Clinical trial NCT03939637: Eltrombopag vs Standard Front Line Management for Newly Diagnosed Immune Thrombocytopenia (ITP) in Children
Official title: A Phase III Study of Eltrombopag vs Standard Front Line Management for Newly Diagnosed Immune Thrombocytopenia in Children
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immune Thrombocytopenia
Keywords: ITP
Immune Thrombocytopenia
Newly Diagnosed Immune Thrombocytopenia
Newly Diagnosed ITP
Lead sponsor: Baylor College of Medicine
Sponsor class: OTHER
Collaborators: name: Boston Children's Hospital
name: University of California, San Francisco
First posted: 2019-05-07
Enrollment: 122
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an investigator initiated, multicenter, open label, randomized phase 3 study for subjects with newly diagnosed ITP from ages 1 to less than 18 years old.

Detailed description: This is a prospective, open label, randomized, two-arm, multi-center Phase 3 trial.

Patients with newly diagnosed ITP are randomized 2:1 to receive the experimental treatment, eltrombopag, or investigator's choice of 3 standard therapies. The primary objective is to determine if the proportion of patients with platelet response is significantly greater in patients treated with eltrombopag compared to those treated with standard therapies.

Eligibility criteria: Inclusion Criteria:

* Age: 1- \<18 years
* Newly diagnosed ITP (\<3 months from diagnosis (first abnormal platelet count), per international working group definition17)
* Platelets \<30 x 10\^9/L at screening
* Requires pharmacologic treatment from the perspective of the treating clinician.

Need to treat is at the discretion of the investigator, but there should be clinical equipoise about the use of eltrombopag vs standard treatment options (patients should not, in the opinion of the investigator, require concomitant therapy at time of enrollment).

* Treatment options include one of three standard therapies, (IVIg, steroids, or Anti-D). For example, if patient has previously shown no response to IVIg or steroids and is Rh-negative, patient would not be eligible for study.
* Patient population includes both:

  1. Upfront treatment: Patient within 10 days of ITP diagnosis who has not received previous treatment OR
  2. Treatment failure: Patients who have failed standard management (observation or treatment with one or more first-line agents)

     * Failure of observation: no platelet recovery (\>30 x 10\^9/L) with observation \>10 days from diagnosis, with need to treat
     * Poor response to first-line agent (platelets remain \<30 x10\^9/L)
     * Initial response to first-line agent, but response wanes and platelets fall below 30 x10\^9/L
* Family willing and able to return for required lab studies

Exclusion Criteria:

* Severe bleeding: Buchanan Overall Grade 4 or 5 bleeding, or severe bleeding requiring emergent treatment at the discretion of the provider. (e.g., intracranial hemorrhage, pulmonary hemorrhage, bleeding with ongoing need for pRBC transfusion)
* Prior treatment with TPO-RA (eltrombopag or romiplostim)
* Known secondary ITP (due to lupus, CVID, ALPS)
* Known HIV (or history of HIV positivity) or Hepatitis C (screening not required if no clinical suspicion)
* Evans Syndrome: positive direct Coombs with evidence of active hemolysis (elevated lactate dehydrogenase (LDH) or reticulocyte count not attributable to recent treatment or bleeding)
* Any Malignancy
* History of stem cell transplant or solid organ transplant
* aspartate aminotransferase (AST) or ALT \>2 x upper limit of normal (ULN)
* Total bilirubin \>1.5 × ULN
* Subjects with liver cirrhosis (as determined by the investigator)
* Creatinine \>2.5 × ULN
* Known active or uncontrolled infections not responding to appropriate therapy
* On anticoagulation or anti-platelet agents
* 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.
* Baseline ophthalmic problems that may potentiate cataract development
* Impaired cardiac function, such as:

  * Known prolonged QTc, with corrected QTc \>450 msec
  * Other clinically significant cardio-vascular disease (e.g., uncontrolled hypertension, history of labile hypertension),
  * History of known structural abnormalities (e.g. cardiomyopathy).
* History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:

  * Recent myocardial infarction (within last 6 months),
  * Uncontrolled congestive heart failure,
  * Unstable angina (within last 6 months),
  * Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker.)
  * Long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome or additional risk factors for cardiac repolarization abnormality, as determined by the investigator.
* Known immediate or delayed hypersensitivity reaction to eltrombopag or its excipient.
* Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Women of childbearing potential (have achieved menarche) must have a negative serum or urine pregnancy test and agree to use basic methods of contraception (if sexually active) or maintain abstinence for the duration of the study. Basic contraception methods include:

  * Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
  * Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
  * Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject
  * Barrier methods of contraception: Condom or Occlusive cap. For the UK: with spermicidal foam/gel/film/cream/ vaginal suppository
  * Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
* Male patients who are sexually active and do not agree to abstinence or to use a condom during intercourse while taking eltrombopag, and for 7 days after stopping treatment.
* History of alcohol/drug abuse
* Presence of a medical condition that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
* Concurrent participation in an investigational study within 30 days prior to enrollment or within 5-half-lives of the investigational product, whichever is longer. Note: parallel enrollment in a non-therapeutic trial such as disease registry or biology study is permitted.

Other Eligibility Criteria Considerations All patients and/or their parents or legal guardians must sign a written informed consent (and assent when applicable)

* Patients and/or parents who are unable to read at a grade 2 level will be excluded from the patient-reported outcome component of the study, as will non-English speaking patients and/or parents when there is no availability of translated versions in their spoken language . They will not be excluded from all other aspects of the study

Primary outcomes:
measure: Proportion of patients with a platelet response
timeFrame: 12 weeks
Secondary outcomes:
measure: Bleeding Score
timeFrame: 1 year
measure: Number of rescue therapies
timeFrame: 12 weeks
measure: Platelet response
timeFrame: 12 weeks
measure: Need for treatment
timeFrame: 6 months
measure: Treatment response
timeFrame: 1 year
measure: Number of 2nd line therapies
timeFrame: 52 weeks
measure: Regulatory T-Cells
timeFrame: 1 year
measure: KIT Scores
timeFrame: 1 year
measure: Hockenberry Fatigue Scale-Parent
timeFrame: 1 year
measure: Blood Iron values
timeFrame: 1 year
measure: Safety evaluations
timeFrame: 1 year
Other outcomes:
measure: Time to response
timeFrame: 1 year
measure: Platelet-specific endpoints
timeFrame: 1 year
measure: Time to platelet count
timeFrame: 1 year
measure: Treatment response
timeFrame: 1 year
measure: Loss of treatment response
timeFrame: 1 year
measure: Extreme thrombocytosis
timeFrame: 1 year
measure: Patient-reported outcomes endpoints
timeFrame: 1 year
measure: Change in Hockenberry fatigue
timeFrame: 1 year
measure: Global Change Scale scores
timeFrame: 1 year
measure: Number of Hospitalizations
timeFrame: 1 year
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix CHildren's Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Benioff Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Atlanta
country: United States
facility: Alfac Cancer and Blood Disorder Center: Scottish Rite
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children-Indiana University
state: Indiana
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: Children's Hospital and Clinics of Minnesota
state: Minnesota
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Randall Children's Hospital
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Providence
country: United States
facility: Hasbro Children's Hospital
state: Rhode Island
city: Memphis
country: United States
facility: St. Jude Children's Hospital
state: Tennessee
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
Study officials:
affiliation: Baylor College of Medicine - Texas Children's Hospital
name: Amanda Grimes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shimano KA, Grace RF, Despotovic JM, Neufeld EJ, Klaassen RJ, Bennett CM, Ma C, London WB, Neunert C. Phase 3 randomised trial of eltrombopag versus standard first-line pharmacological management for newly diagnosed immune thrombocytopaenia (ITP) in children: study protocol. BMJ Open. 2021 Aug 27;11(8):e044885. doi: 10.1136/bmjopen-2020-044885.