A Longitudinal 2-year Bone Marrow Study of Eltrombopag in Previously Treated Adults, With Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Purpura, Thrombocytopaenic, Idiopathic Clinical Trial

Official title:

A Longitudinal 2-year Bone Marrow Study of Eltrombopag Olamine (SB-497115-GR) in Previously Treated Adults, With Chronic Immune (Idiopathic) Thrombocytopenic Purpura (ITP)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01098487
• Other study ID #: 112940
• Status: Completed
• Phase: Phase 4
• First received: March 25, 2010
• Last updated: February 26, 2015
• Start date: May 2010
• Est. completion date: May 2014

Study information

• Verified date: February 2015
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Hong Kong: Department of HealthKorea: Korea Food & Drug AdministrationUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

A open-label, multi-center 2-year safety study to ascertain the baseline levels of bone marrow fibers in previously treated adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) and to evaluate the long-term effect of eltrombopag on bone marrow fibers. The study will also describe the long-term safety and tolerability of oral eltrombopag treatment in subjects with chronic ITP.

Description:

This is a phase IV, open-label safety study, designed to determine baseline levels of bone marrow fibers in previously treated adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP)and to evaluate the long-term effect of eltrombopag on bone marrow reticulin and/or collagen fibers.

The duration of the screening period is up to 8 weeks. Eltrombopag will be administered for at least 2-years followed by a 4-week follow-up period. Bone marrow biopsies will be performed at screening, after 1-year and 2-years of eltrombopag treatment, and at early withdrawal of treatment. The screening bone marrow biopsy should be performed within 8 weeks of planned start of study medication and the bone marrow biopsy block must be available for central laboratory processing.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Subjects must have signed and dated a written informed consent and be able to understand and comply with protocol requirements and instructions.

• Adults (=18 years) diagnosed with chronic ITP according to the American Society for Hematology/British Committee for Standards in Hematology (ASH/BCSH) guidelines [George, 1996; BCSH, 2003; Provan, 2009]. In addition, a peripheral blood smear should support the diagnosis of ITP with no evidence of other disease causative of thrombocytopenia (e.g., pseudo thrombocytopenia, myelofibrosis). The physical examination should not suggest any disease, which may cause thrombocytopenia other than ITP.

• Subjects must be physically eligible for serial bone marrow biopsies and must have a bone marrow biopsy performed during screening, and be willing to remain on the study for at least 2 years with annual bone marrow biopsies.

• Subjects, who previously received eltrombopag or romiplostim, must have completed treatment with these therapies at least 6 months prior to the screening bone marrow biopsy.

• Subjects must have the following clinical chemistry values:

• ALT and AST < 2xULN;

• Bilirubin <1.5xULN (except for Gilbert's Syndrome);

• Subjects are practicing an acceptable method of contraception as specified in the protocol.

• In France, subjects will be eligible for inclusion in this study, only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Subjects with any clinically relevant abnormality, other than ITP, or any other medical condition or circumstance, which in the opinion of the investigator makes the subject unsuitable for participation in the study or suggests another primary diagnosis (e.g., thrombocytopenia is secondary to another disease).

• Subjects with any concurrent malignant disease and/or a recent history of cancer treatment with systemic chemotherapy and/or radiotherapy.

Exception: Subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.

• Subjects with any prior history of arterial or venous thrombosis (stroke, transient ischemic attack, myocardial infarction, deep vein thrombosis or pulmonary embolism), AND = two of the following risk factors: hormone replacement therapy, systemic contraception (containing estrogen), smoking, diabetes, hypercholesterolemia, hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII deficiency, etc), or any family history of arterial or venous thrombosis.

• Subjects with screening bone marrow fibers of either MF Grade 3 using European Consensus scale or Grade 4 using Bauermeister scale.

• Subjects with a QTc >450 msec or > 480 msec for subjects with Bundle Branch Block.

• Female subjects who are nursing or pregnant (positive serum or urine ß-human chorionic gonadotrophin (ß-hCG) pregnancy test) at screening.

• Subjects treated with an investigational drug (other than a thrombopopoetin-receptor (TPO-R) agonist) within 30 days or five half-lives (whichever is longer) preceding the first dose of eltrombopag in the study. (For romiplostim or eltrombopag, see inclusion criterion #4).

• Subjects treated with any TPO-R agonist other than romiplostim or eltrombopag.

