Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00008464

Trial Description

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Title

A Randomized, Double-blind, Placebo-controlled, Phase III, Multi-centre Study of Eltrombopag or Placebo in Combination With Azacitidine in Subjects With IPSS Intermediate-1, Intermediate 2 and High-risk Myelodysplastic Syndromes (MDS) SUPPORT: A StUdy of eltromboPag in myelodysPlastic SyndrOmes Receiving azaciTidine

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

Eltrombopag olamine (SB-497115-GR) is an orally bioavailable, small molecule thrombopoietin
receptor agonist that may be beneficial in medical disorders associated with
thrombocytopenia. Eltrombopag has been shown to increase platelet counts in patients with
thrombocytopenia from various etiologies (Idiopathic thrombocytopenic purpura [ITP], liver
disease, aplastic anemia and chemotherapy induced thrombocytopenia). Approximately 350
subjects will be randomized in a 1:1 ratio (175 into the eltrombopag arm and 175 into the
placebo arm). Approximately 55 subjects will be enrolled into the azacitidine. Subjects with
intermediate-1, intermediate-2 or high risk MDS by IPSS, and baseline platelet count of <75
Giga (10^9) per liter (Gi/L) will only be enrolled. This is a randomized, double-blind,
parallel group, placebo-controlled study designed to explore the platelet supportive care
effects of eltrombopag versus placebo in combination with the standard of care
hypomethylating agent, azacitidine. 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. Key secondary endpoints
include overall survival, disease response, and disease progression.

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Brief Summary in Scientific Language

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Do you plan to share individual participant data with other researchers?

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00008464
  •   2016/09/16
  •   2014/06/05
  •   no
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Secondary IDs

  •   NCT02158936  (ClinicalTrials.gov)
  •   112121  (GlaxoSmithKline)
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Health Condition or Problem studied

  •   Thrombocytopaenia
  •   D46 -  Myelodysplastic syndromes
  •   D69.6 -  Thrombocytopenia, unspecified
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Interventions/Observational Groups

  •   Drug: Eltrombopag
  •   Drug: Azacitidine
  •   Drug: Placebo
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Placebo
  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- Cycle 1-4 platelet transfusion independence (The proportion of subjects who are platelet transfusion free during Cycles 1-4 of azacitidine therapy); time frame: 4 cycles (Cycle = 28 days); A subject is defined as being platelet transfusion independent if they receive no platelet transfusions within the first 4 cycles of treatment with azacitidine

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Secondary Outcome

- Overall survival (OS); time frame: Approximately 5.5 years; Overall survival is defined as the time from randomization until death due to any cause. Subjects still alive at the time of the analysis and subjects who have withdrawn from the study will be censored at the time of last contact
- Disease Response categorized as CR, PR, or marrow CR, stable disease, disease progression, and as non-evaluable as per IWG criteria for MDS; time frame: Approximately 6 Cycles (Cycle = 28 days); The investigator will assess best disease response categorized as complete remission (CR), partial remission (PR), or marrow CR, stable disease, disease progression, and as non-evaluable; according to modified 2006 International Working Group (IWG) criteria for MDS
- Duration of Disease Response; time frame: Approximately 5.5 years; Duration of disease response will be summarized for subjects who had some form of response
- Progression Free Survival; time frame: Approximately 5.5 years; Progression-free survival is defined as the time from randomization until either disease progression or death
- Time to Progression; time frame: Approximately 5.5 years; The time to progression defined as the time from patient inclusion to the date of the first documented date of disease progression (using the modified 2006 IWG response criteria for MDS)
- Proportion of subjects that progress to Acute Myeloid Leukemia (AML); time frame: Approximately to 5.5 years; AML progression will be defined as meeting the definition of disease progression according to the modified 2006 IWG response criteria for MDS, with the additional requirement that post-baseline bone marrow and/or peripheral blasts must be >= 20%
- Time to AML progression; time frame: Approximately 5.5 years; The time to progression defined as the time from patient inclusion to the date of the first documented date of AML progression (defined as meeting the definition of disease progression
- Hematologic improvement (HI) in platelets, neutrophils, and hemoglobin calculated based on the modified IWG criteria for MDS; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); HI in platelets, neutrophils and haemoglobin will be calculated based on the modified IWG criteria for MDS
- Duration of HI of platelets, neutrophils and hemoglobin; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); Duration of HI will be summarized for subjects who had some form of response
- Number of platelet and Red Blood Cells (RBC) transfusions; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up)
- Duration of platelet and RBC transfusion independence; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); Duration of platelet and RBC transfusion-independence is defined as a time period where subjects do not receive any platelet or RBC transfusions during the treatment period and follow-up
- Bleeding adverse events (AEs) >= Grade 3; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); Bleeding will be assessed by recording AEs or serious adverse events (SAEs) as graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0
- Proportion of subjects with azacitidine dose delays and dose reductions; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); The proportion of subjects with any delay or reduction in dosage of Azacitidine excluding those for non-medical reasons will be analyzed
- Evaluation of Adverse event reporting (including bleeding and transfusion-related adverse events) and clinical laboratory tests; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); An AE is any untoward medical occurrence temporally associated with the use of the medicinal product, whether or not considered associated with the product. Common Terminology Criteria for Adverse Events (CTCAE) will be used for toxicity grading
- Changes from baseline in all domains of Euroquol-5 Dimensions of Health, 3 Response Levels (EQ-5D-3L™); time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); The EQ-5D is a general health status and health utility measure which captures 5 dimensions of health state: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The survey also includes a visual analog scale (VAS or thermometer) measuring overall health state. (EQ-5D is a trademark of the Stichting EuroQol Group) .
- Changes from baseline in all domains of Functional Assessment of Chronic Disease Therapy-fatigue subscale (FACIT-Fatigue); time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); The FACIT-Fatigue subscale measures severity and impact of fatigue on functioning and Health Related QoL experienced in the past 7 days (The FACIT Fatigue Scale is owned by David Cella, Ph.D.)
- Changes from baseline in all domains of European Organization for Research and Treatment of Cancer - Quality of Life questionnaire - 30 item (EORTC QLQ-C30); time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); Cancer related symptoms and quality of life (QoL) will be assessed with the EORTC QLQ-C30 version 3. This is composed of multi-item and single-item scales. These include five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, pain), a global health status scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties) (EORTC QLQ-C30 is owned by the EORTC Quality of Life Group)
- Changes from baseline in all domains of independent questions regarding the value of transfusion independence; time frame: At 4 week follow-up; Upon study permanent discontinuation of study treatment, a supplementary set of questions will evaluate subjects' perceived value in achieving transfusion independence and the consequences of maintaining dose density of azacitidine.
- Medical resource utilization (MRU): Event and use of site specific medical resources; time frame: From Day 1 to 4-week follow-up (Approximate median 9 Cycles+4 weeks follow-up); MRU data will be collected for each subject. Events corresponding to unscheduled (not scheduled per protocol) hospitalizations, office visits including consultations, laboratory and diagnostic tests (lab results, imaging etc.), and procedures prior to therapy initiation and during therapy will be collected
- Composite of pharmacokinetic (PK) parameters of Eltrombopag including evaluation of covariates, and estimates of between and within subject variability; time frame: Cycle 1, Week 2: Pre-dose, 1.5 and 3 hour post dose; Cycle 1, Week 3: 4, 5.5, and 7 hours post dose; Plasma eltrombopag population pharmacokinetic parameters, including evaluation of covariates, and estimates of between and within subject variability
- Composite of PK parameters of Azacitidine (subset of 55 subjects) including Cmax, tmax, AUC(0-t), AUC(0-infinity), and t1/2; time frame: Samples will be collected on Cycle 2 Day 1 before the azacitidine dose and 15 min, 0.5, 1, 2, and 4 hours after the azacitidine dose; 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-infinity)], and half-life (t1/2) will be assessed
- Number of platelet transfusion-free cycles; time frame: 6 cycles (Cycle = 28 days); The number of the cycles without a platelet transfusion amongst the first 6 cycles will be calculated

