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NCT01566695

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)

Completed Phase 3 Results posted Last updated 7 January 2025
What this trial tests

Phase 3 trial testing Oral Azacitidine in Myelodysplastic Syndrome in 216 participants. Completed in 21 December 2023.

Timeline
26 April 2013
Primary endpoint
25 January 2019
21 December 2023

Quick facts

Lead sponsorCelgene
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment216
Start date26 April 2013
Primary completion25 January 2019
Estimated completion21 December 2023
Sites196 locations across Italy, Finland, Poland, South Korea, Denmark, Netherlands, Belgium, Sweden

Drugs / interventions tested

Conditions studied

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Myelodysplastic Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

GroupValue95% CI
Oral Azacitidine and Best Supportive Care30.822.1 – 39.6
Placebo Plus Best Supportive Care11.95.8 – 18.0
Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days Secondary · 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 mai

GroupValue95% CI
Oral Azacitidine and Best Supportive Care11.18.2 – 26.0
Placebo Plus Best Supportive Care12.02.3 – NA
Time to RBC Transfusion Independence for at Least 56 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 56 Days Secondary · 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).

GroupValue95% CI
Oral Azacitidine and Best Supportive Care2.370.0 – 10.9
Placebo Plus Best Supportive Care2.040.0 – 14.3
Duration of RBC Transfusion Reduction for Participants Who Achieved RBC Transfusion Reduction of at Least 4 Units of RBCs for at Least 8 Weeks Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care10.07.1 – 13.3
Placebo Plus Best Supportive Care2.32.0 – 5.0
Percentage of Participants Who Achieved RBC Transfusion Independence for ≥ 84 Days Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care28.019.5 – 36.5
Placebo Plus Best Supportive Care6.41.8 – 11.0
Duration of RBC Transfusion Independence Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care11.18.2 – 26.0
Placebo Plus Best Supportive CareNA5.0 – NA
Time to RBC Transfusion Independence for at Least 84 Days Among Participants Who Achieved RBC Transfusion Independence for at Least 84 Days Secondary · 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).

GroupValue95% CI
Oral Azacitidine and Best Supportive Care2.640.0 – 9.9
Placebo Plus Best Supportive Care4.010.5 – 14.3
Percentage of Participants With an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria Secondary · 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.

HI-E Response
GroupValue95% CI
Oral Azacitidine and Best Supportive Care43.033.6 – 52.4
Placebo Plus Best Supportive Care32.123.3 – 40.9
≥ 1.5 g/dL Hemoglobin Increase
GroupValue95% CI
Oral Azacitidine and Best Supportive Care23.415.3 – 31.4
Placebo Plus Best Supportive Care5.51.2 – 9.8
RBC Transfusion Reduction
GroupValue95% CI
Oral Azacitidine and Best Supportive Care42.132.7 – 51.4
Placebo Plus Best Supportive Care31.222.5 – 39.9
Percentage of Participants With a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care24.316.2 – 32.4
Placebo Plus Best Supportive Care7.32.4 – 12.2
Percentage of Participants Who Achieved Platelet Transfusion Independence With a Duration of ≥ 8 Weeks (56 Days) Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care16.7
Placebo Plus Best Supportive Care14.3
Time to Platelet Transfusion Independence Secondary · 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).

GroupValue95% CI
Oral Azacitidine and Best Supportive Care9.69.6 – 10.9
Placebo Plus Best Supportive CareNANA – NA
Overall Survival (OS) Secondary · 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.

GroupValue95% CI
Oral Azacitidine and Best Supportive Care17.312.9 – 20.8
Placebo Plus Best Supportive Care16.712.8 – 24.0

Adverse events — posted to ClinicalTrials.gov

Time frame: Participants were assessed for all-cause mortality from their randomization to study completion, (up to approximately 10 years). SAEs and Other AEs were assessed from first dose to 28 days following last dose (up to approximately 6 months). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Oral Azacitidine and Best Supportive Care
Serious: 83/107 (78%)
Deaths: 83/107
Placebo Plus Best Supportive Care
Serious: 69/109 (63%)
Deaths: 86/109

Serious adverse events (192 terms)

