Myelodysplastic Syndrome (MDS)
Conditions
Brief summary
The purpose of the study is to determine whether azacitidine is safe and effective in the treatment of Chinese patients with higher risk Myelodysplastic Syndromes (MDS).
Interventions
DRUGAzacitidine
Subcutaneous administration of azacitidine 75 mg/m\^2/day for 7 days every 28 days optimally for at least 6 cycles until disease progression, unacceptable toxicity, or treatment discontinuation for any other reason
Sponsors
Celgene
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must satisfy the following criteria to be enrolled in the study: * Chinese males and females of Asian descent ≥ 18 years of age at the time of signing the informed consent document; * Must have a documented diagnosis of refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T) according to French-American-British (FAB) classification for Myelodysplastic Syndrome (MDS) and with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high risk or a diagnosis of myelodysplastic chronic myelomonocytic leukemia (CMML) per modified FAB criteria meeting the following: * Monocytosis in peripheral blood \> 1 x 10\^9/L; * Dysplasia in one or more myeloid cell lines; * 10% to 29% blasts in the bone marrow; and White blood cell (WBC) count \< 13 x 10\^9/L * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 ; * Adequate organ function, defined as: * Serum bilirubin ≤ 1.5 times the upper limit of normal (ULN); * Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.0 times the ULN; * Serum Creatinine ≤ 1.5 times the ULN; * Females of childbearing potential (FCBP) must: * Agree to the use of a physician-approved contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on azacitidine; and * for 3 months following the last dose of azacitidine; and have a negative serum pregnancy test within 72 hours prior to starting Investigational Product (IP). * Male subjects with a female partner of childbearing potential must agree to the use of a physician-approved contraceptive method throughout the course of the study and avoid fathering a child during the course of the study and for 3 months following the last dose of azacitidine; * Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted; * Able to adhere to the study visit schedule and other protocol requirements.
Exclusion criteria
The presence of any of the following will exclude a subject from enrollment: * Previous treatment with azacitidine or decitabine; * Diagnosis of malignant disease within the previous 12 months (excluding basal cell carcinoma of the skin without complications, in-situ carcinoma of the cervix or breast, or other local malignancy excised or irradiated with a high probability of cure); * Uncorrected red cell folate deficiency or vitamin B12 deficiency; * Diagnosis of metastatic disease; * Malignant hepatic tumors; * Known or suspected hypersensitivity to azacitidine or mannitol; * Candidate to proceed to bone marrow or stem cell transplant during the study; * Prior transplantation or cytotoxic therapy, including azacitidine and chemotherapy, administered to treat MDS; * Treatment with erythropoietin or myeloid growth factors (granulocyte colony-stimulating factor \[G-CSF\] or granulocyte-macrophage colony-stimulating factor \[GM-CSF\]) during the 21 days prior to Day 1 of Cycle 1; * Treatment with androgenic hormones during the 14 days prior to Day 1 of Cycle 1; * Active viral infection with known human immunodeficiency virus (HIV) or viral hepatitis type B or C; * Treatment with other investigational drugs, including thalidomide and arsenic trioxide, within the previous 30 days prior to Day 1 of Cycle 1, or ongoing adverse events from previous treatment with investigational drugs, regardless of the time period; and * Pregnant or lactating females; * Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study; * Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study; * Any condition that confounds the ability to interpret data from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days | Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia. |
| Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator | Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days | Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia. |
| Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Up to 29 January 2015; 894 days | Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major \>20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10\^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of \>0.5x10\^9/L. Minor: ≥100% increase and absolute increase of \<0.5x10\^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin \<100g/L or RBC transfusion-dependent, platelet count \<100x10\^9/L or platelet transfusion dependent, absolute neutrophil count \<1.5x10\^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of RBC Transfusions by Cycle | Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days | The number of RBC transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. |
| The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days | The on-treatment adverse event of infection requiring IV antibiotics, antifungals, or antivirals per 28 days/cycle. The overall post-baseline average is the average of number of infections requiring IV antibiotics or IV antiviral per 28 days/cycle. |
