Immune Thrombocytopenia
Conditions
Keywords
ITP, Immune Thrombocytopenia, Newly Diagnosed Immune Thrombocytopenia, Newly Diagnosed ITP
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.
Interventions
DRUGEltrombopag
Starting dose for eltrombopag will be based on manufacturer recommendations, and drug will be titrated to effect per guidelines. * Children 1 to 5 years: Initial: 25 mg once daily * Children ≥6 years and Adolescents: Initial: 50 mg once daily (25 mg once daily for patients of East-Asian ethnicity \[e.g., Chinese, Japanese, Korean, Taiwanese\]) Dose should be titrated based on platelet response. Maximum dose: 75 mg once daily.
DRUGSteroids
Prednisone/Prednisolone 4mg/kg/day (Max 120 mg/day) x 4 day
DRUGIVIG
IVIG 1 g/kg x1 (no steroids for pre-medication or adjunctive therapy)
DRUGRho(D) Immune Globulin
Anti-D globulin 75 mcg/kg x1 (no steroids for pre-medication or adjunctive therapy)
Sponsors
Boston Children's Hospital
University of California, San Francisco
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With a Platelet Response | 12 weeks | To determine if the percentage of patients with a platelet response is significantly greater in patients with newly diagnosed ITP treated with eltrombopag than those treated with standard first-line treatments |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Number of Rescue Therapies Required | 12 weeks | The percentage of patients who received rescue therapy in the experimental (eltrombopag) arm vs the comparator (standard therapy) arm during the first 12 weeks of treatment |
| Bleeding Score | 1 year | Poor bleeding score (binary) at 1, 2, 3, 4 weeks, 12 weeks, and 1 year after study enrollment defined as World Health Organization (WHO) Bleeding Scale ≥ 2 or Modified Buchanan Scale ≥ 3 |
| Platelet Response Among Patients Requiring Rescue Therapy During Weeks 1-2 of Study | 12 weeks | Platelet response (binary), defined as ≥ 3 of 4 weeks with platelets \>50 x109/L during weeks 6-12 of therapy, but patient required a rescue treatment during weeks 1-2 of study. |
| Need for Treatment | 6 months | No further need for treatment (binary) after 12 weeks or 6 months of study |
| Treatment Response | 1 year | Treatment response (binary endpoints) at 1 year defined as: * CR is defined as platelet count \>/= 150 x 10\^9/L * Primary Remission at 1 year is defined as CR at 1 year with no second-line agents required and \>/= 3 months after discontinuing most recent platelet active medication * Disease resolution at 1 year is defined as complete response (CR) at 1 year \>/= 3 months after discontinuing most recent platelet active medication. May have received a second-line therapy, excluding rituximab or splenectomy. * Disease stability at 1 year is defined as platelets \>/= 50 x 10\^9/L but \<150 x 10\^9/L \>/= 3 months after discontinuing most recent platelet active medication. |
| Number of 2nd Line Therapies | 52 weeks | Number of 2nd-line therapies in weeks 13-52 |
| Regulatory T-Cells | 1 year | Absolute change in percentage of CD4+25+Foxp3+ regulatory T cells from baseline at 12 weeks and 1 year |
| KIT Scores | 1 year | Change in parent proxy-reported Kids ITP tool (KIT) overall scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment |
| Hockenberry Fatigue Scale-Parent | 1 year | Total scale intensity ratings (continuous) from the Hockenberry Fatigue Scale-Parent (FS-P) at 1 week, 4 weeks, 12 weeks, and 1 year |
| Blood Iron Values | 1 year | Serum iron, total iron binding capacity (TIBC), transferrin saturation, ferritin, mean corpuscular volume (MCV), and hemoglobin at 12 weeks, 6 months, and 1 year after study enrollment |
| Safety Evaluations | 1 year | Safety evaluations as defined by: * Abnormal liver function tests (LFTs): ALT ≥ 3 x upper limit of normal (ULN) in patients with normal baseline ALT ≥ 3 x baseline or ≥ 5 x ULN (whichever is lower) in patients with abnormal baseline ALT ≥ 3 x ULN AND bilirubin ≥ 1.5 x ULN (\>35% direct) * Incidence of adverse events * Incidence of serious adverse events |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Platelet Count | 1 year | Time to platelet count \>100x10\^9/L and absence of bleeding (IWG definition) |
| Treatment Response | 1 year | Treatment response (platelet count \>100x10\^9/L and absence of bleeding) (IWG definition) at 12 weeks |
| Loss of Treatment Response | 1 year | Loss of treatment response (platelet count below 30x10\^9/L, or less than 2-fold increase in the baseline count or bleeding) (IWG definition) at any time during the study period after achieving response during the first 12 weeks |
| Extreme Thrombocytosis | 1 year | Extreme thrombocytosis (platelets \>1 x10\^12/L) |
| Patient-reported Outcomes Endpoints | 1 year | Change in child self-reported and parent impact KIT scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment |
