E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Red Blood Cell Transfusion-Dependent Anemia and Thrombocytopenia due to IPSS Lower-Risk Myelodysplastic Syndromes |
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E.1.1.1 | Medical condition in easily understood language |
Subjects with a lack of normal red blood cells requiring a transfusion and low platelets in the blood caused by lower risk myelodysplastic syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068361 |
E.1.2 | Term | MDS |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia (platelet count ≤ 75 x
109/L) due to IPSS lower-risk MDS. |
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E.2.2 | Secondary objectives of the trial |
To evaluate in both treatment arms:
- overall survival (OS);
- hematologic improvement-platelet response (HI-P);
- duration of RBC transfusion independence and time to RBC transfusion independence;
- progression to acute myeloid leukemia (AML), and time to AML progression;
- hematologic improvement-erythroid response (HI-E);
- platelet-transfusion independence, duration of platelet transfusion independence, and time to platelet transfusion independence;
- hematologic response;
- clinically significant bleeding events;
- safety;
- health-related quality-of-life (HRQoL); and
- healthcare resource utilization. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years at the time of signing the informed consent document
2. Have a documented diagnosis of MDS according to WHO 2008 classification
3. Be RBC transfusion-dependent as defined by:
• Average transfusion requirement of ≥ 2 units** per 28 days of RBCs confirmed for a minimum of 56 days immediately preceding randomization (please note that the period covering the transfusion history overlaps with the screening phase)
• Hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion must have been ≤ 10.0 g/dL in order for the transfusion to be counted towards RBC transfusion-dependent status. Red blood cell transfusions administered when Hgb levels were > 10.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of providing evidence of RBC transfusion-dependent status
- No consecutive 28 days that are RBC-transfusion-free during the 56 days immediately preceding randomization
4. Have thrombocytopenia as defined by two platelet counts that are ≤ 75 x 109/L and ≥ 21 days apart. The second confirmatory platelet count must be obtained ≤ 14 days prior to randomization
• At least one platelet count must be centrally analyzed within the 56 day screening period with results of ≤ 75 x 109/L; the second platelet count may be centrally or locally analyzed, with results that are also ≤ 75 x 109/L.
• Prior documented medical history of thrombocytopenia may be used to demonstrate
eligibility for the study if at least one historical platelet count of ≤ 75 x 109/L was obtained within 56 days of randomization and ≥ 21 days apart from the centrally
analyzed platelet count.
• If additional platelet counts were obtained during the interim period, these must also have been ≤ 75 x 109/L. If platelet counts within the interim period are >75 x 109/L, this would be acceptable only if directly associated with a platelet transfusion administered within 7 days prior to the date of the platelet count.
5. Have an ECOG performance status of 0, 1, or 2
6. Females of childbearing potential (FCBP)†† may participate, providing they meet the following conditions:
• Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following the last dose of IP; and
• Have a negative serum pregnancy test at screening ; and
• Have a negative serum or urine pregnancy test (investigator’s discretion; sensitivity of at least 25 mIU/mL) within 72 hours prior to starting IP in the treatment phase (note that the screening serum pregnancy test can be used as the test prior to starting study therapy in the treatment phase if it is performed within the 72-hour timeframe)
7. Male subjects with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose of IP
Once all 216 subjects enrolled have completed 12 months of double-blind treatment or have discontinued before reaching 12 months of double-blind treatment and Amendment 5 of the protocol is approved at the respective sites, and after study unblinding by Celgene, eligible subjects can enter the Extension Phase.
Subject Eligibility for the Extension Phase:
At the Investigator’s discretion and following confirmation of eligibility criteria below, subjects
can enter the extension phase:
- Subjects who have signed the informed consent for the EP of the study;
- Subjects randomized to the oral azacitidine treatment arm and continuing in the Treatment Phase demonstrating clinical benefit as assessed by the Investigator are eligible to receive oral azacitidine in the EP;
- Subjects randomized into the placebo arm of the study will not receive oral azacitidine in the EP, but will be followed for survival in the EP;
- Subjects currently in the Follow-up Phase, after permanent study treatment discontinuation, will continue to be followed for survival in the EP;
- Subjects who do not meet any of the criteria for study discontinuation (see Section 12 of the protocol). |
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E.4 | Principal exclusion criteria |
1. IPSS higher-risk (INT-2 or High risk) MDS
2. Secondary MDS
3. Hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy based on investigator’s judgment, unless subject received last dose from prior Chemo~ or Immunotherapy ≥ 24 weeks prior to randomization
4. CMML, atypical chronic myeloid leukemia (CML) and unclassifiable myeloproliferative disease (MPD)
5. Prior treatment with any of the following:
• Azacitidine (any formulation), decitabine or other hypomethylating agent
• Lenalidomide, unless the subject received the last dose ≥ 8 weeks prior to randomization
6. Prior allogeneic or autologous stem cell transplant
7. 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 that would interfere with the absorption, distribution, metabolism or excretion of the IP and/or predispose the subject to an increased risk of gastrointestinal toxicity
8. Thrombocytopenia secondary to other possible causes, including medication(s), congenital disorder(s), immune disorder(s) (eg, idiopathic thrombocytopenic purpura [ITP]), or microvascular disorder(s) (eg, disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura)
9. Use of any of the following within 28 days prior to randomization:
• cytotoxic, chemotherapeutic, targeted or investigational agents/therapies
• thrombopoiesis-stimulating agents (TSAs; eg, Romiplostim, Eltrombopag, Interleukin-11)
• ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3)
• hydroxyurea
10. Ongoing medically significant adverse events from previous treatment, regardless of the
time period
11. Concurrent use of any of the following:
• 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
12. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions are allowed:
• Basal or squamous cell carcinoma of the skin
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
13. Significant active cardiac disease within the previous 6 months, including:
• New York Heart Association (NYHA) class IV congestive heart failure;
• Unstable angina or angina requiring surgical or medical intervention; and/or
• Myocardial infarction
14. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
15. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection
16. Abnormal coagulation parameters (PT > 15 seconds, PTT > 40 seconds, and/or INR > 1.5). After consultation with the medical monitor, higher than normal range levels may be acceptable if the subject is being treated with a stable dose of anticoagulants for thrombotic prophylaxis (ie with atrial fibrillation, previous thromboembolic event, mechanical cardiac valve replacement or presence of lupus or
antiphospholipid antibodies). The decision to include such patients would be the responsibility of the investigator.
17. Any of the following laboratory abnormalities:
• Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN) unless these abnormal liver function test(s) can be attributed to iron overload as demonstrated by a serum transferrin saturation of > 65% and a serum ferritin of > 1000 μg/L
• Serum bilirubin > 1.5 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome. Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% of indirect bilirubin
• Serum creatinine > 2.5 x ULN
18. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding. Iron deficiency would be determined by a bone marrow aspirate stain for iron, the transferrin saturation (iron/total iron binding capacity [Fe/TIBC] ≤ 20%), or serum ferritin ≤ 15 ng/mL
19. Known or suspected hypersensitivity to azacitidine or mannitol
20. Pregnant or lactating females
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects in the overall population achieving RBC transfusion independence with duration ≥ 56 days (8 weeks). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After all patients have either completed 12 months treatment or discontinued |
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E.5.2 | Secondary end point(s) |
- OS;
- HI-P (IWG 2006 criteria);
- Proportion of subjects in the overall population achieving RBC transfusion independence with duration of ≥ 84 days (12 weeks);
- Duration of RBC transfusion independence of ≥ 84 days (12 weeks);
- Duration of RBC transfusion independence of ≥ 56 days (8 weeks);
- Time to RBC transfusion independence of ≥ 84 days (12 weeks);
- Time to RBC transfusion independence of ≥ 56 days (8 weeks);
- Proportion of subjects progressing to AML and time to AML progression;
- HI-E (IWG 2006 criteria);
- Duration of RBC transfusion reduction;
- Proportion of platelet transfusion-dependent subjects at baseline achieving platelet transfusion independence with duration ≥ 56 days (8 weeks);
- Duration of platelet transfusion-independence;
- Time to platelet transfusion independence;
- Hematologic response (IWG 2006 criteria);
- Proportion of subjects experiencing clinically significant bleeding events;
- Safety (type, frequency, severity of AEs and relationship of AEs to oral azacitidine/placebo; monitoring for progression to AML and second primary malignancy);
- HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and EuroQoL Group EQ-5D-3L instruments; and
- Measures of healthcare resource utilization.
Exploratory:
-Correlative analyses to assess the relationship between azacitidine exposure and pharmacodynamic (eg, safety, efficacy) and other exploratory (eg, biomarker) endpoints.
- Biomarker assessments (molecular and/or cellular features in bone marrow and/or peripheral blood) potentially include, but are not limited to, cytogenetics, DNA methylation, gene variants (single nucleotide polymorphisms [SNPs] and gene
sequence) analysis, messenger ribonucleic acid (mRNA) expression, micro RNA (miRNA) expression, RNA methylation, immunophenotyping and plasma protein evaluation.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints including interim OS with exception of AML progression: after all patients have either completed 12 months treatment or discontinued
Final OS: Approx 205 events in total. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
Israel |
Korea, Republic of |
Mexico |
United States |
Finland |
France |
Poland |
Sweden |
Netherlands |
Spain |
Czechia |
Germany |
Greece |
Italy |
Belgium |
Denmark |
Norway |
Portugal |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will conclude once all subjects have completed or discontinued from the extension phase. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 11 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 11 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |