Clinical trial NCT00351468: EXTEND (Eltrombopag Extended Dosing Study)
Official title: EXTEND (Eltrombopag Extended Dosing Study): An Extension Study of Eltrombopag Olamine (SB-497115-GR) in Adults, With Idiopathic Thrombocytopenic Purpura (ITP), Previously Enrolled in an Eltrombopag Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Purpura, Thrombocytopaenic, Idiopathic
Keywords: eltrombopag olamine
SB-497115-GR
idiopathic thrombocytopenic purpura
thrombocytopenia
ITP
platelets
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2006-07-12
Enrollment: 302
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: An open-label, dose-adjustment, extension study to evaluate the safety and efficacy of eltrombopag for the treatment of subjects with idiopathic thrombocytopenic purpura (ITP) who have previously been enrolled in an eltrombopag trial. This study will allow adjustment of the eltrombopag dose to achieve an individualized dose and schedule for each subject. In addition, the ability to reduce the dose of concomitant ITP medications in the presence of eltrombopag, while maintaining platelet counts = 50,000/μL will be investigated.


Eligibility criteria: Inclusion Criteria:

* Subject has signed and dated a written informed consent.
* Adults (≥18 years) diagnosed with ITP according to the American Society for Hematology/British Committee for Standards in Haematology (ASH/BCSH) guidelines \[George, 1996; BCSH, 2003\]. 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.
* Prior completion of treatment and follow up periods in an ITP study of eltrombopag (e.g., TRA100773 or TRA102537/RAISE or TRA108057/REPEAT).
* Subjects previously enrolled in Study TRA100773 must have completed the prescribed follow-up ophthalmic assessment at 6 months.
* Subjects previously enrolled in TRA102537/RAISE or other studies that may lead into EXTEND (e.g., TRA108057/REPEAT) must have completed the treatment and follow-up periods as defined in that protocol.
* Subject experienced no eltrombopag-related toxicity or other drug intolerance on prior eltrombopag study (e.g., TRA100773 or TRA102537/RAISE or TRA108057/REPEAT) even if resolved; subjects discontinued from previous study due to toxicity will not be eligible unless they received placebo.
* Subject has no intercurrent medical event, including thrombosis.
* Subjects must have either initially responded (platelet count \> 100,000/mL) to a previous ITP therapy or have had a bone marrow examination consistent with ITP within 3 years to rule out myelodysplastic syndromes or other causes of thrombocytopenia
* Previous therapy for ITP with immunoglobulins (IVIg and anti-D) must have been completed at least 1 week prior to first dose of study medication and the platelet count must show a clear downward trend after the last treatment with immunoglobulins. Previous treatment for ITP with splenectomy, rituximab and cyclophosphamide must have been completed at least 4 weeks prior to randomization, or clearly be ineffective.
* Subjects treated with concomitant ITP medication (e.g. corticosteroids or azathioprine) must be receiving a dose that has been stable for at least 4 weeks prior to randomization. Subjects treated with cyclosporine A, mycophenolate mofetil or danazol must be receiving a dose that has been stable for at least 3 months prior to the first dose of study medication.
* Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range with no history of hypercoagulable state.
* A complete blood count (CBC), within the reference range (including WBC differential not indicative of a disorder other than ITP), with the following exceptions:
* Hemoglobin: Subjects with hemoglobin levels between 10.0 g/dL and the lower limit of normal are eligible for inclusion, if anemia is clearly attributable to ITP (excessive blood loss).
* ANC≥1500/mL (1.5 x 10\^9/L) is required for inclusion (elevated WBC/ANC due to steroid treatment is acceptable).
* The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range by more than 20%: creatinine, ALT, AST, total bilirubin, and alkaline phosphatase. In addition, total albumin must not be below the lower limit of normal (LLN) by more than 10%.
* Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal \> 1 year), or of childbearing potential and use one of the following highly effective methods of contraception (i.e., Pearl Index \<1.0%) from two weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study:
* Complete abstinence from intercourse;
* Intrauterine device (IUD);
* Two forms of barrier contraception (diaphragm plus spermicide, and for males condom plus spermicide);
* Male partner is sterile prior to entry into the study and is the only partner of the female;
* Systemic contraceptives (combined or progesterone only).
* Subject is able to understand and comply with protocol requirements and instructions.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