| Kaplan Meier Estimates for Overall Survival (OS) | Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days | Overall survival is defined as time to death from any cause, is calculated using date of first dose and date of death, or date of last follow-up for censored participants. Those, who die regardless of the cause of death, will be considered to have an event. |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | Up to 29 January 2015; from the first dose of study drug to 28 days after the date of the last dose of study drug (maximum time on study was 244 days) | A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following multiple doses of Azacitidine on Day 7; if possible, the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. No AUC extrapolation will be performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ will not be reported |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. |
| The Number of Units of Platelet Transfusions by Cycle | Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days | The number of units of platelet transfusions received 56 days prior to treatment, considered the baseline period, (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. |
| Time to Maximum Plasma Concentration (Tmax) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. |
| Terminal Phase of Half-life (T1/2) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz. |
| Apparent Total Plasma Clearance (CL/F) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞ |
| Apparent Volume of Distribution (Vd/F) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz |
| Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | Up to final data cut off date of 25 April 2018; from the first dose of study drug extesnion of 29 December 2014 to 28 days after the date of the last dose of study drug; median duration of any dose of study drug was 169 days | A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event. |
| Maximum Observed Plasma Concentration (Cmax) of Azacitidine | PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7 | The observed maximum plasma concentration obtained directly from the observed concentration versus time data. |
| The Number of Platelet Transfusions by Cycle | Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days | The number of platelet transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. |
| The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days | The number of units of RBC received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for RBC. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine Azacitidine 75 mg/m\^2/day subcutaneously (SC) for 7 days every 28 days until disease progression (DP), adverse events (AE), withdrawal of consent from further treatment, withdrawal of consent, death, lost to follow-up, or protocol violation. | 72 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Phase | Disease Progression | 1 |
| Extension Phase | Lack of Therapeutic Effect | 4 |
| Extension Phase | Stopped to Receive Stem Cell Transplant | 1 |
| Extension Phase | Study Closure | 1 |
| Extension Phase | Withdrawal by Subject | 8 |
| Primary Parent Phase | Adverse Event | 5 |
| Primary Parent Phase | Death | 13 |
| Primary Parent Phase | Disease Progression | 7 |
| Primary Parent Phase | Lack of Therapeutic Effect | 9 |
| Primary Parent Phase | Other | 2 |
| Primary Parent Phase | Protocol Violation | 1 |
| Primary Parent Phase | Withdrawal by Subject | 20 |
Baseline characteristics
| Characteristic | Azacitidine |
|---|---|
| Age, Continuous | 54.3 years STANDARD_DEVIATION 11.78 |
| French-American-British classification (FAB) Modified CMML=Chronic myelomonocytic leukemia | 1 Participants |
| French-American-British classification (FAB) RAEB in transformation | 8 Participants |
| French-American-British classification (FAB) RAEB=Refractory anemia with excess blasts | 63 Participants |
| International Prognostic Scoring System (IPSS) Risk Classification High (>=2.5) | 25 Participants |
| International Prognostic Scoring System (IPSS) Risk Classification Intermediate 1 (0.5-1.0) | 0 Participants |
| International Prognostic Scoring System (IPSS) Risk Classification Intermediate 2 (1.5-2.0) | 47 Participants |
| International Prognostic Scoring System (IPSS) Risk Classification Low (0) | 0 Participants |
| MDS World Health Organization (WHO) Classification Acute Myelogenous Leukemia (AML) | 7 Participants |
| MDS World Health Organization (WHO) Classification CMML | 1 Participants |
| MDS World Health Organization (WHO) Classification MDS and myeloproliferative disease (MPD) | 0 Participants |
| MDS World Health Organization (WHO) Classification RAEB-1=Refractory anemia with excess blasts | 14 Participants |
| MDS World Health Organization (WHO) Classification RAEB -2 with MPD=Myeloproliferative disease | 50 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 72 | 0 / 15 |
| other Total, other adverse events | 72 / 72 | 14 / 15 |
| serious Total, serious adverse events | 38 / 72 | 5 / 15 |
Outcome results
Primary
Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Hematologic improvements (HI) have 4 categories: 1. Erythroid response (HI-E): Major \>20g/L increase or transfusion independent. Minor: 10-20g/L increase or ≥50% decrease in transfusion requirements. 2. Platelet response (HI-P): Major absolute increase of ≥30x10\^9/L or platelet transfusion independence. Minor: ≥50% increase. 3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of \>0.5x10\^9/L. Minor: ≥100% increase and absolute increase of \<0.5x10\^9/L 4. Progression or relapse after HI Hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin \<100g/L or RBC transfusion-dependent, platelet count \<100x10\^9/L or platelet transfusion dependent, absolute neutrophil count \<1.5x10\^9/L. Sponsor's determination was derived using clinically relevant data. Denominator for progression/relapse after HI included participants who had achieved HI.
