The Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo and Best Supportive Care in Subjects With Red Blood Cell (RBC) Transfusion-Dependent Anemia and Thrombocytopenia Due to International Prognostic Scoring System (IPSS) Low Risk Myelodysplastic Syndrome (MDS)

A Phase 3, Multicenter, Randomized, Double-blind Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Subjects With Red Blood Cell Transfusion-dependent Anemia and Thrombocytopenia Due to IPSS Lower-risk Myelodysplastic Syndromes.

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01566695

Enrollment

216

Registered

2012-03-29

Start date

2013-04-26

Completion date

2023-12-21

Last updated

2025-01-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Myelodysplastic Syndrome

Brief summary

Evaluation of the Efficacy and Safety of Oral Azacitidine plus Best Supportive care versus Placebo and Best Supportive care in subjects with red blood cell (RBC) transfusion-dependent anemia and thrombocytopenia due to International Prognostic Scoring System (IPSS) lower risk myelodysplastic syndromes (MDS).

Interventions

DRUGOral Azacitidine

300 mg daily, days 1 to 21 of each 28-day treatment cycle

DRUGPlacebo

Identically matching placebo tablets on day 1 to 21 of each 28-day treatment cycle.

OTHERBest Supportiv Care (BSC)

BSC included and was not limited to packed RBC (packed red blood cell \[pRBC\] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

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

Inclusion criteria

* 18 years or older * Have a documented diagnosis of MDS * Anemia that requires red blood cell transfusions * Thrombocytopenia (sustained for at least 21 days) within 14 days prior to randomization * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 * Must agree to follow pregnancy precautions as required by protocol. * Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted

Exclusion criteria

* Secondary or hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy * Prior treatment with azacitidine, decitabine, other hypomethylating agents and lenalidomide (for lenalidomide : unless the last dose received is \>= 8 weeks prior to inclusion into the study). * Prior allogeneic or autologous stem cell transplant * Eligible for allogenic or autologous stem cell transplant * History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect * Thrombocytopenia secondary to other possible causes, including medication(s), congenital disorder(s), immune disorder(s), or microvascular disorder(s) * Use of cytotoxic, chemotherapeutic, targeted or investigational agents/therapies, thrombopoiesis-stimulating agents (TSAs), erythropoiesis-stimulating agents (ESAs) and other red blood cell hematopoietic growth factors, and within 28 days prior to randomization * Ongoing medically significant adverse events from previous treatment, regardless of the time period * Concurrent use of iron-chelating agents, (except for subjects on a stable or decreasing dose for at least 8 weeks (56 days) prior to randomization), corticosteroid (except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS) * Prior history of cancer, other than MDS, unless the subject has been free of the disease for ≥ 3 years. (Basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, and incidental histologic finding of prostate cancer) (T1a or T1b using the tumor, nodes, metastasis \[TNM\] clinical staging system is allowed) * Significant active cardiac disease within the previous 6 months * Uncontrolled systemic fungal, bacterial, or viral infection * Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection * Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding * Abnormal coagulation parameters * Abnormal liver function test results * Abnormal kidney function test results * Known or suspected hypersensitivity to azacitidine or mannitol * Any significant medical condition, laboratory abnormality, or psychiatric illness

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days	Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.	RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive rolling 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.

