Myelodysplastic Syndrome
Conditions
Keywords
Myelodysplastic Syndrome, MDS, Blood and lymphatic diseases, Siltuximab, Anemic
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).
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.
Interventions
DRUGSiltuximab
15 mg/kg administered as a 1-hour intravenous infusion every 4 weeks
DRUGPlacebo
Administered as a 1-hour intravenous infusion every 4 weeks
DRUGBest supportive care (BSC)
Best supportive care according to local standards and guidelines
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 |
| Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13 | Baseline and Week 13 |
| Change From Baseline in the Mean Hemoglobin Concentrations at Week 13 | Baseline and Week 13 |
| 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 |
| 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 |
Countries
Australia, Belgium, Netherlands, Russia, Spain, Sweden, United States
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 details
All 76 participants were enrolled and randomly assigned in the study.
Participants by arm
| Arm | Count |
|---|---|
| Siltuximab 15 mg/kg of siltuximab administered as a 1-hour infusion every 4 weeks + best supportive care (BSC) | 50 |
| Placebo Placebo administered as a 1-hour infusion every 4 weeks + best supportive care (BSC) | 26 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Study terminated by sponsor | 18 | 18 |
| Overall Study | Withdrawal by Subject | 15 | 4 |
Baseline characteristics
| Characteristic | Siltuximab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 70.2 years STANDARD_DEVIATION 7.7 | 72 years STANDARD_DEVIATION 7.61 | 70.8 years STANDARD_DEVIATION 7.67 |
| Region of Enrollment Australia | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Belgium | 4 participants | 4 participants | 8 participants |
| Region of Enrollment Netherlands | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Russian Federation | 5 participants | 3 participants | 8 participants |
| Region of Enrollment Spain | 10 participants | 5 participants | 15 participants |
| Region of Enrollment Sweden | 3 participants | 0 participants | 3 participants |
| Region of Enrollment United States | 23 participants | 11 participants | 34 participants |
| Sex: Female, Male Female | 23 Participants | 9 Participants | 32 Participants |
| Sex: Female, Male Male | 27 Participants | 17 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 50 | 18 / 26 |
| serious Total, serious adverse events | 10 / 50 | 8 / 26 |
Outcome results
Primary
Percentage of Participants Who Achieved a Reduction in Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS)
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
Population: Intent-to-treat population: Included all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siltuximab | Percentage of Participants Who Achieved a Reduction in Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) | 12 Percentage of participants |
| Placebo | Percentage of Participants Who Achieved a Reduction in Red Blood Cell (RBC) Transfusions to Treat Anemia of Myelodysplastic Syndrome (MDS) | 3.8 Percentage of participants |
p-value: 0.27195% CI: [-0.03, 0.2]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in the Mean Hemoglobin Concentrations at Week 13
Time frame: Baseline and Week 13
Population: Intent-to-treat population: Included all randomized participants with evaluable data at Week 13
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Siltuximab | Change From Baseline in the Mean Hemoglobin Concentrations at Week 13 | -0.07 g/dL | Standard Deviation 1.503 |
| Placebo | Change From Baseline in the Mean Hemoglobin Concentrations at Week 13 | -0.13 g/dL | Standard Deviation 1.375 |
p-value: 0.87295% CI: [-0.79, 0.93]ANCOVA
Secondary
Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13
Time frame: Baseline and Week 13
Population: Intent-to-treat population: Included all randomized participants with evaluable data at Week 13
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Siltuximab | Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13 | 2.1 Percentage of Bone Marrow Blast Cells | Standard Deviation 8.22 |
| Placebo | Mean Changes From Baseline in Percentages of Bone Marrow Blast Cells at Week 13 | 0.2 Percentage of Bone Marrow Blast Cells | Standard Deviation 2.08 |
p-value: 0.36395% CI: [-2.35, 6.27]ANCOVA
Secondary
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
Population: Intent-to-treat population: Included all randomized participants who completed Week 13 unblinding
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Siltuximab | 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 | 6.0 RBC Transfusions |
| Placebo | 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 | 6.5 RBC Transfusions |
p-value: 0.07395% CI: [-3.55, 0.17]ANCOVA
Secondary
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
Population: Intent-to-treat population: Included all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siltuximab | Percentage of Participants Achieving Hemoglobin Improvement (≥1.5 g/dL Increase From Baseline) Unrelated to Red Blood Cell (RBC) Transfusion at Week 13 | 8.0 Percentage of Participants |
| Placebo | Percentage of Participants Achieving Hemoglobin Improvement (≥1.5 g/dL Increase From Baseline) Unrelated to Red Blood Cell (RBC) Transfusion at Week 13 | 3.8 Percentage of Participants |
p-value: 0.49495% CI: [-0.06, 0.15]Cochran-Mantel-Haenszel
Secondary
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
Population: Intent-to-treat population: Included all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Siltuximab | 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 | 4.0 Percentage of Participants |
| Placebo | 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 | 3.8 Percentage of Participants |
p-value: 0.98695% CI: [-0.09, 0.09]Cochran-Mantel-Haenszel