A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00922883
• Collaborator: (none)
• Enrollment: 43
• Location: 1
• Arm: 1
• Duration (Months): 106.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe cytopenias, requiring regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications.

Thrombopoietin (TPO) is the principal endogenous regulator of platelet production and also stimulates hematopoietic stem and progenitor cells. A small molecule oral TPO-agonist, eltrombopag has been shown to increase platelets in healthy subjects and in patients with immune thrombocytopenic purpura (ITP), and received FDA approval in 2008 for the treatment of thrombocytopenia in ITP. This Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia will test the safety and potential efficacy of eltrombopag treatment patients with refractory thrombocytopenia following immunosuppression for aplastic anemia.

Subjects will initiate study medication at an oral dose of 50 mg/day, which will be increased up to 150 mg/day as clinically indicated to the lowest dose that maintains a stable platelet count 20,000/(micro)L above baseline while maximizing tolerability. Response will be assessed at 3-4 months. Platelet response is defined as platelet count increases to 20,000/L above baseline at three months. or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive weeks compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater than 0.5 times 10(9)/L. Subjects with response at 3-4 months may continue study medication (extended access) until they meet an off study criteria. The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia. Secondary objectives include the analysis of the incidence and severity of bleeding episodes, and the impact on quality of life.

Condition or Disease	Intervention/Treatment	Phase
Anemia, Aplastic; Anemia, Hypoplastic; Thrombocytopenia	Drug: Eltrombopag	Phase 2

Detailed Description

Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe thrombocytopenia. Even patients that respond to immunosuppressive therapies with an improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia. Both groups of patients (i.e. nonresponders to immunosuppressive therapy and responders with persistent thrombocytopenia) require regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications.

Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. On binding to the megakaryocyte progenitor TPO receptor, TPO initiates a number of signal transduction events to increase the production of mature megakaryocytes and platelets. Thrombopoietin also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. A 2nd generation small molecule TPO-agonist, eltrombopag (Promacta ) has been shown to increase platelets in healthy subjects and in thrombocytopenic patients with chronic immune thrombocytopenic purpura (ITP) and hepatitis C virus (HCV) infection. Eltrombopag is administered orally and has been well-tolerated in clinical trials. Unlike recombinant TPO, it has not been found to induce autoantibodies. Eltrombopag received FDA accelerated approval on Nov 20, 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Because a paucity of megakaryocytes and decreased platelet production is responsible for thrombocytopenia in aplastic anemia patients, we now propose this Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia.

Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East Asians), which will be increased or decreased as clinically indicated to the lowest dose that maintains a stable platelet count greater than or equal to 20,000/microL above baseline while maximizing tolerability. Platelet treatment response is defined as platelet count increases to 20,000/microL above baseline at three months, or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell (PRBC) transfusion support, or a reduction in the units of transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive weeks compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with a pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater than 0.5 times 10(9)/L. Subjects with a platelet, erythroid, and/or neutrophil response at 12 weeks may continue study medication (extended access) until they meet an off study criteria. Subjects with platelet, erythroid, or neutrophil response at 12 weeks may continue study medication for an additional 4 weeks (to ensure eligibility) prior to being consented for entry into the extended access part of the trial. Patients may remain on the extended access trial until they met an off study criteria.

The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia.

Secondary objectives include the analysis of the incidence and severity of bleeding episodes, and the impact on quality of life.

The primary endpoint will be the portion of drug responders as defined by changes in the platelet count and/or platelet transfusion requirements, hemoglobin levels, number of red blood cell transfusions, or neutrophil counts as measured by International Working Group criteria and the toxicity profile as measured using the CTCAE criteria. Platelet treatment response is defined as platelet count increases to 20,000/microL above baseline at three months, or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL or a reduction in the units of PRBC transfusions by at least 50% during the eight consecutive weeks prior to response assessment compared with the pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined in those with pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase in ANC, or an ANC increase greater than 0.5 times 10(9)/L.