ReactionSystemOral Azacitidine and Best …Placebo Plus Best Supporti…
Febrile neutropeniaBlood and lymphatic system disorders
PneumoniaInfections and infestations
PyrexiaGeneral disorders
SepsisInfections and infestations
AnaemiaBlood and lymphatic system disorders
Septic shockInfections and infestations
Transformation to acute myeloid leukaemiaNeoplasms benign, malignant and unspecified (incl cysts and polyps)
ThrombocytopeniaBlood and lymphatic system disorders
Neutropenic sepsisInfections and infestations
Lower respiratory tract infectionInfections and infestations
Upper respiratory tract infectionInfections and infestations
FallInjury, poisoning and procedural complications
Cardiac failure congestiveCardiac disorders
Abdominal painGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
General physical health deteriorationGeneral disorders
Myelodysplastic syndromeNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute kidney injuryRenal and urinary disorders
Bone marrow failureBlood and lymphatic system disorders
NeutropeniaBlood and lymphatic system disorders
Atrial fibrillationCardiac disorders
Cardiac failureCardiac disorders
TachyarrhythmiaCardiac disorders
Gastrointestinal haemorrhageGastrointestinal disorders
MelaenaGastrointestinal disorders
Other adverse events (55 terms — click to expand)

ReactionSystemOral Azacitidine and Best …Placebo Plus Best Supporti…
NauseaGastrointestinal disorders
DiarrhoeaGastrointestinal disorders
VomitingGastrointestinal disorders
NeutropeniaBlood and lymphatic system disorders
ConstipationGastrointestinal disorders
PyrexiaGeneral disorders
ThrombocytopeniaBlood and lymphatic system disorders
Oedema peripheralGeneral disorders
EpistaxisRespiratory, thoracic and mediastinal disorders
Decreased appetiteMetabolism and nutrition disorders
AstheniaGeneral disorders
FatigueGeneral disorders
AnaemiaBlood and lymphatic system disorders
PetechiaeSkin and subcutaneous tissue disorders
Abdominal painGastrointestinal disorders
ContusionInjury, poisoning and procedural complications
CoughRespiratory, thoracic and mediastinal disorders
Back painMusculoskeletal and connective tissue disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
Urinary tract infectionInfections and infestations
HypokalaemiaMetabolism and nutrition disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Weight decreasedInvestigations
HypomagnesaemiaMetabolism and nutrition disorders
Iron overloadMetabolism and nutrition disorders
InsomniaPsychiatric disorders
HaematomaVascular disorders
LeukopeniaBlood and lymphatic system disorders
Mouth haemorrhageGastrointestinal disorders
PneumoniaInfections and infestations
Alanine aminotransferase increasedInvestigations
EcchymosisSkin and subcutaneous tissue disorders
DizzinessNervous system disorders
AnxietyPsychiatric disorders
Rectal haemorrhageGastrointestinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
PruritusSkin and subcutaneous tissue disorders
Atrial fibrillationCardiac disorders
Gingival bleedingGastrointestinal disorders
Upper respiratory tract infectionInfections and infestations

Most-reported serious reactions: Febrile neutropenia, Pneumonia, Pyrexia, Sepsis, Anaemia, Septic shock, Transformation to acute myeloid leukaemia, Thrombocytopenia.

Data from ClinicalTrials.gov NCT01566695 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
    Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
  2. A clinical-molecular update on azanucleoside-based therapy for the treatment of hematologic cancers.
    Diesch J, Zwick A, Garz AK, Palau A, et al · · 2016 · cited 139× · PMID 27330573 · DOI 10.1186/s13148-016-0237-y
  3. Small molecule inhibitors targeting the cancers.
    Liu GH, Chen T, Zhang X, Ma XL, et al · · 2022 · cited 127× · PMID 36254250 · DOI 10.1002/mco2.181
  4. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends.
    Nepali K, Liou JP. · · 2021 · cited 122× · PMID 33840388 · DOI 10.1186/s12929-021-00721-x
  5. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.
    Garcia-Manero G, Gore SD, Kambhampati S, Scott B, et al · · 2016 · cited 83× · PMID 26442612 · DOI 10.1038/leu.2015.265
  6. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.
    Garcia-Manero G, Santini V, Almeida A, Platzbecker U, et al · · 2021 · cited 64× · PMID 33764805 · DOI 10.1200/jco.20.02619
  7. Myelodysplastic syndromes: moving towards personalized management.
    Hellström-Lindberg E, Tobiasson M, Greenberg P. · · 2020 · cited 55× · PMID 32439724 · DOI 10.3324/haematol.2020.248955
  8. The Renaissance of Cyclin Dependent Kinase Inhibitors.
    Ettl T, Schulz D, Bauer RJ. · · 2022 · cited 50× · PMID 35053461 · DOI 10.3390/cancers14020293

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Drug Landscape aggregates and links these public records for informational use only. Always verify against the primary source before clinical or regulatory decisions. Canonical URL: https://druglandscape.com/trial/NCT01566695.

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