kingdom	WS11 5XY
12	Novartis Investigative Site	London		United Kingdom	E1 1BB
13	Novartis Investigative Site	London		United Kingdom	NW1 2BU
14	Novartis Investigative Site	London		United Kingdom	SE1 7EH
15	Novartis Investigative Site	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 22, 2018
• Statistical Analysis Plan - Jun 20, 2019

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02961218
• Other Study ID Numbers: CACZ885X2206
• First Posted: Nov 10, 2016
• Last Update Posted: Oct 11, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Sickle cell disease; hemoglobinopathy; pediatric
• Additional relevant MeSH terms: Anemia; Anemia, Sickle Cell

Study Results

Participant Flow

Recruitment Details	A total of 49 participants were randomized into the study from 15 centers in seven countries: Greater Britain (5), Israel (1), Germany (1), Turkey (3), South Africa (1), USA (3) and Canada (1).
Pre-assignment Detail	Subjects who met the eligibility criteria at screening underwent evaluation of baseline clinical and biomarker assessments prior to first dose administration.

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Period Title: Overall Study
STARTED	25	24
Safety Analysis Set	25	24
Pharmacokinetics (PK) Analysis Set	25	0
Primary PD Analysis Set	25	24
COMPLETED	22	19
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	ACZ885	Placebo	Total
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.	Total of all reporting groups
Overall Participants	25	24	49
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	15.8 (2.69)	15.6 (3.28)	15.7 (2.97)
Sex: Female, Male (Count of Participants)
Female	10 40%	11 45.8%	21 42.9%
Male	15 60%	13 54.2%	28 57.1%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	12 48%	13 54.2%	25 51%
White	12 48%	10 41.7%	22 44.9%
Other	1 4%	1 4.2%	2 4.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline of 4- Week Average Daily Pain Measured by Visual Analog Score (VAS) Over the Period of Week 8 to 12
Description	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.
Time Frame	Baseline (upto 28 days prior to start of treatment), Week 8 to 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: included all subjects with available PD data, who received any study drug.

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	25	24
Mean (Standard Deviation) [Score on a scale]	-0.45 (0.384)	-0.37 (0.402)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments	probability reduction of average pain score in ACZ885 > Placebo
	Method	Bayesian model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 90%; -1.03 to 0.85
	Parameter Dispersion	Type: Standard Deviation; Value: 0.57
	Estimation Comments	Lower limit and upper limit represents the credibility interval from the Bayesian analysis.

2. Secondary Outcome

Title	Change From Baseline of Average Daily Pain VAS Over 4 Weeks Intervals up to Week 24
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis set: included all subjects with available PD data, who received any study drug.

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	25	24
0-4 Weeks	-0.337 (1.629)	0.007 (1.428)
4-8 Weeks	-0.173 (1.515)	0.158 (1.847)
8-12 Weeks	-0.444 (1.437)	-0.376 (2.104)
12-16 Weeks	-0.505 (1.744)	0.057 (2.371)
16-20 Weeks	-0.388 (1.772)	0.151 (1.811)
20-24 Weeks	-0.752 (1.678)	0.036 (2.131)

3. Secondary Outcome

Title	Change in the Concentration of High Sensitivity C-Reactive Protein (hsCRP) From Baseline to Week 12
Description	hs-CRP is a biomarker that represents the inflammation process.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	20	19
Geometric Least Squares Mean (90% Confidence Interval) [mg/L]	0.338	0.830

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Mixed-effect Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.408
	Confidence Interval	(2-Sided) 90%; 0.253 to 0.658
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in the Concentration of White Blood Cell (WBC) Count From Baseline to Week 12
Description	WBC count was used as a laboratory marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	19	17
Geometric Least Squares Mean (90% Confidence Interval) [10^9 cells/liter]	0.813	1.081

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments
	Method	Mixed-effect Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.752
	Confidence Interval	(2-Sided) 90%; 0.657 to 0.862
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in the Concentration of Absolute Count of Neutrophils From Baseline to Week 12
Description	Absolute count of neutrophils was measured as a laboratory marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	19	17
Geometric Least Squares Mean (90% Confidence Interval) [10^9 cells/liter]	0.717	1.052