Time frame: Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Any improvement | 52.8 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-E (major) | 35.8 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-E (minor) | 9.0 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-P (major) | 37.9 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-P (minor) | 0.0 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-N (major) | 21.8 percentage of participants |
| Azacitidine | Percentage of Participants Achieving a Hematologic Improvement (HI) Based on 2000 IWG Response Criteria for MDS and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Hematologic Improvement-N (minor) | 0.0 percentage of participants |
Primary
Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data.
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Time frame: Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Overall CR+PR | 1.4 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Overall CR+PR+SD | 95.8 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Complete Remission (CR) | 1.4 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Based on the International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Programmatically Assessed by the Sponsor Using Clinically Relevant Data. | Partial Remission (PR) | 0 percentage of participants |
Primary
Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator
Hematologic Response is defined by those participants who experienced a Complete Response, Partial Response and Stable Disease (SD) based on IWG 2000 response criteria for MDS. CR = repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia • PR = same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment • Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months. • Failure: death during treatment or disease progression • Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence • Disease Progression: change in blast levels • Disease Transformation to Acute Myelogenous Leukemia.
Time frame: Response initially assessed at end of cycle 6, then every 4 cycles; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator | Overall CR+PR | 12.5 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator | Overall CR+PR+SD | 70.8 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator | CR | 6.9 percentage of participants |
| Azacitidine | Percentage of Participants With a Hematologic Response Using IWG Criteria for MDS and Assessed by the Investigator | PR | 5.6 percentage of participants |
Secondary
Apparent Total Plasma Clearance (CL/F) of Azacitidine
Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Apparent Total Plasma Clearance (CL/F) of Azacitidine | 107.2 Liters/hours | Geometric Coefficient of Variation 19.1 |
Secondary
Apparent Volume of Distribution (Vd/F) of Azacitidine
Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Apparent Volume of Distribution (Vd/F) of Azacitidine | 121.5 Liters | Geometric Coefficient of Variation 65.1 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine
Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following multiple doses of Azacitidine on Day 7; if possible, the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. No AUC extrapolation will be performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ will not be reported
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC∞) of Azacitidine | 1172.6 ng*h/mL | Geometric Coefficient of Variation 18 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine
Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUCt) of Azacitidine | 1161.9 ng*h/mL | Geometric Coefficient of Variation 17.7 |
Secondary
Kaplan Meier Estimates for Overall Survival (OS)
Overall survival is defined as time to death from any cause, is calculated using date of first dose and date of death, or date of last follow-up for censored participants. Those, who die regardless of the cause of death, will be considered to have an event.
Time frame: Until the end of the survival follow-up period; Up to data cut-off of 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Kaplan Meier Estimates for Overall Survival (OS) | Median OS | 22.0 months |
| Azacitidine | Kaplan Meier Estimates for Overall Survival (OS) | 25th percentile OS | 8.5 months |
| Azacitidine | Kaplan Meier Estimates for Overall Survival (OS) | 75th Percentile OS | NA months |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Azacitidine
The observed maximum plasma concentration obtained directly from the observed concentration versus time data.