• Subjects with recent history of alcohol/drug abuse as determined by the investigator.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Purpura
• Purpura, Thrombocytopaenic, Idiopathic
• Purpura, Thrombocytopenic
• Purpura, Thrombocytopenic, Idiopathic

Intervention

Drug:
• Eltrombopag olamine
Thrombopoietin receptor agonist

Locations

Country	Name	City	State
Czech Republic	GSK Investigational Site	Hradec Kralove
Czech Republic	GSK Investigational Site	Olomouc
Czech Republic	GSK Investigational Site	Praha 2
France	GSK Investigational Site	Caen cedex 9
France	GSK Investigational Site	Créteil
France	GSK Investigational Site	Pessac Cedex
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Duesseldorf	Nordrhein-Westfalen
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Muenchen	Bayern
Hong Kong	GSK Investigational Site	Shatin, New Territories
Hungary	GSK Investigational Site	Debrecen
Hungary	GSK Investigational Site	Gyor
Hungary	GSK Investigational Site	Szeged
India	GSK Investigational Site	Ludhiana
India	GSK Investigational Site	Pune
India	GSK Investigational Site	Surat
India	GSK Investigational Site	Vellore
Italy	GSK Investigational Site	Bologna	Emilia-Romagna
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Milano	Lombardia
Italy	GSK Investigational Site	Padova	Veneto
Italy	GSK Investigational Site	Vicenza	Veneto
Korea, Republic of	GSK Investigational Site	Seongnam-si Gyeonggi-do
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Pakistan	GSK Investigational Site	Karachi
Pakistan	GSK Investigational Site	Lahore
Russian Federation	GSK Investigational Site	Moscow
Russian Federation	GSK Investigational Site	Novosibirsk
Russian Federation	GSK Investigational Site	St Petersburg
United States	GSK Investigational Site	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Czech Republic,  France,  Germany,  Hong Kong,  Hungary,  India,  Italy,  Korea, Republic of,  Pakistan,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Bone Marrow (BM) Fibers of MF Grade 0, 1, 2 and 3 on the European Consensus (EC) Scale at Baseline	The evaluation of fibrosis was performed using BM biopsies in which the amount of fibrosis was assessed by the EC Grading Scale. This method distinguishes four degrees of fibrosis (myelofibrosis [MF]-0 to MF-3). MF Grade (G) 0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF Grade 1 is loose network of reticulin with many intersections, especially in perivascular areas; MF Grade 2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF Grade 3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.	Baseline	No
Primary	Number of Participants With a Positive or Negative Collagen Level at Baseline	The number of participants with a positive or negative collagen level was analyzed. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.	Baseline	No
Primary	Number of Participants With Indicated Grade Change From Baseline in the EC Grading Scale at 1 Year	The change from baseline to on-treatment assessments of European Consensus (EC) scale was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period. MF-0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF-1 is loose network of reticulin with many intersections, especially in perivascular areas; MF-2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF-3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.	Baseline and 1 year	No
Primary	Number of Participants With Indicated Change From Baseline in the EC Grading Scale at 2 Years	The change from baseline to on-treatment assessments of European Consensus (EC) scale was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period. MF-0 is scattered linear reticulin with no intersections (cross-overs) corresponding to normal BM; MF-1 is loose network of reticulin with many intersections, especially in perivascular areas; MF-2 is diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis; MF-3 is diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis. Baseline is defined as the most recent centrally-reviewed BM biopsy prior to first dose of eltrombopag in the study.	Baseline and 2 years	No
Primary	Number of Participants With a Positive or Negative Collagen Level at 1 Year	The change from Baseline to on-treatment assessments of collagen level was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period.	1 year	No
Primary	Number of Participants With a Positive or Negative Collagen Level at 2 Year	The change from Baseline to on-treatment assessments of collagen level was analyzed. On-treatment is defined as during the treatment period (including dose interruptions) and up to 14 days after the end of the treatment period.	2 years	Yes
Secondary	Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Clinical Chemistry Parameters at Any Time Post-Baseline During the Study	Clinical chemistry parameters were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), sodium (hyponatremia), inorganic phosphorus and creatinine. Baseline values were obtained at Day 1. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during.	From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)	No
Secondary	Number of Participants With the Indicated Maximum Toxicity Grade for the Indicated Hematology Parameters at Any Time Post-Baseline During the Study	Hematology parameters were summarized according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: G0, none; G1, mild; G2, moderate; G3, severe; G4, life-threatening or disabling. Hematology parameters included: hemoglobin (increased), hemoglobin (anemia), lymphocyte count (increased), lymphocyte count (decreased), total absolute neutrophil count (ANC), platelet count and white blood cell (WBC) count. Baseline values were obtained at Day 1. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). The maximum post-Baseline toxicity grade includes any scheduled or unscheduled post-Baseline assessment during.	From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)	No
Secondary	Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE) Started On-therapy + 1 Day, >1 to 30 Days Post Therapy and >30 Days Post Therapy	On-therapy + 1 day is defined as AEs started between the first dose of eltrombopag and up to the day after the last dose of eltrombopag; >1 to 30 days post therapy is defined as AEs that started more than 1 day and up to 30 days after the last dose of eltrombopag; >30 days post therapy is defined as AEs started that started more than 30 days after the last dose of eltrombopag. An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or incapacity, or is a congenital anomaly or birth defect. Medical or scientific judgment should be exercised in other situations.	From Week 1 up to Week 104 and up to 6 months follow-up (4 weeks for most participants) (up to approximately 2.5 years)	No