Secondary

Measure	Time frame	Description
Time to RBC Transfusion Independence for at Least 56 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days	From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Time to RBC transfusion independence of ≥ 56 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 56 without any RBC transfusions).
Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.
Percentage of Participants Who Achieved RBC Transfusion Independence for ≥ 84 Days	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	RBC transfusion independence was defined as the absence of any red blood cell (RBC) transfusion during any consecutive rolling 84 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 84 days (i.e., day 1 to day 84, day 2 to day 85) were considered as a 84-day RBC transfusion independent responder.
Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis.
Time to RBC Transfusion Independence for at Least 84 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Time to RBC transfusion independence of ≥ 84 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 84 without any RBC transfusions).
Percentage of Participants With an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Erythroid HI-E improvement was defined as a hemoglobin increase of ≥ 1.5 g/dL; or a reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment were counted in the RBC transfusion response evaluation.
Percentage of Participants With a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	HI-P response was defined according to IWG 2006 criteria (Cheson, 2006) and as: 1. Absolute increase of ≥ 30 X 10\^9/L for participants\^ starting with \> 20 X 10\^9/L platelets; 2. Increase from \< 20 X 10\^9/L to \> 20 X 10\^9/L and by at least 100%. HI-P must have lasted at least 8 weeks.
Percentage of Participants Who Achieved Platelet Transfusion Independence With a Duration of ≥ 8 Weeks (56 Days)	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Platelet transfusion independence was defined as the absence of any platelet transfusion during any consecutive rolling 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 to 58, etc.). Participants were considered platelet transfusion dependent at baseline if they had received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and had no consecutive 28-day period during which no platelet transfusions were administered.
Time to Platelet Transfusion Independence	From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Time to platelet transfusion independence was defined as the time between randomization and the first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet transfusions).
Overall Survival (OS)	From randomization up to death from any cause; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Overall survival was defined as the time from randomization to death from any cause and was calculated using randomization date and date of death, or date of last follow-up for censored participants. All subjects were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study closure. Participants who dropped out or were alive at study closure (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate.
Percentage of Participants With a Hematologic Response According to the 2006 IWG Criteria for MDS	Response was assessed every 3 cycles; up to the data cut-off date of 25 Jan 2019; median duration of exposure to oral azacitidine was 86.0 days and 119.0 days for placebo	Hematologic response was defined as: • A complete response (CR): \<5% myeloblasts, and normal maturation of all cell lines; Peripheral blood (PB) shows: hemoglobin \>10 g/dL, neutrophils ≥1.0x10\^9/L, platelets ≥100x10\^9/dL, blasts (0%) • Partial Response (PR): same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still \> 5%; Cellularity and morphology not relevant • Marrow CR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB • Stable disease (SD): failure to achieve at least PR, but no evidence of progression for \> 8 wks • Failure: death during treatment or disease progression • Disease Progression for those with: - Less than 5% blasts: ≥ 50% increase in blasts to \> 5% blasts - 5%-10% blasts:≥ 50% increase to \> 10% blasts - 10%-20% blasts:≥ 50% increase to \> 20% blasts - 20%-30% blasts ≥ 50% increase to \> 30% blasts Any of the following: - ≥ 50% decrease from maximum remission/response in granulocytes or platelets
Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)	From randomization of study drug to the end up to final data cut-off date of 25 January 2019; maximum follow-up time was 67.9 months for azacitidine and 64.8 months for placebo group	Participants with a documented diagnosis of AML arising from previous MDS documented diagnosis.
Time to Progression to Acute Myeloid Leukemia (AML) Among Participants Who Progressed to AML	From randomization of study drug to progression of AML; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Time to AML progression was defined as the time from the date of randomization until the date the subject has documented progression to AML. For participants who had progression to AML documented in MLL central lab report, the earliest sample collection date with the diagnosis of s-AML arising from previous MDS was used as the date to AML progression.
Percentage of Participants With Significant Bleeding Events	From date of randomization until 28 days after the last dose of IP; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo	Clinically significant bleeding event was defined as: any intracranial or retroperitoneal bleed; bleeding requiring transfusions of \> 2 units of blood/blood products; bleeding associated with a decrease in hemoglobin of \> 2 g/dL; or bleeding from any site requiring transfusions of \> 2 units of blood.
Number of Participants With Treatment Emergent Adverse Events (TEAE)	From first dose of IP up to 28 days after the last dose of IP or until the last study visit; up to a maximum of approximately 6 months on study	A TEAE was defined as an adverse event that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.
Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Anemia Subscale Within FACT-An Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Fatigue-Related Subscale Within the FACT-An Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.
Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale Within the FACT-An Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-G and FACT-An score are summed to form the FACT-An total score. The FACT-An Trial Outcome Index (TOI) consists of the summation of a summary scale and includes the Physical Well-being, (PWB; 7 items; score range, 0-28), the Functional Well-being (7 items; score range, 0-28) and the Anemia subscale consisting of 20 items on the same five-point scale, with 13 of them measuring fatigue related symptoms (FS) and seven measuring non-FS. The FACT-An TOI has been demonstrated to be a sensitive indicator of clinical outcomes in a number of diseases including MDS. The Fact-TOI score ranges from 0 to 136. Higher scores on all scales of the Fact-An and subscales on the FACT-TOI reflect better quality of life or fewer symptoms.
Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale Within the FACT-An Instrument at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (i.e., the Functional Assessment of Cancer Therapy-General \[FACT-G\]) The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0-28), • Social/Family Well-being (SWB; 7 items; score range, 0-28), • Emotional Well-being (EWB; 6 items; score range, 0-24), and • Functional Well-being (7 items; score range, 0-28). The FACT-G is a summation composed of a summary scale including the PWB, SWB, EWB and FWB. The FACT-G score range is from 0 to 108. For all summary scales including FACT-G, a higher score indicates better HRQoL or lower level of symptoms.
Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6	Baseline to Cycle 6 Day 1	The FACT-G and the anemia subscale (AnS) are summed to form the FACT-An total score and the total score ranges from 0 to 188. The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0-28), • Social/Family Well-being (SWB; 7 items; score range, 0-28), • Emotional Well-being (EWB; 6 items; score range, 0-24), and • Functional Well-being (7 items; score range, 0-28). The AnS consists of 20 items on the same 5-point scale, with 13 of them measuring fatigue-related symptoms (FS) and 7 measuring non-FS. The AnS and FS scores can range from 0-80 and 0-52, respectively. For all domains and summary subscales, a higher score indicates better HRQoL or lower level of symptoms.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain Within the FACT-An Instrument at Cycle 6	Cycle 6 Day 1	A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)	From Baseline to Cycle 2 Day 1 (C2D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 3 Day 1 (C3D1)	From Baseline to Cycle 3 Day 1 (C3D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 4 Day 1 (C4D1)	From Baseline to Cycle 4 Day 1 (C4D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 5 Day 1 (C5D1)	From Baseline to Cycle 5 Day 1 (C5D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 6 Day 1 (C6 D1)	From Baseline to Cycle 6 Day 1 (C6 D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 7 Day 1 (C7D1)	From Baseline to Cycle 7 Day 1 (C7D1)	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Change From Baseline in Responses to the Fact-Anemia Item GP-5 - End of Treatment	From Baseline to End of Treatment	The distribution (frequency and percentage) of the observed responses (i.e., Not at all (0), A little bit (1), Somewhat (2), Quite a bit (3), Very much (4), and missing) to Item GP-5 (I am bothered by side effects of treatment in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved \[i.e., change score from 1 to 4\], no change \[0\], worsened by one level \[-1\], worsened by ≥2 levels \[-2 to -4\], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.
Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6	From Baseline to Cycle 6 Day 1	The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved \[by ≥1 level\], no change, worsened \[by ≥1 level\], and missing) from baseline are reported.
Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level of Self-Care Dimension Responses at Cycle 6	From Baseline to Cycle 6 Day 1	The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved \[by ≥1 level\], no change, worsened \[by ≥1 level\], and missing) from baseline are reported.
Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days	From the date of randomization of study drug up to the data cut-off date of 25 January 2019	Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going.
Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Pain/Discomfort Dimension Responses at Cycle 6	From Baseline to Cycle 6 Day 1	The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved \[by ≥1 level\], no change, worsened \[by ≥1 level\], and missing) from baseline are reported.
Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level in the Anxiety/Depression Dimension Responses at Cycle 6	From Baseline to Cycle 6 Day 1	The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved \[by ≥1 level\], no change, worsened \[by ≥1 level\], and missing) from baseline are reported.
Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo	The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason	From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo	The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years	From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo	The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.
Percentage of Participants With Improved, Worsened, or No Change in the European Quality of Life-Five Dimension-Three Level Usual Activities Dimension Responses at Cycle 6	From Baseline to Cycle 6 Day 1	TThe EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent's self-rated health on a vertical, 0-100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved \[by ≥1 level\], no change, worsened \[by ≥1 level\], and missing) from baseline are reported.