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Maximum Observed Plasma Concentration (Cmax) of Azacitidine | 1264.6 ng/mL | Geometric Coefficient of Variation 30.7 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
Time frame: Up to final data cut off date of 25 April 2018; from the first dose of study drug extesnion of 29 December 2014 to 28 days after the date of the last dose of study drug; median duration of any dose of study drug was 169 days
Population: Safety population included all participants who received at least one dose of azacitidine and had at least one post-dose safety assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 TEAE | 14 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 TEAE related to study drug | 8 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 Grade 3 or 4 TEAE | 13 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 Grade 3 or 4 TEAE related to study drug | 6 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 serious TEAE | 5 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 serious TEAE related to study drug | 1 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥ 1 Grade 3 or 4 serious TEAE | 5 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥1 TEAE leading to dose interruption of study drug | 4 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Extension Phase | ≥1 TEAE leading to dose reduction/interruption | 4 participants |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase
A treatment-emergent adverse events (TEAE) was defined as AEs with an onset date on or after the date of first dose and within 28 days after the date of the last dose. Any AE that occurred beyond this timeframe and was assessed by the investigator as possibly related to study drug was considered treatment-emergent. The intensity and severity of AEs was assessed by the investigator according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 4.0. For any AEs not listed in the CTCAE grading system, the intensities of these events was assessed by the Investigator using the 5-point scale: Grade 1 = Mild, Grade 2 = Moderate; Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. An SAE is any AE occurring that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and constitutes an important medical event.
Time frame: Up to 29 January 2015; from the first dose of study drug to 28 days after the date of the last dose of study drug (maximum time on study was 244 days)
Population: Safety population included all participants who received at least one dose of azacitidine and had at least one post-dose safety assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 Grade 3 or 4 TEAE | 70 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 TEAE | 72 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 TEAE related to study drug | 68 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 Grade 3 or 4 TEAE related to study drug | 59 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 serious TEAE | 38 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 Grade 3 or 4 serious TEAE | 33 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 serious TEAE related to study drug | 28 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 TEAE leading to discontinuation of study drug | 14 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥ 1 TEAE leading to dose reduction of study drug | 19 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥1 TEAE leading to dose interruption of study drug | 49 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥1 TEAE leading to dose reduction/interruption | 50 participants |
| Azacitidine | Number of Participants With Treatment Emergent Adverse Events (TEAE) During the Parent Phase | ≥1 TEAE with outcome of death | 11 participants |
Secondary
Terminal Phase of Half-life (T1/2) of Azacitidine
The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz.
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Terminal Phase of Half-life (T1/2) of Azacitidine | 0.8 hours | Geometric Coefficient of Variation 69 |
Secondary
The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle
The on-treatment adverse event of infection requiring IV antibiotics, antifungals, or antivirals per 28 days/cycle. The overall post-baseline average is the average of number of infections requiring IV antibiotics or IV antiviral per 28 days/cycle.
Time frame: Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 26 N | 0.0 Infections | — |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Baseline N = 72 | 0.0 Infections | Standard Deviation 0.2 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Overall Post Baseline Average N = 72 | 0.6 Infections | Standard Deviation 1.43 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Overall Change from Baseline N =72 | 0.5 Infections | Standard Deviation 1.45 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 1 N = 72 | 0.6 Infections | Standard Deviation 1.32 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 2 | 0.5 Infections | Standard Deviation 1.67 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 3 | 0.4 Infections | Standard Deviation 0.86 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 4 | 0.5 Infections | Standard Deviation 1.03 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 5 | 0.4 Infections | Standard Deviation 0.72 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 6 | 0.2 Infections | Standard Deviation 0.61 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 7 | 0.3 Infections | Standard Deviation 1.01 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 8 | 0.2 Infections | Standard Deviation 0.47 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 9 | 0.1 Infections | Standard Deviation 0.32 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 10 | 0.2 Infections | Standard Deviation 0.44 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 11 | 0.1 Infections | Standard Deviation 0.31 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle12 | 0.1 Infections | Standard Deviation 0.27 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 13 | 0.1 Infections | Standard Deviation 0.24 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 14 15 | 0.1 Infections | Standard Deviation 0.32 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 15 | 0.3 Infections | Standard Deviation 0.7 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 16 | 0.3 Infections | Standard Deviation 0.42 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 17 | 0.4 Infections | Standard Deviation 0.75 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 18 | 0.4 Infections | Standard Deviation 0.74 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 19 | 0.2 Infections | Standard Deviation 0.41 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 20 | 0.0 Infections | Standard Deviation 0 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 21 | 0.0 Infections | Standard Deviation 0 |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 22 | 0.9 Infections | — |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 23 | 1.0 Infections | — |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 24 | 0.0 Infections | — |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 25 | 0.0 Infections | — |
| Azacitidine | The Number of Infections (Post-baseline Average) Requiring Intravenous (IV) Antibiotics, Anti-fungals, or Antivirals by Cycle | Cycle 27 | 0.0 Infections | — |
Secondary
The Number of Platelet Transfusions by Cycle
The number of platelet transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length.