* Any clinically relevant abnormality, other than ITP, identified on the screening examination, 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 diagnosis.
* Concurrent malignant disease and/or history of cancer treatment with cytotoxic chemotherapy and/or radiotherapy.
* 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, medication for hypertension, cancer, hereditary thrombophilic disorders (e.g., Factor V Leiden, ATIII deficiency, etc), or any other family history of arterial or venous thrombosis
* Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association \[NYHA\] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc \>450 msec.
* Female subjects who are nursing or pregnant (positive serum or urine b-human chorionic gonadotrophin (b-hCG) pregnancy test) at screening or pre-dose on Day 1.
* History of alcohol/drug abuse.
* Treatment with an investigational drug within 30 days or five half-lives (whichever is longer) preceding the first dose of study medication.
* Subject treated with drugs that affect platelet function (including but not limited to aspirin, clopidogrel and/or NSAIDs) or anti-coagulants for \> 3 consecutive days within 2 weeks of the study start and until the end of the study.
* History of platelet agglutination abnormality that prevents reliable measurement of platelet counts.
* All subjects with secondary immune thrombocytopenia, including those with laboratory or clinical evidence of HIV infection, antiphospholipid antibody syndrome, chronic hepatitis B infection, hepatitis C virus infection, or any evidence for active hepatitis at the time of subject screening. If a potential subject has no clinical history that would support HIV infection or hepatitis infection, no further laboratory screening is necessary; however, standard medical practice would suggest further evaluation of patients who have risk factors for these infections.
* A subject is planning to have cataract surgery.
* In France, a subject is neither affiliated with nor a beneficiary of a social security category.

Other Eligibility Criteria Considerations:

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: CIB, SPM.