Secondary endpoints will include incidence of bleeding; changes in serum thrombopoietin level (as measured by enzyme-linked immunosorbent assay, R&D Systems), and health related quality of life (as measured by the Medical Outcomes Study 36-Item Short Form General Health Survey, version 2 [SF36v2J]; Quality-Metric) measured at 12 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 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 Aplastic Anemia Patients With Immunosuppressive-Therapy Refractory Thrombocytopenia
• Study Start Date: May 29, 2009
• Actual Primary Completion Date: May 7, 2013
• Actual Study Completion Date: Apr 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eltrombopag Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.	Drug: Eltrombopag; Other Names: Promacta

Outcome Measures

Primary Outcome Measures

1. The Portion of Drug Responders as Defined by Hematologic Improvements [12-16 weeks]

   Defined as unilineage or multilineage recovery by 1 or more of the following: 1) platelet response (increase to 20 × 103/μL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks in those who were transfusion dependent on entry into the protocol); (2) erythroid response (when pretreatment hemoglobin was <9 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks); and (3) neutrophil response (when pretreatment absolute neutrophil count [ANC] of <0.5 × 103/μL as at least a 100% increase in ANC, or an ANC increase >0.5 × 103/μL, and the toxicity profile as measured using Common Terminology Criteria for Adverse Events).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Diagnosis of aplastic anemia, with refractory thrombocytopenia following at least one treatment course of horse or rabbit ATG/cyclosporine.

2. Platelet count less than or equal to 30,000/microL

3. Age greater than or equal to 12 years old

EXCLUSION CRITERIA:

1. Diagnosis of Fanconi anemia

2. Infection not adequately responding to appropriate therapy

3. Patients with a PNH clone size in neutrophils of greater than or equal to 50%

4. HIV positivity

5. Creatinine > 2.5

6. Bilirubin > 2.0

7. SGOT or SGPT > 5 times the upper limit of normal

8. Hypersensitivity to eltrombopag or its components

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

10. History of malignancy other than localized tumors diagnosed more than one year previously and treated surgically with curative intent (for instance squamous cell or other skin cancers, stage 1 breast cancer, cervical carcinoma in situ, etc)

11. Unable to understand the investigational nature of the study or give informed consent

12. History of congestive heart failure arrhythmia requiring chronic treatment, arterial or venous thrombosis (not excluding line thrombosis) within the last 1 year, or myocardial infarction within 3 months before enrollment

13. ECOG Performance Status of 3 or greater

14. Treatment with horse or rabbit ATG or Campath within 6 months of study entry. Concurrent stable treatment with cyclosporine or G-CSF is permitted.

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)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Emmons RV, Reid DM, Cohen RL, Meng G, Young NS, Dunbar CE, Shulman NR. Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood. 1996 May 15;87(10):4068-71.
• 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.

• Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
• ClinicalTrials.gov Identifier: NCT00922883
• Other Study ID Numbers: 090154; 09-H-0154
• First Posted: Jun 17, 2009
• Last Update Posted: Oct 20, 2020
• Last Verified: Sep 1, 2020

• 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): Promacta; SAA; Aplastic Anemia; Thrombocytopenia
• Additional relevant MeSH terms: Anemia; Thrombocytopenia; Anemia, Aplastic

Study Results

Participant Flow

Pre-assignment Detail	44 patients were consented, but 1 patient was removed before treatment with the investigational agent was initiated because an additional review of baseline bone marrow revealed that the patient was not eligible, because the patient had changes in the bone marrow inconsistent with a diagnosis of aplastic anemia.