Time frame: Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 7 | 0.8 Platelet transfusions | Standard Deviation 2.5 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 21 | 0.0 Platelet transfusions | Standard Deviation 0 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 17 | 0.3 Platelet transfusions | Standard Deviation 0.73 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 24 | 0.0 Platelet transfusions | — |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Baseline N = 72 | 0.8 Platelet transfusions | Standard Deviation 2.36 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Overall Post-Baseline Average N = 72 | 1.6 Platelet transfusions | Standard Deviation 2.83 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Overall Change from Baseline N = 72 | 0.8 Platelet transfusions | Standard Deviation 3.29 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 1 N = 72 | 1.8 Platelet transfusions | Standard Deviation 2.89 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 2 | 1.3 Platelet transfusions | Standard Deviation 2.59 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 3 | 1.2 Platelet transfusions | Standard Deviation 2.28 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 4 | 1.3 Platelet transfusions | Standard Deviation 2.18 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 5 | 0.9 Platelet transfusions | Standard Deviation 1.58 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 6 | 0.7 Platelet transfusions | Standard Deviation 1.34 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 8 | 0.8 Platelet transfusions | Standard Deviation 1.66 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 9 | 0.8 Platelet transfusions | Standard Deviation 2.46 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 10 | 0.8 Platelet transfusions | Standard Deviation 2.08 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 11 | 0.5 Platelet transfusions | Standard Deviation 1 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 12 | 0.3 Platelet transfusions | Standard Deviation 0.78 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 13 | 0.3 Platelet transfusions | Standard Deviation 0.72 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 14 | 0.1 Platelet transfusions | Standard Deviation 0.35 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 15 | 0.3 Platelet transfusions | Standard Deviation 0.9 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 16 | 0.3 Platelet transfusions | Standard Deviation 0.9 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 18 | 0.6 Platelet transfusions | Standard Deviation 1.51 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 19 | 0.3 Platelet transfusions | Standard Deviation 0.64 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 20 | 0.2 Platelet transfusions | Standard Deviation 0.37 |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 22 | 0.0 Platelet transfusions | — |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 23 | 0.0 Platelet transfusions | — |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 25 | 0.0 Platelet transfusions | — |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 26 | 0.0 Platelet transfusions | — |
| Azacitidine | The Number of Platelet Transfusions by Cycle | Cycle 27 | 0.0 Platelet transfusions | — |
Secondary
The Number of RBC Transfusions by Cycle
The number of RBC transfusions received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length.