Countries

Australia, Belgium, Brazil, Canada, Czechia, Denmark, Finland, France, Germany, Greece, Israel, Italy, Mexico, Netherlands, Norway, Poland, Portugal, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

Participants were randomized at 101 sites globally. The sites were located in: Europe (76), North America (13), Asia/Pacific (10), and Latin America (2). Results are reported as of the data cut-off date of 25 January 2019.

Pre-assignment details

Participants were stratified by: average baseline (BL) Red Blood Cell (RBC) transfusion requirement (≤ 4 units versus \> 4 units of RBC per 28 days), BL platelet transfusion status (dependent or independent), country of enrollment and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 to 1 versus 2).

Participants by arm

Arm	Count
Oral Azacitidine Plus Best Supportive Care Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell \[pRBC\] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.	107
Placebo Plus Best Supportive Care Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.	109
Total	216

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	0
Overall Study	Death	79	86
Overall Study	Lack of Efficacy	1	0
Overall Study	Lost to Follow-up	0	3
Overall Study	Other reasons	11	8
Overall Study	Withdrawal by Subject	13	12

Baseline characteristics

Characteristic	Placebo Plus Best Supportive Care	Total	Oral Azacitidine Plus Best Supportive Care
Age, Continuous	73.1 Years STANDARD_DEVIATION 8.36	73.0 Years STANDARD_DEVIATION 8.78	73.0 Years STANDARD_DEVIATION 9.23
Average Red Blood Cell Transfusion Requirement (units per 28 days)	3.33 units per 28 days	3.33 units per 28 days	3.33 units per 28 days
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0-1	94 Participants	185 Participants	91 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 2	15 Participants	31 Participants	16 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 3	0 Participants	0 Participants	0 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 4	0 Participants	0 Participants	0 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 5	0 Participants	0 Participants	0 Participants
Hemoglobin	8.04 g/dL STANDARD_DEVIATION 0.96	8.13 g/dL STANDARD_DEVIATION 0.976	8.22 g/dL STANDARD_DEVIATION 0.988
International Prognostic Scoring System (IPSS) High	0 Participants	0 Participants	0 Participants
International Prognostic Scoring System (IPSS) Intermediate 1 (0.5-1.0)	109 Participants	215 Participants	106 Participants
International Prognostic Scoring System (IPSS) Intermediate 2 (1.5-2.0)	0 Participants	1 Participants	1 Participants
International Prognostic Scoring System (IPSS) Low	0 Participants	0 Participants	0 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification del (5q) MDS Associated with Isolated del 5q	0 Participants	0 Participants	0 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification MDS-U (MDS-unclassified)	2 Participants	4 Participants	2 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RAEB-1 RA with Excess Blasts - 1	29 Participants	46 Participants	17 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RAEB-2 RA with Excess Blasts - 2	0 Participants	0 Participants	0 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RA = Refractory Anemia	3 Participants	7 Participants	4 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RARS = RA with Ringed Sideroblasts	2 Participants	5 Participants	3 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RCMD = R Cytopenia w/ Multilineage Dysplasia	73 Participants	153 Participants	80 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RN = Refractory Neutropenia	0 Participants	0 Participants	0 Participants
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification RT = Refractory Thrombocytopenia	0 Participants	1 Participants	1 Participants
Platelet Count	27.9 10^9 cells/L STANDARD_DEVIATION 18.11	27.5 10^9 cells/L STANDARD_DEVIATION 17.05	27.0 10^9 cells/L STANDARD_DEVIATION 15.97
Platelet Transfusion Status Dependent	35 Participants	65 Participants	30 Participants
Platelet Transfusion Status Independent	74 Participants	151 Participants	77 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Asian	3 Participants	5 Participants	2 Participants
Race/Ethnicity, Customized Black or African American	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Hispanic or Latino	9 Participants	13 Participants	4 Participants
Race/Ethnicity, Customized Japanese	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islanders	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	93 Participants	184 Participants	91 Participants
Race/Ethnicity, Customized Not Reported	7 Participants	19 Participants	12 Participants
Race/Ethnicity, Customized Other	7 Participants	15 Participants	8 Participants
Race/Ethnicity, Customized White	99 Participants	195 Participants	96 Participants
Sex: Female, Male Female	30 Participants	58 Participants	28 Participants
Sex: Female, Male Male	79 Participants	158 Participants	79 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	83 / 107	86 / 109
other Total, other adverse events	107 / 107	104 / 109
serious Total, serious adverse events	83 / 107	69 / 109