Primary outcomes:
measure: Overall Summary of On-Therapy Adverse Events (Safety Population)
timeFrame: Start date was the first dose of investigational product and up to the day after the last dose . Post-therapy: start date was more than 1 day after the last dose and up to 30 days after last dose of investigational product up to week 364
Secondary outcomes:
measure: Subjects Achieving Maximum Platelet Counts Greater Than or Equal to 30 Gi/L or 50 Gi/L in the Absence of Rescue Medication
timeFrame: Baseline up to 2 years
measure: Summary of Subjects Achieving Platelet Count Levels by Week, in the Absence of Rescue Medication
timeFrame: Baseline up to Year 7/Week 364
measure: Number of Subjects Who Responded to Eltrombopag in a Previous Study and Who Respond to Retreatment With a Rise in Platelet Count to Either ≥ 50,000/µL or ≥30,000/µL
timeFrame: Baseline up to 2 years
measure: Number of Participants With Reduction and/or Sparing of Concomitant ITP Therapies, While Maintaining a Platelet Count ≥ 50,000/mL.
timeFrame: Baseline up to 2 years
measure: Number of Subjects Who Required Rescue Therapy During Treatment With Eltrombopag.
timeFrame: Baseline up to 2 years
measure: Maximum ITP Bleeding Score at Any Time During the Study During All Stages.
timeFrame: Baseline up to 2 years
measure: Best Post-Baseline Change in SF-36v2 Questionnaire Score From Any Time Point Compared With Baseline
timeFrame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years
measure: Best Post-Baseline Change in the Short Form of the Motivation and Energy Scale (MEI-SF) From Any Time Point Compared With Baseline
timeFrame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years
measure: Best Post-Baseline Change in the FACIT-Fatigue 13 Item Subscale Score From Any Time Point Compared to Baseline
timeFrame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years
measure: Best Post-Baseline Change in the FACT-TH6 at Any Time Point Compared to Baseline
timeFrame: Baseline, beginning of each stage, change in therapy and minimum frequency of every 3 months during stages, prior to early discontinuation, up to 2 years
Other outcomes:
Locations:
city: Huntsville
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Mobile
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Jonesboro
country: United States
facility: Novartis Investigative Site
state: Arkansas
city: Duarte
country: United States
facility: Novartis Investigative Site
state: California
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Savannah
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Peoria
country: United States
facility: Novartis Investigative Site
state: Illinois
city: New Orleans
country: United States
facility: Novartis Investigative Site
state: Louisiana
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Detroit
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Brunsville
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: Albuquerque
country: United States
facility: Novartis Investigative Site
state: New Mexico
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Lubbock
country: United States
facility: Novartis Investigative Site
state: Texas
city: Arlington
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Tacoma
country: United States
facility: Novartis Investigative Site
state: Washington
city: Vancouver
country: United States
facility: Novartis Investigative Site
state: Washington
city: Garran
country: Australia
facility: Novartis investigative Site
state: Australian Capital Territory
city: Kogarah
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Hamilton
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Jiang Su Province
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Tianjin
country: China
facility: Novartis Investigative Site
city: Brno
country: Czech Republic
facility: Novartis Investigative Site
city: Olomouc
country: Czech Republic
facility: Novartis Investigative Site
city: Praha 2
country: Czech Republic
facility: Novartis Investigative Site
city: Odense
country: Denmark
facility: Novartis Investigative Site
city: Kuopio
country: Finland
facility: Novartis Investigative Site
city: Caen cedex 9
country: France
facility: Novartis Investigative Site
city: Créteil
country: France
facility: Novartis Investigative Site
city: Pessac
country: France
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
state: Bayern
city: Giessen
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Hannover
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Hannover
country: Germany
facility: Novartis Investigative Site
state: Niedersachsen
city: Saarbruecken
country: Germany
facility: Novartis Investigative Site
state: Saarland
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: Emilia-Romagna
city: Albano Laziale (Roma)
country: Italy
facility: Novartis Investigative Site
state: Lazio
city: Milano
country: Italy
facility: Novartis investigative Site
state: Lombardia
city: Padova
country: Italy
facility: Novartis Investigative Site
state: Veneto
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amersfoort
country: Netherlands
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Den Haag
country: Netherlands
facility: Novartis Investigative Site
city: Nijmegen
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Auckland
country: New Zealand
facility: Novartis Investigative Site
city: Christchurch
country: New Zealand
facility: Novartis Investigative Site
city: Grafton
country: New Zealand
facility: Novartis Investigative Site
city: Takapuna, Auckland
country: New Zealand
facility: Novartis Investigative Site
city: Karachi
country: Pakistan
facility: Novartis Investigative Site
city: Lahore
country: Pakistan
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Lima
country: Peru
facility: Novartis Investigative Site
city: Bialystok
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Lublin
country: Poland
facility: Novartis Investigative Site
city: Slupsk
country: Poland
facility: Novartis Investigative Site
city: Torun
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Novosibirsk
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis investigative Site
city: Kosice
country: Slovakia
facility: Novartis Investigative Site
city: Presov
country: Slovakia
facility: Novartis Investigative Site
city: Ljubljana
country: Slovenia
facility: Novartis Investigative Site
city: Badalona/Barcelona
country: Spain
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Palma de Mallorca
country: Spain
facility: Novartis Investigative Site
city: Pamplona
country: Spain
facility: Novartis Investigative Site
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
city: Göteborg
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
city: Montfleury
country: Tunisia
facility: Novartis investigative Site
city: Sfax
country: Tunisia
facility: Novartis investigative Site
city: Sousse
country: Tunisia
facility: Novartis Investigative Site
city: Tunis
country: Tunisia
facility: Novartis Investigative Site
city: Dnipropetrovsk
country: Ukraine
facility: Novartis Investigative Site
city: Lviv
country: Ukraine
facility: Novartis Investigative Site
city: Plymouth
country: United Kingdom
facility: Novartis Investigative Site
state: Devon
city: Taunton
country: United Kingdom
facility: Novartis Investigative Site
state: Somerset
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Reading
country: United Kingdom
facility: Novartis Investigative Site
city: Swansea
country: United Kingdom
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Wong RSM, Saleh MN, Khelif A, Salama A, Portella MSO, Burgess P, Bussel JB. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017 Dec 7;130(23):2527-2536. doi: 10.1182/blood-2017-04-748707. Epub 2017 Oct 17.
citation: Tarantino MD, Fogarty P, Mayer B, Vasey SY, Brainsky A. Efficacy of eltrombopag in management of bleeding symptoms associated with chronic immune thrombocytopenia. Blood Coagul Fibrinolysis. 2013 Apr;24(3):284-96. doi: 10.1097/MBC.0b013e32835fac99.
citation: Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A; EXTEND Study Group. Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label EXTEND study. Blood. 2013 Jan 17;121(3):537-45. doi: 10.1182/blood-2012-04-425512. Epub 2012 Nov 20.
citation: Fogarty PF, Tarantino MD, Brainsky A, Signorovitch J, Grotzinger KM. Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia. Curr Med Res Opin. 2012 Jan;28(1):79-87. doi: 10.1185/03007995.2011.644849. Epub 2011 Dec 20.
citation: Signorovitch J, Brainsky A, Grotzinger KM. Validation of the FACIT-fatigue subscale, selected items from FACT-thrombocytopenia, and the SF-36v2 in patients with chronic immune thrombocytopenia. Qual Life Res. 2011 Dec;20(10):1737-44. doi: 10.1007/s11136-011-9912-9. Epub 2011 May 1.