Time frame: Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | The Number of RBC Transfusions by Cycle | Baseline N = 72 | 1.1 RBC Transfusions | Standard Deviation 1.79 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 2 | 1.7 RBC Transfusions | Standard Deviation 2.56 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 9 | 0.4 RBC Transfusions | Standard Deviation 0.74 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 12 | 0.4 RBC Transfusions | Standard Deviation 0.87 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Overall Post-Baseline Average N = 72 | 1.6 RBC Transfusions | Standard Deviation 1.97 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Overall Change from Baseline N = 72 | 0.5 RBC Transfusions | Standard Deviation 2.12 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 1 N = 72 | 1.7 RBC Transfusions | Standard Deviation 1.64 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 3 | 1.4 RBC Transfusions | Standard Deviation 1.81 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 4 | 1.2 RBC Transfusions | Standard Deviation 1.73 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 5 | 1.1 RBC Transfusions | Standard Deviation 1.81 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 6 | 0.9 RBC Transfusions | Standard Deviation 1.63 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 7 | 0.8 RBC Transfusions | Standard Deviation 1.97 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 8 | 0.8 RBC Transfusions | Standard Deviation 1.23 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 10 | 0.5 RBC Transfusions | Standard Deviation 0.94 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 11 | 0.5 RBC Transfusions | Standard Deviation 0.78 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 13 | 0.5 RBC Transfusions | Standard Deviation 0.94 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 14 | 0.2 RBC Transfusions | Standard Deviation 0.53 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 15 | 0.4 RBC Transfusions | Standard Deviation 0.77 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 16 | 0.4 RBC Transfusions | Standard Deviation 0.57 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 17 | 0.3 RBC Transfusions | Standard Deviation 0.91 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 18 | 0.7 RBC Transfusions | Standard Deviation 1.17 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 19 | 0.4 RBC Transfusions | Standard Deviation 0.64 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 20 | 0.6 RBC Transfusions | Standard Deviation 0.71 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 21 | 0.2 RBC Transfusions | Standard Deviation 0.31 |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 22 | 0.0 RBC Transfusions | — |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 23 | 0.0 RBC Transfusions | — |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 24 | 0.0 RBC Transfusions | — |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 25 | 0.0 RBC Transfusions | — |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 26 | 0.0 RBC Transfusions | — |
| Azacitidine | The Number of RBC Transfusions by Cycle | Cycle 27 | 0.0 RBC Transfusions | — |
Secondary
The Number of Units of Platelet Transfusions by Cycle
The number of units of platelet transfusions received 56 days prior to treatment, considered the baseline period, (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length.
Time frame: Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Population: Intent to Treat (ITT) includes all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Baseline N = 72 | 1.9 Units of platelet transfusions | Standard Deviation 4.91 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Overall Post-Baseline Average N = 72 | 4.7 Units of platelet transfusions | Standard Deviation 17.79 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Overall Change from Baseline N = 72 | 2.8 Units of platelet transfusions | Standard Deviation 17.89 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 1 N = 72 | 5.2 Units of platelet transfusions | Standard Deviation 18.83 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 2 | 2.4 Units of platelet transfusions | Standard Deviation 5.86 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 3 | 3.3 Units of platelet transfusions | Standard Deviation 11.44 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 4 | 2.7 Units of platelet transfusions | Standard Deviation 6.13 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 5 | 2.5 Units of platelet transfusions | Standard Deviation 7.69 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 6 | 1.5 Units of platelet transfusions | Standard Deviation 4.15 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 7 | 1.0 Units of platelet transfusions | Standard Deviation 2.84 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 8 | 1.1 Units of platelet transfusions | Standard Deviation 2.05 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 9 | 0.8 Units of platelet transfusions | Standard Deviation 2.46 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 10 | 0.8 Units of platelet transfusions | Standard Deviation 2.08 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 11 | 0.5 Units of platelet transfusions | Standard Deviation 1 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 12 | 0.3 Units of platelet transfusions | Standard Deviation 0.78 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 13 | 0.3 Units of platelet transfusions | Standard Deviation 0.72 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 14 | 0.1 Units of platelet transfusions | Standard Deviation 0.35 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 15 | 0.3 Units of platelet transfusions | Standard Deviation 0.9 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 16 | 0.3 Units of platelet transfusions | Standard Deviation 0.9 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 17 | 0.3 Units of platelet transfusions | Standard Deviation 0.73 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 18 | 0.6 Units of platelet transfusions | Standard Deviation 1.51 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 19 | 0.3 Units of platelet transfusions | Standard Deviation 0.64 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 20 | 0.2 Units of platelet transfusions | Standard Deviation 0.37 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 21 | 0.0 Units of platelet transfusions | Standard Deviation 0 |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 22 | 0.0 Units of platelet transfusions | — |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 23 | 0.0 Units of platelet transfusions | — |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 24 | 0.0 Units of platelet transfusions | — |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 25 | 0.0 Units of platelet transfusions | — |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 26 | 0.0 Units of platelet transfusions | — |
| Azacitidine | The Number of Units of Platelet Transfusions by Cycle | Cycle 27 | 0.0 Units of platelet transfusions | — |
Secondary
The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle
The number of units of RBC received 56 days prior to treatment, considered the baseline period (baseline period defined as the screening period before the date of the first dose of azacitidine; any laboratory and blood transfusion data reported on the day of the first dose of azacitidine was considered to be baseline data) and during study was standardized per 28 days and summarized by cycle for RBC. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length.