Outcome results

Primary

Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive rolling 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.

Time frame: Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.

Population: The intent-to-treat (ITT) population included all participants who were randomized, regardless of whether they received treatment or not.

Arm	Measure	Value (NUMBER)
Oral Azacitidine and Best Supportive Care	Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days	30.8 Percentage of Participants
Placebo Plus Best Supportive Care	Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days	11.9 Percentage of Participants

p-value: 0.000595% CI: [8.3, 29.6]Stratified Mantel-Haenszel Chi-squared

Secondary

Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days

Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going.

Time frame: From the date of randomization of study drug up to the data cut-off date of 25 January 2019

Population: Intent to Treat population. Participants who achieved RBC transfusion independence of ≥ 56 days on treatment.

Arm	Measure	Value (MEDIAN)
Oral Azacitidine and Best Supportive Care	Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days	11.1 months
Placebo Plus Best Supportive Care	Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days	12.0 months

Secondary

Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days

Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis.

Time frame: From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

Population: Intent to Treat population. Participants who achieved RBC transfusion independence for at least 84 days on treatment.

Arm	Measure	Value (MEDIAN)
Oral Azacitidine and Best Supportive Care	Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days	11.1 months
Placebo Plus Best Supportive Care	Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days	NA months

p-value: 0.4347Two-Sided Unstratified Log Rank Test

Secondary

Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks

A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.

Population: Intent to Treat population; includes participants who achieved RBC transfusion reduction of at least 4 units for at least 8 weeks.

Arm	Measure	Value (MEDIAN)
Oral Azacitidine and Best Supportive Care	Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks	10.0 months
Placebo Plus Best Supportive Care	Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks	2.3 months

Secondary

Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized

The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

Time frame: From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

Population: The safety population includes all randomized participants who received at least one dose of study drug.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Adverse Events	79 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Procedure Planned Prior to Signing Consent	0 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Non-Protocol Driven Procedures	9 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Elective Procedures	4 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Protocol Driven Procedures	2 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Social, Technical or Practical Reason except AEs	4 Participants
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Transfusion	32 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Social, Technical or Practical Reason except AEs	6 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Adverse Events	65 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Protocol Driven Procedures	7 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Non-Protocol Driven Procedures	19 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Transfusion	33 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Procedure Planned Prior to Signing Consent	4 Participants
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized	Elective Procedures	10 Participants

Secondary

Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason

The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

Population: The safety population includes all randomized participants who received at least one dose of study drug.

Arm	Measure	Value (NUMBER)
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason	3513 Days
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to Any Reason	2688 Days

Secondary

Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years

The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

Population: The safety population includes all randomized participants who received at least one dose of study drug.

Arm	Measure	Value (NUMBER)
Oral Azacitidine and Best Supportive Care	Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years	41.44 Days Per Total Patient Years
Placebo Plus Best Supportive Care	Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years	40.53 Days Per Total Patient Years

Secondary

Mean Change From Baseline in the Anemia Subscale Within FACT-An Instrument at Cycle 6

The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.