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.
Period Title: Overall Study
STARTED	43
COMPLETED	43
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.
Overall Participants	44
Age (Count of Participants)
<=18 years	4 9.1%
Between 18 and 65 years	27 61.4%
>=65 years	13 29.5%
Sex: Female, Male (Count of Participants)
Female	19 43.2%
Male	25 56.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 25%
Not Hispanic or Latino	33 75%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 25%
White	21 47.7%
More than one race	3 6.8%
Unknown or Not Reported	8 18.2%

Outcome Measures

1. Primary Outcome

Title	The Portion of Drug Responders as Defined by Hematologic Improvements
Description	Defined as unilineage or multilineage recovery by 1 or more of the following: 1) platelet response (increase to 20 × 103/μL above baseline or stable platelet counts with transfusion independence for a minimum of 8 weeks in those who were transfusion dependent on entry into the protocol); (2) erythroid response (when pretreatment hemoglobin was <9 g/dL, defined as an increase in hemoglobin by 1.5 g/dL or, in transfused patients, a reduction in the units of packed red blood cell transfusions by an absolute number of at least 4 transfusions for 8 consecutive weeks, compared with the pretreatment transfusion number in the previous 8 weeks); and (3) neutrophil response (when pretreatment absolute neutrophil count [ANC] of <0.5 × 103/μL as at least a 100% increase in ANC, or an ANC increase >0.5 × 103/μL, and the toxicity profile as measured using Common Terminology Criteria for Adverse Events).
Time Frame	12-16 weeks

Outcome Measure Data

Analysis Population Description

All subjects who received Eltrombopag were analyzed.

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.
Measure Participants	43
Count of Participants [Participants]	17 38.6%