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Mixed-effect Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.682
	Confidence Interval	(2-Sided) 90%; 0.547 to 0.849
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in the Concentration of Absolute Count of Blood Monocytes From Baseline to Week 12
Description	Absolute count of blood monocytes was measured as a laboratory marker to determine the effect of the drug.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	19	17
Geometric Least Squares Mean (90% Confidence Interval) [10^9 cells/liter]	0.712	0.992

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Mixed-effect Model for Repeated Measures
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.718
	Confidence Interval	(2-Sided) 90%; 0.556 to 0.925
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in the Concentration of Hemoglobin From Baseline to Week 12
Description	Hemoglobin was used as a hemolysis marker to determine the effect of the drug.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	19	19
Mean (Standard Deviation) [g/L]	-0.97 (4.727)	1.11 (7.975)

8. Secondary Outcome

Title	Change in the Reticulocyte Count From Baseline to Week 12
Description	Reticulocyte count was used as a hemolysis marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	18	19
Mean (Standard Deviation) [10^9 cells/liter]	-6.578 (64.1131)	25.358 (47.6483)

9. Secondary Outcome

Title	Change in the Concentration of Bilirubin From Baseline to Week 12
Description	Bilirubin was used as a hemolysis marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	20	19
Mean (Standard Deviation) [umol/L]	5.05 (19.796)	-1.95 (11.591)

10. Secondary Outcome

Title	Change in the Concentration of Lactate Dehydrogenase (LDH) From Baseline to Week 12
Description	LDH was used as a hemolysis marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	18	19
Mean (Standard Deviation) [Units per liter (U/L)]	19.06 (70.862)	-33.74 (209.259)

11. Secondary Outcome

Title	Change in the Concentration of Haptoglobin From Baseline to Week 12
Description	Haptoglobin was used as a hemolysis marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	13	19
Mean (Standard Deviation) [g/L]	-0.0112 (0.04022)	-0.0213 (0.07923)

12. Secondary Outcome

Title	Change in the Concentration of Oxygen Percent Saturation (SAO2) From Baseline to Week 12
Description	SAO2 was used as a hemolysis marker to determine the effect of the drug
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	20	19
Mean (Standard Deviation) [Oxygen Saturation Percent]	-0.5 (2.16)	-0.3 (1.82)

13. Secondary Outcome

Title	Number of Days Absent From School or Work Due to Pain as Recorded by E-diary
Description	The number of SCA-related days absent from school or work were derived from eDiary records.
Time Frame	up to Week 24

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	22	19
Mean (90% Confidence Interval) [Days]	2.20	1.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ACZ885, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.455
	Comments
	Method	Generalized Linear Model (GLM)
	Comments
Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 90%; 0.58 to 3.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.45
	Estimation Comments

14. Secondary Outcome

Title	Number of Acute Blood Transfusions Per Patient by Study Period - Double-blind Period
Description	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.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Pharmacodynamics (PD) analysis including patients with a valid measurements for the outcome measure

Arm/Group Title	ACZ885	Placebo
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects	Monthly doses of placebo to match the administered dose of ACZ885 s.c.
Measure Participants	25	24
0 transfusions	20 80%	18 75%
1 transfusion	4 16%	4 16.7%
2 transfusions	1 4%	1 4.2%
3 transfusions	0 0%	1 4.2%
0 transfusions	23 92%	19 79.2%
1 transfusion	2 8%	4 16.7%
2 transfusions	0 0%	1 4.2%
3 transfusions	0 0%	0 0%
0 transfusions	22 88%	22 91.7%
1 transfusion	2 8%	1 4.2%
2 transfusions	1 4%	1 4.2%
3 transfusions	0 0%	0 0%

15. Secondary Outcome

Title	Mean Serum Concentration After Repeated Dosing of ACZ885
Description	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
Time Frame	Baseline, Week 4, 12, 20 and 24

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) analysis set consisted of ACZ885 treated patients. Placebo patients were excluded from the PK analysis

Arm/Group Title	ACZ885
Arm/Group Description	Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects
Measure Participants	25
Baseline	0 (0)
Week 4	13100 (5490)
Week 12	18700 (5860)
Week 20	19700 (5810)
Week 24	20600 (5930)

