A Study Comparing Siltuximab Plus Best Supportive Care to Placebo Plus Best Supportive Care in Anemic Patients With International Prognostic Scoring System Low- or Intermediate-1-Risk Myelodysplastic Syndrome

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01513317
• Collaborator: (none)
• Enrollment: 76
• Locations: 23
• Arms: 2
• Duration (Months): 10
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of siltuximab, demonstrated by a reduction in red blood cell (RBC), transfusions to treat the anemia of Myelodysplastic Syndrome (MDS).

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: Siltuximab; Drug: Placebo; Drug: Best supportive care (BSC)	Phase 2

Detailed Description

The study treatments will be administered double-blind for 12 weeks, meaning that the patient and study personnel will not know the identity of the treatment. Approximately 75 patients will be randomized (patients are assigned to a treatment by a chance) in a 2:1 ratio to receive siltuximab plus best supportive care (BSC) (Group A) or placebo plus BSC (Group B). BSC includes RBC transfusion, antimicrobials, white blood cell (WBC) growth factors, and platelet transfusions. Patients who complete 12 weeks of treatment may qualify to receive siltuximab as open-label (identity of treatment will be known) treatment. Treatment may continue until death, unacceptable toxicity, withdrawal of consent, or the clinical cutoff (defined as 24 weeks after the last patient is randomized), whichever occurs first. The study will end approximately 36 weeks after the last patient is randomized. Patient safety will be monitored. Siltuximab and matching placebo will be supplied as a sterile, lyophilized formulation for reconstitution and intravenous (IV) infusion. Group A: siltuximab (15 mg/kg) administered as a 1-hour infusion every 4 weeks + BSC, or Group B: placebo administered as a 1-hour infusion every 4 weeks + BSC.

Study Design

• Study Type: Interventional
• Actual Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter Study Comparing Siltuximab Plus Best Supportive Care to Placebo Plus Best Supportive Care in Anemic Subjects With International Prognostic Scoring System Low- or Intermediate-1-Risk Myelodysplastic Syndrome
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Siltuximab 15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Drug: Siltuximab; 15 mg/kg administered as a 1-hour intravenous infusion every 4 weeks; Drug: Best supportive care (BSC); Best supportive care according to local standards and guidelines
Experimental: Placebo Placebo administered as a 1-hour infusion every 4 weeks + BSC	Drug: Placebo; Administered as a 1-hour intravenous infusion every 4 weeks; Drug: Best supportive care (BSC); Best supportive care according to local standards and guidelines

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved a Reduction in Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) [Up to Week 13]

   Reduction in RBC transfusions to treat the anemia of MDS is defined as a ≥50 percentage relative decrease and a ≥2 unit absolute decrease in RBC transfusions in the 8 weeks before the unblinding (scheduled to occur after 12 weeks of treatment) compared with RBC transfusions in the 8 weeks before the date the informed consent form was signed.

Secondary Outcome Measures

1. Change From Baseline in the Mean Hemoglobin Concentrations at Week 13 [Baseline and Week 13]

2. Percentage of Participants Achieving Hemoglobin Improvement (≥1.5 g/dL Increase From Baseline) Unrelated to Red Blood Cell (RBC) Transfusion at Week 13 [Week 13]

3. Percentage of Participants Who Did Not Require a Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) in the 8 Weeks of Treatment Before Unblinding at Week 13 [8 weeks]

4. Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13 [Baseline and Week 13]

5. Median Number of Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) During the 8 Weeks of Treatment Before Unblinding at Week 13 [8 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of myelodysplastic syndrome (MDS), according to World Heath Organization or the French-American-British Cooperative Group pathologic classification, with an International Prognostic Scoring System score 0, 0.5, or 1.0, indicating Low- or INT-1-risk disease.

• Documented RBC transfusion of at least 2 units of RBC for the treatment of the anemia of MDS in the 8 weeks preceding the start of the Screening Period.

• Adequate iron stores, demonstrated by either the presence of stainable iron in the bone marrow or a serum ferritin of > 100 ng/mL.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.

• Symptomatic anemia (defined by a score > 0 on the Non-Chemotherapy Anemia Symptom Scale [NCA-SS]).

Exclusion Criteria:

• Had treatment with drugs or other agents targeting IL-6 or its receptor within 4 weeks of randomization.

• Any condition that, in the opinion of the investigator, would make participation not in the best interest (eg, compromise the well-being) of the patient or that could prevent, limit, or confound the protocol-specified assessments.

• Patients with Chronic Myelomonocytic Leukemia (CMML).