Adverse Events

Arm/Group Title	Eltrombopag
Arm/Group Description	Eltrombopag (Promacta): Subjects commenced eltrombopag at a dose of 50 mg, which was increased by 25 mg every 2 weeks if the platelet count had not increased by 20 × 103/µL, to a maximum dose of 150 mg.
All Cause Mortality
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	4/43 (9.3%)
Serious Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	16/43 (37.2%)
Blood and lymphatic system disorders
Anaemia	1/43 (2.3%)
Febrile neutropenia	7/43 (16.3%)
Neutropenia	1/43 (2.3%)
Thrombocytopenia	1/43 (2.3%)
Eye disorders
Conjunctival haemorrhage	2/43 (4.7%)
Gastrointestinal disorders
Abdominal pain	1/43 (2.3%)
Clostridium difficile colitis	1/43 (2.3%)
Gingivitis ulcerative	1/43 (2.3%)
General disorders
Drug eruption	1/43 (2.3%)
Pyrexia	1/43 (2.3%)
Hepatobiliary disorders
Hepatic neoplasm	1/43 (2.3%)
Infections and infestations
Bacteraemia	1/43 (2.3%)
Influenza	1/43 (2.3%)
Sepsis	3/43 (7%)
Urinary tract infection	1/43 (2.3%)
Investigations
Aspartate aminotransferase increased	1/43 (2.3%)
Vascular disorders
Deep vein thrombosis	1/43 (2.3%)
Hypotension	1/43 (2.3%)
Other (Not Including Serious) Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	38/43 (88.4%)
Blood and lymphatic system disorders
Febrile neutropenia	3/43 (7%)
Hyperbilirubinaemia	1/43 (2.3%)
Jaundice	1/43 (2.3%)
Petechiae	3/43 (7%)
Purpura	1/43 (2.3%)
Cardiac disorders
Chest pain	2/43 (4.7%)
Dizziness	4/43 (9.3%)
Dyspnoea	1/43 (2.3%)
Dyspnoea exertional	2/43 (4.7%)
Eye disorders
Cataract	1/43 (2.3%)
Conjunctival haemorrhage	2/43 (4.7%)
Dry eye	2/43 (4.7%)
Eye contusion	1/43 (2.3%)
Eye irritation	1/43 (2.3%)
Myopia	1/43 (2.3%)
Ocular hyperaemia	1/43 (2.3%)
Vision blurred	1/43 (2.3%)
Vitreous floaters	1/43 (2.3%)
Gastrointestinal disorders
Abdominal discomfort	2/43 (4.7%)
Abdominal injury	3/43 (7%)
Abdominal pain	4/43 (9.3%)
Anal fissure	1/43 (2.3%)
Anorectal discomfort	1/43 (2.3%)
Constipation	1/43 (2.3%)
Diarrhoea	4/43 (9.3%)
Dyspepsia	1/43 (2.3%)
Gastrointestinal disorder	1/43 (2.3%)
Gingival bleeding	2/43 (4.7%)
Gingival disorder	1/43 (2.3%)
Gingival swelling	1/43 (2.3%)
Lip ulceration	1/43 (2.3%)
Nausea	11/43 (25.6%)
Oral candidiasis	1/43 (2.3%)
Oropharyngeal pain	4/43 (9.3%)
Pelvic organ injury	1/43 (2.3%)
Pericoronitis	1/43 (2.3%)
Periodontal disease	1/43 (2.3%)
Tooth abscess	1/43 (2.3%)
Tooth injury	1/43 (2.3%)
Toothache	1/43 (2.3%)
Vomiting	3/43 (7%)
General disorders
Asthenia	1/43 (2.3%)
Axillary pain	1/43 (2.3%)
Catheter site pain	1/43 (2.3%)
Fatigue	11/43 (25.6%)
Induration	1/43 (2.3%)
Injection site infection	1/43 (2.3%)
Night sweats	1/43 (2.3%)
Pain	2/43 (4.7%)
Pyrexia	4/43 (9.3%)
Hepatobiliary disorders
Cholecystitis	1/43 (2.3%)
Hepatitis viral	1/43 (2.3%)
Immune system disorders
Hypersensitivity	1/43 (2.3%)
Rhinitis allergic	2/43 (4.7%)
Urticaria	2/43 (4.7%)
Infections and infestations
Cellulitis	1/43 (2.3%)
Herpes zoster	1/43 (2.3%)
Influenza	1/43 (2.3%)
Kidney infection	1/43 (2.3%)
Upper respiratory tract infection	8/43 (18.6%)
Viral infection	1/43 (2.3%)
Investigations
Alanine aminotransferase increased	3/43 (7%)
Aspartate aminotransferase increased	2/43 (4.7%)
Blood creatine phosphokinase increased	1/43 (2.3%)
Neutrophil count decreased	1/43 (2.3%)
Weight decreased	1/43 (2.3%)
Metabolism and nutrition disorders
Gout	1/43 (2.3%)
Osteoporosis	1/43 (2.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/43 (4.7%)
Back pain	2/43 (4.7%)
Bone pain	1/43 (2.3%)
Muscle spasms	5/43 (11.6%)
Musculoskeletal disorder	1/43 (2.3%)
Musculoskeletal pain	2/43 (4.7%)
Pain in extremity	2/43 (4.7%)
Piriformis syndrome	1/43 (2.3%)
Synovial cyst	1/43 (2.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cyst	1/43 (2.3%)
Seborrhoeic keratosis	1/43 (2.3%)
Skin cancer	1/43 (2.3%)
Nervous system disorders
Headache	7/43 (16.3%)
Insomnia	3/43 (7%)
Peripheral sensory neuropathy	1/43 (2.3%)
Psychiatric disorders
Anxiety	1/43 (2.3%)
Depressed mood	1/43 (2.3%)
Depression	1/43 (2.3%)
Libido decreased	1/43 (2.3%)
Mood altered	1/43 (2.3%)
Nightmare	1/43 (2.3%)
Personality disorder	1/43 (2.3%)
Renal and urinary disorders
Chromaturia	1/43 (2.3%)
Dysuria	1/43 (2.3%)
Pollakiuria	1/43 (2.3%)
Respiratory, thoracic and mediastinal disorders
Cough	3/43 (7%)
Epistaxis	2/43 (4.7%)
Nasal disorder	1/43 (2.3%)
Pulmonary haemorrhage	1/43 (2.3%)
Rhinorrhoea	1/43 (2.3%)
Skin and subcutaneous tissue disorders
Ingrowing nail	1/43 (2.3%)
Pruritus	2/43 (4.7%)
Rash	3/43 (7%)
Skin discolouration	1/43 (2.3%)
Skin lesion	1/43 (2.3%)
Skin ulcer	1/43 (2.3%)
Surgical and medical procedures
Platelet transfusion	1/43 (2.3%)
Tooth extraction	1/43 (2.3%)
Vascular disorders
Haematoma	1/43 (2.3%)
Hypotension	1/43 (2.3%)

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.