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Countries of Recruitment

  •   United States
  •   Argentina
  •   Australia
  •   Austria
  •   Belgium
  •   Canada
  •   Czech Republic
  •   Denmark
  •   France
  •   Germany
  •   Greece
  •   Hong Kong
  •   Hungary
  •   Ireland
  •   Israel
  •   Italy
  •   Korea, Republic of
  •   Norway
  •   Peru
  •   Poland
  •   Puerto Rico
  •   Russian Federation
  •   Spain
  •   Sweden
  •   Switzerland
  •   Taiwan, Province of China
  •   Thailand
  •   Turkey
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Locations of Recruitment

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Recruitment

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  •   2014/06/30
  •   350
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Age >=18 years (For subjects in Taiwan, Age >= 20 years)

- MDS by World Health Organization (WHO) or French-American-British (FAB)
classification

- Intermediate 1, intermediate 2 or high risk MDS by IPSS

- At least one platelet count < 75 Gi/L

- Eastern Cooperative Oncology Group (ECOG) Status 0-2

- Adequate baseline organ function defined by the criteria below: total bilirubin =<
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 alanine aminotransferase [ALT] abnormality); ALT =<
2.5xULN; creatinine =< 2.5xULN

- Subjects with a corrected QT interval (QTc) <450 milliseconds (msec) 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

- Subject is able to understand and comply with protocol requirements and instructions

- Subject has signed and dated informed consent

- 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

- 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 during the study and for 3 months following the last dose of study
treatment

- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception from time of randomization until 16
weeks after the last dose of study treatment

- 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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Exclusion Criteria

- Previous treatment with hypomethylating agent or induction chemotherapy for MDS

- Proliferative type chronic myelomonocytic leukemia with white blood cell count >12
Gi/L at any time during the 28 days before Day 1

- History of treatment with eltrombopag, romiplostim or other thrombopoietin receptor
(TPO-R) agonists

- Previous allogeneic stem-cell transplantation

- 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

- Treatment with an investigational drug within 30 days or 5 half-lives (whichever is
longer) preceding the first dose of investigational product (eltrombopag/placebo)

- Active and uncontrolled infections, including hepatitis B or C

- Human Immunodeficiency Virus (HIV) infection

- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to eltrombopag or its excipient, or azacitidine, that
contraindicates the subjects' participation

- Pregnant or lactating female

- Any serious and/or unstable pre-existing medical condition (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

- French subjects: the French subject has participated in any study using an
investigational drug during the previous 30 days

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Addresses

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    • GlaxoSmithKline
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    • GlaxoSmithKline
    • GSK Clinical Trials 
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    • US GSK Clinical Trials Call Center 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   1
  •   2015/05/04
* This entry means the parameter is not applicable or has not been set.