E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute myelogenous leukemia |
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E.1.1.1 | Medical condition in easily understood language |
Acute myelogenous leukemia – a cancer of blood cells with the growth of abnormal white blood cells in the bone marrow that interferes with normal blood cell growth. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the safety and tolerability of eltrombopag versus placebo in subjects receiving standard induction therapy for acute myeloid leukemia (AML) |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives compare the following in subjects treated with eltrombopag versus placebo:
To assess plasma PK parameters of daunorubicin and daunorubicinol
To assess the effects on blood counts including platelets, absolute neutrophil count (ANC), and haemoglobin
To assess the incidence and severity of haemorrhagic events
To assess the effect on AML disease control
To evaluate off-treatment medical resource utilization |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following inclusion criteria:
1. Age 18 years and over
2. Diagnosed with AML according to the WHO 2008 classification
Note: subjects with secondary AML following MDS or secondary to previous leukemogenic therapy are allowed provided that a record of previous MDS history or leukemogenic therapy history is available
3. Eligible for induction by daunorubicin + cytarabine
4. Eligible to give informed consent to participate in the study
5. Have adequate baseline organ function defined by the following criteria:
a. Total bilirubin=<1.5 x upper limit of normal (ULN) except for Gilbert’s syndrome, or other conditions that are not indicative of inadequate liver function (i.e. elevation of indirect bilirubin (haemolytic) in the absence of ALT abnormality)
b. ALT =< 3 x ULN
c. Serum Creatinine =< 2.5 x ULN
6. Adequate cardiac function with LVEF =>50% as assessed by echocardiogram (ECHO) or Multi Gated Acquisition Scan (MUGA)
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 either Bazett’s formula (QTcB), Fridericia’s formula (QTcF) or another method, 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. Women must be either of non-childbearing potential (Refer to Section 7.3.7), or women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study (Refer to Section 7.3.7).
9. 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 7.3.7 from time of randomization until 30 days after the last dose of investigational product.
10. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in Section 7.3.7, during the study and for 30 days following the last dose of
investigational product. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the following exclusion criteria must not be enrolled in the study:
1. A diagnosis of acute promyelocytic (M3) or acute megakaryocytic leukaemia (M7)
2. Previous history of exposure to an anthracycline compound
3. Previous AML treatment (other than hydroxyurea)
4. Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent
5. History of thromboembolic event or other condition requiring ongoing use of anticoagulation either with warfarin or low molecular-weight heparin
Note: Occlusion of a central line is not an exclusion
6. Treatment with an investigational drug within 30 days or 5 half lives, whichever is longer, preceding the first dose of study medication
7. Current and continued use during study treatment period of known BCRP inhibitors or known P-gp inhibitors (see Prohibited Medications, Section 6.2) (please see Table 2 in protocol P31.)
8. Known active hepatitis B, hepatitis C or Human immunodeficiency Virus (HIV) nfection
9. Known hypersensitivity to any of the study drugs or its excipients |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability as assessed by adverse events (AE), changes in left ventricular ejection fraction (LVEF) and other safety data including clinical laboratory parameters for eltrombopag-treated subjects versus placebo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The safety endpoint is assessed within 14 days of the remission bone marrow assessment. |
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E.5.2 | Secondary end point(s) |
1.Cycle 1 Day 3 daunorubicin and daunorubicinol half-life and dose-normalized plasma AUC(0-∞), AUC(24-∞), AUC(0-t), AUC(24-t), and Cmax
2.Cycle 2 Day 1 daunorubicin and daunorubicinol dose-normalized plasma AUC(0-24) and Cmax
3.Number of platelet transfusions
4.Time to platelet counts =>20 Gi/L and =>100 Gi/L
5.Proportion of subjects who achieve platelet count recovery by day 21
6.Summary of platelet counts
7.Duration of platelet transfusion independence
8.Time to ANC engraftment defined as ANC recovery > 0.5 Gi/L sustained for 3 days
9. Assessment of changes in absolute neutrophil counts
10. Assessment of changes in haemoglobin
11. Number of bleeding events
12. Disease response rate and type of response
13. Overall survival
14. Medical resource utilization
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Cycle 1 Day 3
2. Cycle 2 Day 1
3. At Remission Assessment Visit
4. During treatment period
5. At Remission Assessment Visit
6. At Remission Assessment Visit
7. At Remission Assessment Visit
8. During treatment period
9. During treatment period
10. During treatment period
11. At Remission Assessment Visit
12. At Remission Assessment Visit
13. At 1- and 2- year Follow up assessment
14. At Remission Assessment Visit
15. Baseline, 7-10 days after last daunorubicin dose, 30 (±3 days) after last daunorubicin dose
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
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 |
Canada |
Israel |
Korea, Republic of |
Russian Federation |
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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |