E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Thrombocytopenic patients with myelodysplastic syndromes |
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E.1.1.1 | Medical condition in easily understood language |
Low platelet count due to myelodysplastic syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10029104 |
E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028534 |
E.1.2 | Term | Myelodysplastic syndrome NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective of this study is to determine the effect of eltrombopag versus placebo on the proportion of subjects who are platelet transfusion free during the first 4 cycles of azacitidine therapy. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives compare the following in
subjects treated with eltrombopag/azacitidine versus
placebo/azacitidine:
Overall survival (OS)
Disease Response
Hematologic improvement (HI)
Platelet and red blood cell (RBC) transfusions
Bleeding adverse events (AEs) greater than Grade 3 Bleeding AEs
Azacitidine treatment
Safety and tolerability
Health related quality of life (HRQoL)
Medical resource utilization (MRU)
Pharmacokinetic
Characterize the pharmacokinetics of steady-state eltrombopag in subjects with MDS treated with
azacitidine
Characterize the effect of eltrombopag on the PK of azacitidine in a subset of subjects. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Azacitidine Pharmacokinetic Substudy
A subset of subjects (~55) will participate in a PK substudy to evaluate the effect of eltrombopag on azacitidine PK. Pharmacokinetic samples will be obtained on Day 1 of Cycle 2 from all subjects enrolled into the substudy. If not possible for logistical reasons, PK samples may be
obtained on Day 1 of a later cycle.
Genetic and translational Research" (Appendix 1 to the protocol dated 19-12-2013) The objectives of genetic research are to investigate the relationship between genetic variants and:
• Response to medicine, including any treatment regimens under investigation in this study or any concomitant medicines;
• MDS susceptibility, severity, clonality, and progression and related conditions |
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E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria. The eligibility criteria are to be met during the screening period, defined as the period up to 28 days prior to randomization on Day 1. Informed consent may be obtained >28 days before Day 1, if required, to allow time for receipt of cytogenetic results.
1. Age ≥ 18 years. (For subjects in Taiwan, Age ≥ 20 years).
2. 2. MDS by World Health Organization (WHO) or French-American-British (FAB) classification.
3. Intermediate 1, intermediate 2 or high risk MDS by IPSS.
• A bone marrow for the determination of IPSS must be completed during the screening period, or within 3 months prior to randomization. Assessment of bone marrow blasts must be completed by bone marrow slide review.
4. At least one platelet count < 75 Gi/L.
5. Eastern Cooperative Oncology Group (ECOG) Status 0-2.
6. Adequate baseline organ function defined by the criteria below
• total bilirubin less than 1.5x the upper limit of normal (ULN) except for Gilbert’s syndrome or cases clearly not indicative of inadequate liver function (i.e. elevation of indirect [haemolytic] bilirubin in the absence of ALT abnormality)
• alanine aminotransferase (ALT) less than 2.5xULN
• creatinine less than 2.5xULN
7. Subjects with a QTc <450msec or <480msec for subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF), machine or manual overread.
For subject eligibility and withdrawal, QTcF will be used.
For purposes of data analysis, QTcF will be used.
The QTc should be based on single or averaged QTc values of triplicate
electrocardiograms (ECGs) obtained over a brief recording period
8. Subject is able to understand and comply with protocol requirements and instructions.
9. Subject has signed and dated informed consent.
10. Women must be either of non-child bearing potential, or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study.
11. Women of childbearing potential must have a negative serum or urine pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception
(as defined in Section 7.3.3) during the study and for 3 months following the last dose of study treatment.
12. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception (as described in Section 7.3.3) from time of randomization until 16 weeks after the last dose of study treatment.
13. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria at the time of randomization must not be enrolled in the study:
1. Previous treatment with hypomethylating agent or induction chemotherapy for MDS.
2. Proliferative type chronic myelomonocytic leukemia with white blood cell count >12 Gi/L at any time during the 28 days before Day 1.
3. History of treatment with eltrombopag, romiplostim or other TPO-R agonists.
4. Previous allogeneic stem-cell transplantation.
5. Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of participating in the study outweigh the potential risks of thromboembolic events, as determined by the investigator.
6. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of investigational product (eltrombopag/placebo).
7. Active and uncontrolled infections, including hepatitis B or C.
8. Human Immunodeficiency Virus (HIV) infection.
9. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to eltrombopag or its excipient, or azacitidine, that contraindicates the subjects’ participation.
10. Pregnant or lactating female.
11. Any serious and/or unstable pre-existing medical (including any advanced malignancy other than the disease under study), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance with the study procedures.
12. French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cycle 1-4 platelet transfusion independence (The proportion of subjects who are platelet transfusion free during Cycles 1-4 of azacitidine
therapy)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary endpoint to be evaluated once all subjects recruited into study have completed 6 cycles, withdrawn from the study or died. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints compare the following in subjects treated with eltrombopag/azacitidine versus placebo/azacitidine.
OS
Disease Response Disease response (per 2006 International Working
Group (IWG) criteria)
Duration of Disease Response
Progression Free Survival
Time to Progression
Proportion of subjects that progress to AML
Time to AML progression
HI in platelets, neutrophils and haemoglobin (per 2006 IWG criteria)
Duration of HI of platelets, neutrophils, and hemoglobin
Number of platelet and RBC transfusions
Duration of platelet and RBC transfusion independence
Number of platelet transfusion-free cycles
Bleeding AEs greater than Grade 3
Azacitidine dose delays and dose reductions
Evaluation of adverse event reporting (including bleeding and transfusion-related adverse events), and clinical laboratory tests
EQ-5D-3L, EORTC-QLQ-C30, FACIT-Fatigue subscale, independent questions regarding the value of transfusion independence
Event and use of site specific medical resources
Pharmacokinetic
Plasma eltrombopag population and individual PK parameters, including evaluation of covariates, and estimates of between and within subject variability.
Azacitidine plasma maximum concentration (Cmax), time to maximum concentration (tmax), area under the plasma concentration-time curve over the dosing interval [AUC(0-t)], area under the concentration-time curve from time zero extrapolated to infinite time [AUC(0; inifinity)], and half-life (t1/2). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Once at least 140 subjects have completed 4 cycles, withdrawn or died:
-Interim IDMC analysis for futility of the primary endpoint of Cycle 1-4 transfusion independence.
The IDMC will also meet at predefined times to identify potential treatment harm
Once all recruited 350 subjects have completed 6 cycles, withdrawn or died:
-The primary endpoint of Cycle 1-4 transfusion independence will be tested.
-Interim analysis for the key secondary endpoint of OS.*
-Analysis of all other secondary endpoints
Once 275 events (deaths) occur:
-Final analysis for the key secondary endpoint of OS
*The endpoint of OS will be tested only if the null hypothesis for the test of Cycle 1-4 transfusion independence is rejected.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Argentina |
Australia |
Austria |
Belgium |
Brazil |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Ireland |
Israel |
Italy |
Korea, Republic of |
Mexico |
Norway |
Peru |
Poland |
Russian Federation |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
United States |
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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
|
Study completion (Last Subject Last Visit) is defined as a maximum of 5 years after the last subject completes 6 cycles or when 275 subjects die. |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |