Eltrombopag for Moderate Aplastic Anemia

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01328587
• Collaborator: (none)
• Enrollment: 34
• Location: 1
• Arm: 1
• Duration (Months): 168
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Background:

• Moderate aplastic anemia is a blood disease which may require frequent blood and platelet transfusions. Sometimes patients with this disease can be treated with immunosuppressive drugs. Not all patients respond and not all patients are suitable for this treatment.

• Thrombopoietin (TPO) is a protein made by the body. The bone marrow needs TPO to produce platelets. TPO may also be able to stimulate bone marrow stem cells to produce red cells and white cells. However, TPO cannot be given by mouth. This has led researchers to develop the drug eltrombopag, which acts in the same way and can be given by mouth. Eltrombopag has been shown to safely increase platelet numbers in healthy volunteers and in patients with other chronic blood diseases, including severe aplastic anemia. Researchers are interested in looking at whether eltrombopag can be given to people with moderate aplastic anemia and significantly low blood cell counts.

Objectives:

• To evaluate the safety and effectiveness of eltrombopag in people with moderate aplastic anemia or patients with bone marrow failure and unilineage cytopenia who need treatment for significantly low blood cell counts.

Eligibility:

• People at least 2 years of age who have moderate aplastic anemia or bone marrow failure and unilineage cytopenia,and significantly low blood cell counts.

Design:

• Patients will be screened with a physical examination, medical history, blood tests, a bone marrow biopsy, and an eye exam.

• Patients will receive eltrombopag by mouth once a day.

• Patients will have weekly blood tests to monitor the effectiveness of the treatment and adjust the dose in response to possible side effects.

• Patients may continue to take eltrombopag if their platelet count or hemoglobin increases, their requirement for platelet or blood transfusion decreases after 16 to 20 weeks of treatment, and there have been no serious side effects. Access to the drug will continue until the study is closed. Patients will be asked to return for a follow-up visit 6 months after the last dose of medication.

Condition or Disease	Intervention/Treatment	Phase
Moderate Aplastic Anemia; Unilineage Bone Marrow Failure Disorders	Drug: Eltrombopag	Phase 2

Detailed Description

Moderate aplastic anemia (MAA) is a blood disease which can be effectively treated with immunosuppressive drug regimens. However, a significant number of patients have persistent cytopenias. Currently, the treatment of these patients is regular transfusion, which are expensive, inconvenient, and associated with serious side effects related to iron overload, or cytokines such as erythropoietin or G-CSF, which are expensive, and not effective in many patients.

Thrombopoietin (TPO) is a protein made by the body that is important for normal production of platelets by the bone marrow. TPO may also be able to stimulate bone marrow stem cells to produce red cells and white cells. TPO cannot be given by mouth, and as an alternative, a drug, eltrombopag, has been designed that acts in the same way as TPO but is stable and active when given by mouth. Eltrombopag has been shown to safely increase platelet numbers in healthy volunteers and in patients with chronic immune thrombocytopenic purpura (ITP). It has been recently granted accelerated approval by FDA on November 20, 2008 for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) who have had an insufficient response to standard therapies.

We have previously shown encouraging results when eltrombopag is used to treat patients with severe aplastic anemia, with some patients responding with increases in platelets, red cells and white cells. Given these encouraging early preliminary results in our clinical trial using eltrombopag in Severe Aplastic Anemia (SAA), and low toxicity and ease of administration of this drug, we now propose a non-randomized pilot phase II study of eltrombopag in moderate aplastic anemia patients with clinically significant thrombocytopenia or anemia. Patients with MAA may not reach criteria for SAA, but none the less may be transfusion-dependent or have significant symptoms from cytopenias. We hypothesize that patients with MAA as compared to SAA may have a better chance of response, due to better residual marrow function in MAA patients compared to SAA.

Eligible patients can have treated or untreated MAA, as well as counts meeting criteria for MAA following a partial response to treatment with immunosuppression for SAA. We will also include patients with bone marrow failure and unilineage cytopenia. Treatment response for the platelet lineage is defined as platelet count increases to 20,000/microL above baseline at 16 to 20 weeks, or freedom from platelet transfusions for greater than or equal to 8 weeks in transfusion-dependent patients. For patients with anemia (untransfused hemoglobin less than or equal to 8.5 g/dL), a treatment response will be an increase in Hb by greater than or equal to 1.5g/dl at four months, measured on at least 2 serial measurements and sustained for 1 month or more without transfusion support OR for transfusion dependent patients, reduction of units of RCC transfused by 50 percent/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks or transfusion independence (no transfusions for greater than or equal to 8 weeks). Subjects with evidence for a clinical response in any lineage at 16 weeks but not yet meeting full primary endpoint response criteria, and who are tolerating investigational treatment, may receive an additional 4 weeks of eltrombopag and be reassessed after 20 weeks. At that time, if they meet primary endpoint response criteria, they will be eligible to enter the extended access part of the study. If they do not meet primary endpoint response criteria, eltrombopag will be discontinued.

The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in moderate aplastic anemia patients or patients with bone marrow failure and unilineage cytopenia. Secondary objectives include the analysis of the incidence and severity of bleeding, clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia and the impact on quality of life.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of a Thrombopoietin-Receptor Agonist (TPO-R Agonist), Eltrombopag, in Moderate Aplastic Anemia Patients
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Mar 30, 2018
• Anticipated Study Completion Date: Mar 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eltrombopag Eltrombopag will be administered for 16 to 20 weeks at a starting dose of 50mg/day (East Asian ancestry 25mg/day). The dose will decreased and increased (maximum dose 300mg/day) based on safety and response.	Drug: Eltrombopag; Eltrombopag will be administered for 16 to 20 weeks at a starting dose of 150mg/day (East Asian ancestry 75mg /day). The dose will decreased and increased (maximum dose 300mg/day) based on safety and response.

Outcome Measures

Primary Outcome Measures

1. Proportion of Drug Responders [16-20 weeks from start of drug]

   Defined by changes in platelet count and/or platelet transfusion requirements or hemoglobin (Hb) and/or PRBC transfusion requirements and the toxicity profile as measured by CTCAE. Response for platelet lineage is defined as absolute increase of ≥20x10^9/L above baseline at 16 or 20 weeks, with at least 2 serial measurements performed 1 week apart and sustained for 1 month or more without platelet transfusions, or for transfusion dependent patients stable platelet counts with transfusion independence for ≥ 8 weeks. Patients with anemia (untransfused hemoglobin ≤ 8.5 g/dL), a response will be an increase in Hb by ≥1.5g/dL at 4 months, with at least 2 serial measurments and sustained for 1 month or more without transfusion support OR for transfusion dependent patients, reduction of units of RCC transfused by 50%/8 weeks compared with the pretreatment transfusion number in the pretreatment transfusion number in the previous 8 weeks or transfusion independence (no transfusions ≥ 8 weeks).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Current diagnosis of moderate aplastic anemia or unilineage bone marrow failure disorders.

• Moderate aplastic anemia is defined as aplastic anemia (hypocellular bone marrow for age) with no evidence for other disease processes causing marrow failure, and depression of at least two out of three blood counts below the normal values:

• ANC less than or equal to 1200/mm(3)

• platelet count less than or equal to 70,000/mm(3)

• anemia with hemoglobin less than or equal to 8.5 g/dL and absolute reticulocyte count less than or equal to 60,000/mm(3) in transfusion-dependent patients but not fulfilling the criteria for severe disease defined by depression of two of the three peripheral counts:

• ANC less than or equal to 500/mm(3)

• platelet count less than or equal to 20,000/mm(3)

• reticulocyte count less than or equal to 60,000/mm(3)

• Unilineage bone marrow failure disorders are defined:

• Hemoglobin less than 8.5 g/dL and reticulocyte count less than 60,000 or red cell transfusion dependent and hypocellular to normocellular bone marrow for age with significantly reduced erythroid precursors.

• OR thrombocytopenia less than or equal to 30,000/uL or platelet transfusion dependent and hypocellular to normocellular bone marrow for age with reduced megakaryocytes.

• No evidence of viral or drug suppression of the marrow, dysplasia, or underproduction anemias secondary to B12, folate, iron or other reversible causes.

Platelet transfusion dependent is defined as the need for platelet transfusion due to platelet counts of < 10,000/microL with no bleeding (prophylactic transfusion) or < 20,000/microL with bleeding (therapeutic transfusion). Red cell transfusion dependent is defined as transfusion of greater than 4 units of blood in the 8 weeks prior to study entry.

Age greater than or equal to 2 years old

Weight greater than 12 kg

EXCLUSION CRITERIA:

Known diagnosis of Fanconi anemia

Counts that meet criteria for severe aplastic anemia

Infection not adequately responding to appropriate therapy

HIV positivity

Creatinine > 2.5 mg/dL

Bilirubin > 2.0 mg/dL, including congenital abnormalities in the bilirubin count

SGOT or SGPT >5 times the upper limit of normal

Hypersensitivity to eltrombopag or its components

Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential

Evidence of an active malignant hematological or clonal disorder, or abnormal cytogenetic studies of the bone marrow performed within 12 weeks of study entry.

Unable to understand the investigational nature of the study or give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent

Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy, or that death within 7-10 days is likely.

Treatment with horse or rabbit ATG or Campath within 6 months of study entry.

Treatment with cytokines such as G-CSF or Erythropoietin.

Subjects with known cirrhosis in severity that would preclude tolerability of eltrombopag as evidenced by albumin less than 35g/L.

Life expectancy of less than 3 months

Patients with an active diagnosis of cancer who have received chemotherapeutic treatment or other specific antineoplastic drugs or radiation therapy within 6 months of study entry.

Unable to take investigational drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Cynthia E Dunbar, M.D., National Heart, Lung, and Blood Institute (NHLBI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 2, 2019

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood. 1995 Jun 15;85(12):3367-77. Review.
• Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006 Oct 15;108(8):2509-19. Epub 2006 Jun 15. Review.
• Zeng W, Maciejewski JP, Chen G, Risitano AM, Kirby M, Kajigaya S, Young NS. Selective reduction of natural killer T cells in the bone marrow of aplastic anaemia. Br J Haematol. 2002 Dec;119(3):803-9.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT01328587
• Other Study ID Numbers: 110134; 11-H-0134
• First Posted: Apr 4, 2011
• Last Update Posted: Dec 6, 2021
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Heart, Lung, and Blood Institute (NHLBI): Autoimmunity; Neutropenia; Cytokine; Hematopoiesis; Thrombocytopenia; Aplastic Anemia
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic; Bone Marrow Failure Disorders; Pancytopenia

Study Results

Participant Flow

Arm/Group Title	Eltrombopag
Arm/Group Description	Patients will receive Eltrombopag ( thrombopoietin receptor agonist) by mouth once a day.
Period Title: Overall Study
STARTED	34
COMPLETED	34
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eltrombopag
Arm/Group Description	Patients will receive Eltrombopag ( thrombopoietin receptor agonist) by mouth once a day.
Overall Participants	34
Age (Count of Participants)
<=18 years	4 11.8%
Between 18 and 65 years	27 79.4%
>=65 years	3 8.8%
Sex: Female, Male (Count of Participants)
Female	17 50%
Male	17 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 8.8%
Not Hispanic or Latino	31 91.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 11.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 14.7%
White	23 67.6%
More than one race	0 0%
Unknown or Not Reported	2 5.9%

Outcome Measures

1. Primary Outcome

Title	Proportion of Drug Responders
Description	Defined by changes in platelet count and/or platelet transfusion requirements or hemoglobin (Hb) and/or PRBC transfusion requirements and the toxicity profile as measured by CTCAE. Response for platelet lineage is defined as absolute increase of ≥20x10^9/L above baseline at 16 or 20 weeks, with at least 2 serial measurements performed 1 week apart and sustained for 1 month or more without platelet transfusions, or for transfusion dependent patients stable platelet counts with transfusion independence for ≥ 8 weeks. Patients with anemia (untransfused hemoglobin ≤ 8.5 g/dL), a response will be an increase in Hb by ≥1.5g/dL at 4 months, with at least 2 serial measurments and sustained for 1 month or more without transfusion support OR for transfusion dependent patients, reduction of units of RCC transfused by 50%/8 weeks compared with the pretreatment transfusion number in the pretreatment transfusion number in the previous 8 weeks or transfusion independence (no transfusions ≥ 8 weeks).
Time Frame	16-20 weeks from start of drug

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag will be administered for 16 to 20 weeks at a starting dose of 50mg/day (East Asian ancestry 25mg/day). The dose will decreased and increased (maximum dose 300mg/day) based on safety and response. Eltrombopag: Eltrombopag will be administered for 16 to 20 weeks at a starting dose of 150mg/day (East Asian ancestry 75mg /day). The dose will decreased and increased (maximum dose 300mg/day) based on safety and response.
Measure Participants	34
Count of Participants [Participants]	17 50%

Adverse Events

Time Frame	42 months from enrollment
Arm/Group Title	Eltrombopag
Arm/Group Description	Patients will receive Eltrombopag ( thrombopoietin receptor agonist) by mouth once a day.
All Cause Mortality
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)
Serious Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	1/34 (2.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic Ovarian CA	1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	29/34 (85.3%)
Blood and lymphatic system disorders
blood and lymphatic system d/s other, specify	1/34 (2.9%)
Gingival Bleeding	1/34 (2.9%)
Hematuria	1/34 (2.9%)
spleen disorder/splenic varices	1/34 (2.9%)
spleen disorder/splenomegaly	1/34 (2.9%)
Cardiac disorders
abdominal edema	1/34 (2.9%)
BLE edema	1/34 (2.9%)
dyspnea on exertion	1/34 (2.9%)
fatigue	2/34 (5.9%)
fatigue/angina	1/34 (2.9%)
Palpitations	1/34 (2.9%)
scrotal edema	1/34 (2.9%)
Ear and labyrinth disorders
Ear Pain	1/34 (2.9%)
External Ear pain/discomfort	1/34 (2.9%)
otitis media/external ear inflammation	1/34 (2.9%)
Eye disorders
Burning Eyes	1/34 (2.9%)
eye tingling/pain	1/34 (2.9%)
Gastrointestinal disorders
Abdominal Discomfort	1/34 (2.9%)
Abdominal Pain	2/34 (5.9%)
Blood in stool	1/34 (2.9%)
collagenous colitis	1/34 (2.9%)
Dehydration	1/34 (2.9%)
diarrhea	6/34 (17.6%)
diarrhea/stomach cramps	1/34 (2.9%)
epigastric tenderness	1/34 (2.9%)
food poisoning	1/34 (2.9%)
foodpoisoning/gastroenteritis	1/34 (2.9%)
Gastroenteritis	1/34 (2.9%)
GI illness(nausea, vmitting, diarrhea)	1/34 (2.9%)
Gi symptoms	1/34 (2.9%)
Gum Bleeding	1/34 (2.9%)
h pylori	1/34 (2.9%)
intermittent lower pelvic pain	1/34 (2.9%)
Loose Stool	1/34 (2.9%)
Loose stools	2/34 (5.9%)
Mild constipation	1/34 (2.9%)
nausea	6/34 (17.6%)
nausea/diarrhea	1/34 (2.9%)
nausea/vomiting	2/34 (5.9%)
nausea/vomiting/abd cramps	1/34 (2.9%)
Pinworms	1/34 (2.9%)
rectal bleeding	1/34 (2.9%)
Viral Gastroenteritis	1/34 (2.9%)
Vomiting	1/34 (2.9%)
Worsening GERD	1/34 (2.9%)
General disorders
chills	1/34 (2.9%)
facial edema	1/34 (2.9%)
Fatigue	1/34 (2.9%)
Fever	3/34 (8.8%)
Flu like symptoms	1/34 (2.9%)
Headache	4/34 (11.8%)
Influenza	1/34 (2.9%)
intermittent night sweats	1/34 (2.9%)
LE edema	1/34 (2.9%)
lightheaded	1/34 (2.9%)
Hepatobiliary disorders
cirrhosis	1/34 (2.9%)
Elevated AST	1/34 (2.9%)
Elevated Bilirubin	1/34 (2.9%)
portal hypertension	1/34 (2.9%)
Immune system disorders
CTLA 4 deficiency	1/34 (2.9%)
Infections and infestations
Abscessed Tooth	2/34 (5.9%)
C diff	1/34 (2.9%)
strep throat	1/34 (2.9%)
tooth #30 infection	1/34 (2.9%)
UTI	1/34 (2.9%)
UTI/Inflammed prostate	1/34 (2.9%)
yeast infection	1/34 (2.9%)
Injury, poisoning and procedural complications
easy bruising	1/34 (2.9%)
Foot pain from fall	1/34 (2.9%)
shoulder pain from fall	1/34 (2.9%)
Investigations
ALT increase	1/34 (2.9%)
AST increase	1/34 (2.9%)
Elevated Liver Enzymes	1/34 (2.9%)
yellowing skin/eye	1/34 (2.9%)
Musculoskeletal and connective tissue disorders
muscle cramps	1/34 (2.9%)
R Breast Pain	1/34 (2.9%)
R Calf Cramps	1/34 (2.9%)
Rib pain	1/34 (2.9%)
Nervous system disorders
dizzy	1/34 (2.9%)
fingers tingly'-peripheral sensory neuropathy	1/34 (2.9%)
headaches	1/34 (2.9%)
Seizure	1/34 (2.9%)
Renal and urinary disorders
Dark urine	1/34 (2.9%)
UTI	2/34 (5.9%)
Respiratory, thoracic and mediastinal disorders
Chest cold	1/34 (2.9%)
Cold Sxs	2/34 (5.9%)
cough	1/34 (2.9%)
dry cough	1/34 (2.9%)
Dyspnea on Exertion	1/34 (2.9%)
Flu-like symptoms	1/34 (2.9%)
hoarseness	1/34 (2.9%)
Mild Flu-like symptoms	1/34 (2.9%)
nasal congestion	1/34 (2.9%)
shortness of breath	1/34 (2.9%)
sinus pressure	1/34 (2.9%)
sleep apnea	1/34 (2.9%)
sore throat	1/34 (2.9%)
URI	4/34 (11.8%)
Viral URI	1/34 (2.9%)
Skin and subcutaneous tissue disorders
Dermatitis	1/34 (2.9%)
facial rash	1/34 (2.9%)
left post auricular skin	1/34 (2.9%)
Rash on Arm	1/34 (2.9%)
Shingles	1/34 (2.9%)
skin rash	1/34 (2.9%)
vitiligo	1/34 (2.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.