| Change in Hockenberry Fatigue | 1 year | Change in Hockenberry fatigue (FS-C, FS-A, FS-P) scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment |
| Global Change Scale Scores | 1 year | Global Change Scale scores at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment |
| Number of Hospitalizations | 1 year | Number of hospitalizations |
| Platelet-specific Endpoints | 1 year | Treatment response (platelets \>30x10\^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition) at 12 weeks |
| Time to Response | 1 year | Time to response (platelets \>30x10\^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Eltrombopag Patients ages 1 to \<18 years with newly diagnosed primary ITP, platelets \<30 x 10\^9/L, requiring pharmacological treatment, but without severe bleeding or need for rapid rise in counts, randomized to receive the experimental therapy (eltrombopag). | 78 |
| Comparator: Standard Therapy Patients ages 1 to \<18 years with newly diagnosed primary ITP, platelets \<30 x 10\^9/L, requiring pharmacological treatment, but without severe bleeding or need for rapid rise in counts, randomized to receive standard therapy (investigator choice of glucocorticoids, IVIg, anti-D immunoglobulin). | 40 |
| Total | 118 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | patient retrospectively deemed ineligible (Day 0 plt ct >30 x 10^9/L) | 1 | 1 |
| Overall Study | patient retrospectively deemed ineligible (did not have primary ITP) | 2 | 0 |
Baseline characteristics
| Characteristic | Comparator: Standard Therapy | Total | Experimental: Eltrombopag |
|---|---|---|---|
| Age, Continuous | 8.7 years | 8.2 years | 7.9 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 26 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 83 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 9 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) White | 26 Participants | 85 Participants | 59 Participants |
| Sex: Female, Male Female | 18 Participants | 60 Participants | 42 Participants |
| Sex: Female, Male Male | 22 Participants | 58 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 78 | 0 / 39 |
| other Total, other adverse events | 8 / 78 | 3 / 39 |
| serious Total, serious adverse events | 6 / 78 | 3 / 39 |
Outcome results
Primary
Proportion of Patients With a Platelet Response
To determine if the percentage of patients with a platelet response is significantly greater in patients with newly diagnosed ITP treated with eltrombopag than those treated with standard first-line treatments
Time frame: 12 weeks
Population: This study included 118 pediatric patients (median age 8y, 49% male), 78 randomized to eltrombopag and 40 to standard therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Eltrombopag | Proportion of Patients With a Platelet Response | 52 Participants |
| Comparator: Standard Therapy | Proportion of Patients With a Platelet Response | 14 Participants |
Secondary
Bleeding Score
Poor bleeding score (binary) at 1, 2, 3, 4 weeks, 12 weeks, and 1 year after study enrollment defined as World Health Organization (WHO) Bleeding Scale ≥ 2 or Modified Buchanan Scale ≥ 3
Time frame: 1 year
Secondary
Blood Iron Values
Serum iron, total iron binding capacity (TIBC), transferrin saturation, ferritin, mean corpuscular volume (MCV), and hemoglobin at 12 weeks, 6 months, and 1 year after study enrollment
Time frame: 1 year
Secondary
Cumulative Number of Rescue Therapies Required
The percentage of patients who received rescue therapy in the experimental (eltrombopag) arm vs the comparator (standard therapy) arm during the first 12 weeks of treatment
Time frame: 12 weeks
Population: Patients who received \>/= 1 dose of protocol-directed therapy were evaluable for secondary objectives.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Eltrombopag | Cumulative Number of Rescue Therapies Required | 13 Participants |
| Comparator: Standard Therapy | Cumulative Number of Rescue Therapies Required | 15 Participants |
Secondary
Hockenberry Fatigue Scale-Parent
Total scale intensity ratings (continuous) from the Hockenberry Fatigue Scale-Parent (FS-P) at 1 week, 4 weeks, 12 weeks, and 1 year
Time frame: 1 year
Secondary
KIT Scores
Change in parent proxy-reported Kids ITP tool (KIT) overall scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
Time frame: 1 year
Secondary
Need for Treatment
No further need for treatment (binary) after 12 weeks or 6 months of study
Time frame: 6 months
Secondary
Number of 2nd Line Therapies
Number of 2nd-line therapies in weeks 13-52
Time frame: 52 weeks
Secondary
Platelet Response Among Patients Requiring Rescue Therapy During Weeks 1-2 of Study
Platelet response (binary), defined as ≥ 3 of 4 weeks with platelets \>50 x109/L during weeks 6-12 of therapy, but patient required a rescue treatment during weeks 1-2 of study.