• Causes other than MDS contributing to anemia, such as Vitamin B12 or folate deficiency, bleeding, hemolysis, hemoglobinopathy, or chronic renal failure.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tampa	Florida	United States
2		Boston	Massachusetts	United States
3		New York	New York	United States
4		Winston-Salem	North Carolina	United States
5		Houston	Texas	United States
6		Box Hill		Australia
7		Camperdown		Australia
8		St Leonards		Australia
9		Antwerpen		Belgium
10		Brugge		Belgium
11		Gent		Belgium
12		Yvoir		Belgium
13		Den Haag		Netherlands
14		Dordrecht		Netherlands
15		Krasnodar		Russian Federation
16		Moscow N/A		Russian Federation
17		Nizhny Novgorod		Russian Federation
18		Barcelona		Spain
19		Madrid		Spain
20		Oviedo (Asturias)		Spain
21		Salamanca		Spain
22		Valencia		Spain
23		Stockholm		Sweden

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01513317
• Other Study ID Numbers: CR100752; CNTO328MDS2001; 2011-000261-12
• First Posted: Jan 20, 2012
• Last Update Posted: Sep 29, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Janssen Research & Development, LLC: Myelodysplastic Syndrome; MDS; Blood and lymphatic diseases; Siltuximab; Anemic
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Siltuximab

Study Results

Participant Flow

Recruitment Details	76 participants were enrolled at 6 sites in Spain, 5 sites in the United States, 4 sites in Belgium, 3 sites each in Australia and the Russian Federation, 2 sites in the Netherlands, and 1 site in Sweden.
Pre-assignment Detail	All 76 participants were enrolled and randomly assigned in the study.

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Period Title: Overall Study
STARTED	50	26
COMPLETED	16	2
NOT COMPLETED	34	24

Baseline Characteristics

Arm/Group Title	Siltuximab	Placebo	Total
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Total of all reporting groups
Overall Participants	50	26	76
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.2 (7.7)	72 (7.61)	70.8 (7.67)
Sex: Female, Male (Count of Participants)
Female	23 46%	9 34.6%	32 42.1%
Male	27 54%	17 65.4%	44 57.9%
Region of Enrollment (participants) [Number]
Australia	3 6%	2 7.7%	5 6.6%
Belgium	4 8%	4 15.4%	8 10.5%
Netherlands	2 4%	1 3.8%	3 3.9%
Russian Federation	5 10%	3 11.5%	8 10.5%
Spain	10 20%	5 19.2%	15 19.7%
Sweden	3 6%	0 0%	3 3.9%
United States	23 46%	11 42.3%	34 44.7%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved a Reduction in Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS)
Description	Reduction in RBC transfusions to treat the anemia of MDS is defined as a ≥50 percentage relative decrease and a ≥2 unit absolute decrease in RBC transfusions in the 8 weeks before the unblinding (scheduled to occur after 12 weeks of treatment) compared with RBC transfusions in the 8 weeks before the date the informed consent form was signed.
Time Frame	Up to Week 13

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	50	26
Number [Percentage of participants]	12 24%	3.8 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	0.082
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in proportion of participants who had a reduction in RBC transfusion to treat the anemia of MDS.

2. Secondary Outcome

Title	Change From Baseline in the Mean Hemoglobin Concentrations at Week 13
Time Frame	Baseline and Week 13

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants with evaluable data at Week 13

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	31	18
Mean (Standard Deviation) [g/dL]	-0.07 (1.503)	-0.13 (1.375)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.872
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in LS means of the change from baseline hemoglobin levels at Week 13.

3. Secondary Outcome

Title	Percentage of Participants Achieving Hemoglobin Improvement (≥1.5 g/dL Increase From Baseline) Unrelated to Red Blood Cell (RBC) Transfusion at Week 13
Time Frame	Week 13

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	50	26
Number [Percentage of Participants]	8.0 16%	3.8 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.494
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	0.042
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in proportion of participants achieving hemoglobin improvement at Week 13.

4. Secondary Outcome

Title	Percentage of Participants Who Did Not Require a Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) in the 8 Weeks of Treatment Before Unblinding at Week 13
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	50	26
Number [Percentage of Participants]	4.0 8%	3.8 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.986
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Difference in proportions
	Estimated Value	0.002
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in proportion of participants who did not require a blood transfusion in the 8 weeks of treatment before unblinding at Week 13.

5. Secondary Outcome

Title	Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13
Time Frame	Baseline and Week 13

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants with evaluable data at Week 13

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	31	15
Mean (Standard Deviation) [Percentage of Bone Marrow Blast Cells]	2.1 (8.22)	0.2 (2.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.363
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	1.96
	Confidence Interval	(2-Sided) 95%; -2.35 to 6.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in LS means for changes from baseline in bone marrow blasts at Week 13.