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment (Week 48) plus 8 weeks post treatment, up to maximum duration of 56 weeks.
Adverse Event Reporting Description	Any sign or symptom collected in the double-blinded period i.e 24 weeks followed by an additional 24-week open label phase (optional). Adverse events were reported separately for the double-blind and the open-label phase.
Arm/Group Title	ACZ885		Placebo		ACZ885 / ACZ885		Placebo / ACZ885
Arm/Group Description	Double-blind period (Week 0 to 24): Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects		Double-blind period (Week 0 to 24): Monthly doses of placebo to match the administered dose of ACZ885 s.c.		Open label Phase (after Week 24 to Week 56) for the participants originally randomized to ACZ885: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects		Open label Phase (after Week 24 to Week 56) for the participants originally randomized to placebo: Monthly doses of 4 mg/kg for subjects weighing ≤40 kg and 300 mg for all other subjects
All Cause Mortality
	ACZ885		Placebo		ACZ885 / ACZ885		Placebo / ACZ885
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Serious Adverse Events
	ACZ885		Placebo		ACZ885 / ACZ885		Placebo / ACZ885
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/25 (44%)		15/24 (62.5%)		11/22 (50%)		11/20 (55%)
Blood and lymphatic system disorders
Aplasia pure red cell	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Sickle cell anaemia with crisis	10/25 (40%)		11/24 (45.8%)		9/22 (40.9%)		10/20 (50%)
General disorders
Asthenia	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Pyrexia	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Hepatobiliary disorders
Cholelithiasis	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		1/20 (5%)
Hyperbilirubinaemia	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Immune system disorders
Alloimmunisation	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Infections and infestations
Lower respiratory tract infection	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Pneumonia	0/25 (0%)		1/24 (4.2%)		2/22 (9.1%)		1/20 (5%)
Pneumonia mycoplasmal	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Sinusitis	0/25 (0%)		1/24 (4.2%)		1/22 (4.5%)		0/20 (0%)
Upper respiratory tract infection	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Investigations
Alanine aminotransferase increased	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Metabolism and nutrition disorders
Hypocalcaemia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Hypomagnesaemia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Osteonecrosis	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Nervous system disorders
Dizziness	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Headache	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Reproductive system and breast disorders
Priapism	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome	0/25 (0%)		2/24 (8.3%)		0/22 (0%)		0/20 (0%)
Epistaxis	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Hypoxia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Pulmonary embolism	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Rhinitis allergic	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	ACZ885		Placebo		ACZ885 / ACZ885		Placebo / ACZ885
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/25 (76%)		20/24 (83.3%)		17/22 (77.3%)		18/20 (90%)
Blood and lymphatic system disorders
Anaemia	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Leukopenia	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Neutropenia	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Thrombocytopenia	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		1/20 (5%)
Thrombocytosis	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Cardiac disorders
Bradycardia	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Eye disorders
Eye pain	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Ocular hyperaemia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Periorbital oedema	1/25 (4%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Vision blurred	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Gastrointestinal disorders
Abdominal pain	0/25 (0%)		0/24 (0%)		0/22 (0%)		3/20 (15%)
Abdominal pain upper	0/25 (0%)		2/24 (8.3%)		1/22 (4.5%)		1/20 (5%)
Abdominal tenderness	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Constipation	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		2/20 (10%)
Diarrhoea	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Dyspepsia	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Gastritis	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Gingival bleeding	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Haemorrhoids	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Lip swelling	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Nausea	1/25 (4%)		2/24 (8.3%)		0/22 (0%)		2/20 (10%)
Swollen tongue	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Toothache	1/25 (4%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Vomiting	1/25 (4%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
General disorders
Fatigue	2/25 (8%)		2/24 (8.3%)		0/22 (0%)		1/20 (5%)
Injection site pain	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Injection site pruritus	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Medical device site irritation	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Non-cardiac chest pain	1/25 (4%)		1/24 (4.2%)		3/22 (13.6%)		2/20 (10%)
Pain	6/25 (24%)		5/24 (20.8%)		3/22 (13.6%)		7/20 (35%)
Pyrexia	2/25 (8%)		0/24 (0%)		2/22 (9.1%)		0/20 (0%)
Hepatobiliary disorders
Cholelithiasis	2/25 (8%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Immune system disorders
Allergy to metals	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Infections and infestations
Conjunctivitis	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Gastrointestinal infection	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Influenza	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		2/20 (10%)