Time frame: 12 weeks
Population: patient required a rescue treatment during weeks 1-2 of study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Eltrombopag | Platelet Response Among Patients Requiring Rescue Therapy During Weeks 1-2 of Study | 4 Participants |
| Comparator: Standard Therapy | Platelet Response Among Patients Requiring Rescue Therapy During Weeks 1-2 of Study | 0 Participants |
Secondary
Regulatory T-Cells
Absolute change in percentage of CD4+25+Foxp3+ regulatory T cells from baseline at 12 weeks and 1 year
Time frame: 1 year
Secondary
Safety Evaluations
Safety evaluations as defined by: * Abnormal liver function tests (LFTs): ALT ≥ 3 x upper limit of normal (ULN) in patients with normal baseline ALT ≥ 3 x baseline or ≥ 5 x ULN (whichever is lower) in patients with abnormal baseline ALT ≥ 3 x ULN AND bilirubin ≥ 1.5 x ULN (\>35% direct) * Incidence of adverse events * Incidence of serious adverse events
Time frame: 1 year
Secondary
Treatment Response
Treatment response (binary endpoints) at 1 year defined as: * CR is defined as platelet count \>/= 150 x 10\^9/L * Primary Remission at 1 year is defined as CR at 1 year with no second-line agents required and \>/= 3 months after discontinuing most recent platelet active medication * Disease resolution at 1 year is defined as complete response (CR) at 1 year \>/= 3 months after discontinuing most recent platelet active medication. May have received a second-line therapy, excluding rituximab or splenectomy. * Disease stability at 1 year is defined as platelets \>/= 50 x 10\^9/L but \<150 x 10\^9/L \>/= 3 months after discontinuing most recent platelet active medication.
Time frame: 1 year
Other Pre-specified
Change in Hockenberry Fatigue
Change in Hockenberry fatigue (FS-C, FS-A, FS-P) scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
Time frame: 1 year
Other Pre-specified
Extreme Thrombocytosis
Extreme thrombocytosis (platelets \>1 x10\^12/L)
Time frame: 1 year
Other Pre-specified
Global Change Scale Scores
Global Change Scale scores at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
Time frame: 1 year
Other Pre-specified
Loss of Treatment Response
Loss of treatment response (platelet count below 30x10\^9/L, or less than 2-fold increase in the baseline count or bleeding) (IWG definition) at any time during the study period after achieving response during the first 12 weeks
Time frame: 1 year
Other Pre-specified
Number of Hospitalizations
Number of hospitalizations
Time frame: 1 year
Other Pre-specified
Patient-reported Outcomes Endpoints
Change in child self-reported and parent impact KIT scores from baseline at 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment
Time frame: 1 year
Other Pre-specified
Platelet-specific Endpoints
Treatment response (platelets \>30x10\^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition) at 12 weeks
Time frame: 1 year
Other Pre-specified
Time to Platelet Count
Time to platelet count \>100x10\^9/L and absence of bleeding (IWG definition)
Time frame: 1 year
Other Pre-specified
Time to Response
Time to response (platelets \>30x10\^9/L, and at least 2-fold increase in the baseline count and absence of bleeding) (IWG definition)
Time frame: 1 year
Other Pre-specified
Treatment Response
Treatment response (platelet count \>100x10\^9/L and absence of bleeding) (IWG definition) at 12 weeks
Time frame: 1 year