6. Secondary Outcome

Title	Median Number of Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) During the 8 Weeks of Treatment Before Unblinding at Week 13
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: Included all randomized participants who completed Week 13 unblinding

Arm/Group Title	Siltuximab	Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)	Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
Measure Participants	36	22
Median (Full Range) [RBC Transfusions]	6.0	6.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Siltuximab, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in LS means
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 95%; -3.55 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	The estimated parameter is the difference in LS means of the number of RBC transfusions during the 8 weeks of treament before unblinding at Week 13.

Adverse Events

Time Frame	Adverse events are reported for the time period between the first dose of study medication through 30 days after the last dose.
Adverse Event Reporting Description	Safety was analyzed for all randomized participants who received at least 1 dose of study medication.
Arm/Group Title	Siltuximab		Placebo
Arm/Group Description	15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)		Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC)
All Cause Mortality
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/50 (20%)		8/26 (30.8%)
Blood and lymphatic system disorders
Neutropenia	0/50 (0%)		1/26 (3.8%)
Cardiac disorders
Acute Myocardial Infarction	0/50 (0%)		1/26 (3.8%)
Cardiac Failure Congestive	0/50 (0%)		1/26 (3.8%)
Cardiovascular Insufficiency	0/50 (0%)		1/26 (3.8%)
Ventricular Fibrillation	0/50 (0%)		1/26 (3.8%)
Gastrointestinal disorders
Femoral Hernia	1/50 (2%)		0/26 (0%)
Intestinal Ischaemia	1/50 (2%)		0/26 (0%)
Nausea	1/50 (2%)		0/26 (0%)
Vomiting	1/50 (2%)		0/26 (0%)
General disorders
Mucosal Haemorrhage	0/50 (0%)		1/26 (3.8%)
Hepatobiliary disorders
Cirrhosis Alcoholic	0/50 (0%)		1/26 (3.8%)
Infections and infestations
Cellulitis	1/50 (2%)		0/26 (0%)
Escherichia Bacteraemia	1/50 (2%)		0/26 (0%)
Pneumonia	4/50 (8%)		0/26 (0%)
Sepsis	0/50 (0%)		1/26 (3.8%)
Septic Shock	1/50 (2%)		0/26 (0%)
Soft Tissue Infection	0/50 (0%)		1/26 (3.8%)
Injury, poisoning and procedural complications
Hip Fracture	1/50 (2%)		1/26 (3.8%)
Metabolism and nutrition disorders
Dehydration	1/50 (2%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease	1/50 (2%)		0/26 (0%)
Vascular disorders
Deep Vein Thrombosis	1/50 (2%)		0/26 (0%)
Peripheral Ischaemia	0/50 (0%)		1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Siltuximab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/50 (60%)		18/26 (69.2%)
Blood and lymphatic system disorders
Neutropenia	1/50 (2%)		2/26 (7.7%)
Thrombocytopenia	3/50 (6%)		1/26 (3.8%)
Gastrointestinal disorders
Abdominal Pain Upper	3/50 (6%)		0/26 (0%)
Constipation	3/50 (6%)		1/26 (3.8%)
Diarrhoea	2/50 (4%)		4/26 (15.4%)
Nausea	4/50 (8%)		3/26 (11.5%)
Vomiting	0/50 (0%)		2/26 (7.7%)
General disorders
Asthenia	2/50 (4%)		2/26 (7.7%)
Oedema Peripheral	8/50 (16%)		2/26 (7.7%)
Hepatobiliary disorders
Hepatic Function Abnormal	5/50 (10%)		3/26 (11.5%)
Infections and infestations
Upper Respiratory Tract Infection	2/50 (4%)		3/26 (11.5%)
Metabolism and nutrition disorders
Hypokalaemia	2/50 (4%)		2/26 (7.7%)
Musculoskeletal and connective tissue disorders
Back Pain	6/50 (12%)		2/26 (7.7%)
Muscle Spasms	1/50 (2%)		2/26 (7.7%)
Myalgia	3/50 (6%)		0/26 (0%)
Pain in Extremity	3/50 (6%)		4/26 (15.4%)
Nervous system disorders
Dizziness	4/50 (8%)		2/26 (7.7%)
Headache	3/50 (6%)		1/26 (3.8%)
Psychiatric disorders
Insomnia	2/50 (4%)		2/26 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	2/50 (4%)		4/26 (15.4%)
Dyspnoea	4/50 (8%)		2/26 (7.7%)
Vascular disorders
Hypotension	3/50 (6%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.