Lower respiratory tract infection	1/25 (4%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Nasopharyngitis	2/25 (8%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Oral candidiasis	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Oral herpes	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Otitis media	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Pneumonia	1/25 (4%)		1/24 (4.2%)		0/22 (0%)		1/20 (5%)
Respiratory tract infection	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Sinusitis	0/25 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/20 (5%)
Tonsillitis	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Tooth abscess	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Upper respiratory tract infection	1/25 (4%)		5/24 (20.8%)		2/22 (9.1%)		6/20 (30%)
Urinary tract infection	2/25 (8%)		1/24 (4.2%)		2/22 (9.1%)		1/20 (5%)
Viral infection	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Viral upper respiratory tract infection	2/25 (8%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
Skin abrasion	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Soft tissue injury	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Wrist fracture	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Investigations
Alanine aminotransferase increased	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Blood bilirubin increased	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Blood creatine phosphokinase increased	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Blood pressure increased	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Cardiac murmur	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Haemoglobin decreased	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Oxygen saturation abnormal	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Oxygen saturation decreased	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Spleen palpable	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Transaminases increased	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Ultrasound Doppler abnormal	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Urine albumin/creatinine ratio increased	1/25 (4%)		2/24 (8.3%)		0/22 (0%)		0/20 (0%)
Vitamin B12 decreased	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Vitamin D decreased	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
White blood cell count decreased	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Dehydration	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Hypocalcaemia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Increased appetite	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Vitamin B complex deficiency	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Vitamin B12 deficiency	0/25 (0%)		0/24 (0%)		0/22 (0%)		2/20 (10%)
Vitamin D deficiency	0/25 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/25 (8%)		0/24 (0%)		2/22 (9.1%)		1/20 (5%)
Back pain	2/25 (8%)		2/24 (8.3%)		2/22 (9.1%)		5/20 (25%)
Bone infarction	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Degenerative bone disease	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Flank pain	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Groin pain	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Muscle swelling	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Musculoskeletal pain	2/25 (8%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Myalgia	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		1/20 (5%)
Neck pain	1/25 (4%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Osteonecrosis	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		1/20 (5%)
Osteoporosis	1/25 (4%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Pain in extremity	3/25 (12%)		3/24 (12.5%)		0/22 (0%)		3/20 (15%)
Pain in jaw	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Spinal deformity	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lymph node neoplasm	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Meningioma	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Nervous system disorders
Benign enlargement of the subarachnoid spaces	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Dizziness	1/25 (4%)		0/24 (0%)		1/22 (4.5%)		2/20 (10%)
Headache	5/25 (20%)		3/24 (12.5%)		2/22 (9.1%)		4/20 (20%)
Lethargy	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Migraine	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Spinal cord oedema	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Psychiatric disorders
Bipolar disorder	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Depression	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Illness anxiety disorder	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Pica	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Renal and urinary disorders
Dysuria	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Nephropathy	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Renal colic	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Urinary retention	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/25 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/20 (5%)
Polymenorrhoea	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Priapism	0/25 (0%)		2/24 (8.3%)		0/22 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome	1/25 (4%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Cough	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Dyspnoea	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		1/20 (5%)
Dyspnoea exertional	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Epistaxis	0/25 (0%)		1/24 (4.2%)		1/22 (4.5%)		1/20 (5%)
Oropharyngeal pain	1/25 (4%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Pharyngeal swelling	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)
Skin and subcutaneous tissue disorders
Dermatitis allergic	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Dermatitis contact	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		0/20 (0%)
Eczema	0/25 (0%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Pruritus	0/25 (0%)		0/24 (0%)		0/22 (0%)		2/20 (10%)
Rash	1/25 (4%)		0/24 (0%)		0/22 (0%)		1/20 (5%)
Urticaria	1/25 (4%)		0/24 (0%)		0/22 (0%)		0/20 (0%)
Xeroderma	0/25 (0%)		1/24 (4.2%)		0/22 (0%)		1/20 (5%)
Vascular disorders
Venous thrombosis	0/25 (0%)		0/24 (0%)		1/22 (4.5%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.