Time frame: Up to cycle 27; The on-treatment period was considered the period from the date of first dose to the last treatment study visit; Up to 29 January 2015; 894 days
Population: ITT includes all participants who were enrolled into the study
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Baseline N = 72 | 2.3 Units of RBC Transfusions | Standard Deviation 3.55 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Overall Change from Baseline N = 72 | 1.2 Units of RBC Transfusions | Standard Deviation 4.34 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 4 | 2.7 Units of RBC Transfusions | Standard Deviation 3.73 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 5 | 2.5 Units of RBC Transfusions | Standard Deviation 3.94 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 6 | 2.0 Units of RBC Transfusions | Standard Deviation 3.46 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 7 | 1.7 Units of RBC Transfusions | Standard Deviation 3.84 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 8 | 1.7 Units of RBC Transfusions | Standard Deviation 2.68 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 9 | 0.9 Units of RBC Transfusions | Standard Deviation 1.56 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 10 | 1.2 Units of RBC Transfusions | Standard Deviation 2.25 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 11 | 1.3 Units of RBC Transfusions | Standard Deviation 1.97 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 12 | 1.1 Units of RBC Transfusions | Standard Deviation 2.21 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 13 | 1.2 Units of RBC Transfusions | Standard Deviation 2.62 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 14 | 0.4 Units of RBC Transfusions | Standard Deviation 1.05 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 15 | 1.1 Units of RBC Transfusions | Standard Deviation 2.07 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 16 | 0.9 Units of RBC Transfusions | Standard Deviation 1.61 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 19 | 0.8 Units of RBC Transfusions | Standard Deviation 1.37 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 20 | 1.1 Units of RBC Transfusions | Standard Deviation 1.42 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 21 | 0.4 Units of RBC Transfusions | Standard Deviation 0.62 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 24 | 0.0 Units of RBC Transfusions | — |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 26 | 0.0 Units of RBC Transfusions | — |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 27 | 0.0 Units of RBC Transfusions | — |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Overall Post-Baseline Average N = 72 | 3.5 Units of RBC Transfusions | Standard Deviation 3.88 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 1 N = 72 | 3.6 Units of RBC Transfusions | Standard Deviation 3.41 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 2 | 3.6 Units of RBC Transfusions | Standard Deviation 4.88 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 3 | 3.0 Units of RBC Transfusions | Standard Deviation 3.68 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 17 | 1.2 Units of RBC Transfusions | Standard Deviation 3.28 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 18 | 1.6 Units of RBC Transfusions | Standard Deviation 3.07 |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 22 N | 0 Units of RBC Transfusions | — |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 23 | 0.0 Units of RBC Transfusions | — |
| Azacitidine | The Number of Units of Red Blood Cell (RBC) Transfusions by Cycle | Cycle 25 | 0.0 Units of RBC Transfusions | — |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Azacitidine
Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.
Time frame: PK blood samples collected at 0.25, 0.5, 1,2,3,4, 6 and 8 hours after azacitidine administration on Day 7
Population: The PK population includes up to 12 participants with evaluable azacitidine plasma PK profile.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Azacitidine | Time to Maximum Plasma Concentration (Tmax) of Azacitidine | 0.25 hours | Full Range 27.66 |