Efficacy and Safety of Eltrombopag In Patients With Severe and Very Severe Aplastic Anemia

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT01703169
• Collaborator: Novartis (Industry)
• Enrollment: 13
• Location: 1
• Arm: 1
• Duration (Months): 43
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The investigators hypothesis is that eltrombopag given to patients with moderate to very severe aplastic anemia will result in an increase in platelet counts. The investigators hypothesize that in patients with moderate to very severe aplastic anemia, treatment with eltrombopag will lead to fewer platelet transfusions, red blood cell transfusions, and fewer bleeding events. The investigators hypothesize that in patients with moderate to very severe aplastic anemia, eltrombopag will have an acceptable toxicity rate <3%, at doses that result in increased platelet counts. Finally the investigators hypothesize that plasma eltrombopag levels in peripheral blood will correlate with improved platelet counts.

Condition or Disease	Intervention/Treatment	Phase
Severe Aplastic Anemia; Very Severe Aplastic Anemia; Moderate Aplastic Anemia	Drug: Eltrombopag	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Eltrombopag In Patients With Severe and Very Severe Aplastic Anemia
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Eltrombopag Single arm study. Dose Escalation.	Drug: Eltrombopag; Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants With Platelet Response [up to 12 weeks]

   Defined as a stable platelet count of 50,000/μl or more during any 4 week period within the possible 12 weeks while on study,and including maximal platelet counts achieved in patients with moderate to very severe aplastic anemia.

Secondary Outcome Measures

1. Platelet Count Twice Baseline. [Between weeks 1-12.]

   Proportion of subjects who achieve platelet counts at least twice their baseline value at any point while on study medication, in patients with moderate to very severe aplastic anemia.

2. Hematology Labs [12 weeks]

   Association between eltrombopag use and response in hemoglobin, hematocrit, total white blood cell count, and absolute neutrophil count to be evaluate by maximal hemoglobin, hematocrit, total white blood cell count, and absolute neutrophil counts achieved in patients with moderate to very severe aplastic anemia

3. Number of Patients With AE to Measure Toxicity, Using NCI CTCAE [12 weeks]

   Evaluated weekly, up to 12 weeks. Association between eltrombopag use, dose, and tolerability in patients with moderate to very severe aplastic anemia

4. Characterization of the PK Profile of Eltrombopag in Patients With Moderate to Very Severe Aplastic Anemia. Evaluated With AUC, Cmax, Cmin, Tmax. [Weeks 2, 6 and 12]

   Samples will for PK analysis will collected as a trough level weeks 2, 6 and 12, prior to dose of eltrombopag. Additional PK level drawn at 2, 4 and 6 hours post-dose at the scheduled week 2 visit.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Able to provide written informed consent and any other authorizations required by local law (e.g., Protected Health Information [PHI])

• Have severe or very severe aplastic anemia, or moderate aplastic anemia with platelet counts that have dropped below 20,000/μl

• Have moderate, severe, or very severe aplastic anemia with moderate bleeding during or after a surgical procedure, (including bone marrow biopsy, lumbar puncture, thoracentesis, paracentesis, port placement, dermal biopsy) or minimal mucocutaneous bleeding otherwise noted

• Subjects with current or previous exposure to approved medications for the treatment of aplastic anemia will not be excluded; these include but may not be limited to, anti-thymocyte globulin (ATG), cyclosporine, corticosteroids, and G-CSF.

Exclusion Criteria:

• Have diagnosis of Fanconi anemia

• Have infection not adequately responding to appropriate therapy

• Have Paroxysmal Nocturnal Hemoglobinuria (PNH) clone size in neutrophils of greater than or equal to 50%

• Have known HIV positivity

• Have creatinine and/or blood urea nitrogen (BUN) ≥2 times the upper limit of normal

• Have serum bilirubin ≥ 1.5 times the upper limit of normal, or ≥4.0 times the upper limit of normal if the patient has been treated with ATG within three weeks of screening.

• Have AST and/or ALT ≥ 3 times the upper limit of normal

• Have hypersensitivity to eltrombopag or its components

• Have chemotherapy given less than or equal to 14 days prior to initiating the study medication. This does not include immunosuppressive agents and growth factor as described above

• Are female and are nursing or pregnant or are unwilling to take oral contraceptives or refrain from pregnancy if of childbearing potential

• Are unable to understand the investigational nature of the study or give informed consent

• Have a history of arterial or venous thrombosis within the last 1 year (excluding those due to indwelling lines)

• Have an ECOG performance status of 3 or greater

• Have had treatment with Campath within 6 months of entry into the study

• Have pre-existing cardiovascular disease (congestive heart failure with New York Heart Association [NYHA] grade III/IV), arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), unstable angina, or QTc > 450 msec (QTc 480 msec for subjects with bundle branch block), or myocardial infarction within the preceding 6 months) at study entry

• Have had other TPO-R agonists medication in the previous 4 weeks.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• University of Utah
• Novartis

Investigators

• Principal Investigator: George M Rodgers, M.D., University of Utah

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Utah
• ClinicalTrials.gov Identifier: NCT01703169
• Other Study ID Numbers: HCI54443; ELT115895
• First Posted: Oct 10, 2012
• Last Update Posted: Oct 19, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by University of Utah: severe aplastic anemia; very severe aplastic anemia; moderate aplastic anemia; bleeding
• Additional relevant MeSH terms: Anemia; Anemia, Aplastic

Study Results

Participant Flow

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Period Title: Overall Study
STARTED	13
COMPLETED	13
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Overall Participants	13
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 61.5%
>=65 years	5 38.5%
Sex: Female, Male (Count of Participants)
Female	5 38.5%
Male	8 61.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 7.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 76.9%
More than one race	0 0%
Unknown or Not Reported	2 15.4%
Region of Enrollment (Count of Participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants With Platelet Response
Description	Defined as a stable platelet count of 50,000/μl or more during any 4 week period within the possible 12 weeks while on study,and including maximal platelet counts achieved in patients with moderate to very severe aplastic anemia.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Measure Participants	13
Number (95% Confidence Interval) [proportion of participants]	0.23 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eltrombopag
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		The proportion of platelet response in a previous study (PMID:22762314) was 0.36 (9/25). The null hypothesis of no difference between the platelet response rate in this study and that of the previous study was tested using a two-sided exact test of binomial proportions. A p-value of 0.40 was obtained. The threshold for significance was 0.05.

2. Secondary Outcome

Title	Platelet Count Twice Baseline.
Description	Proportion of subjects who achieve platelet counts at least twice their baseline value at any point while on study medication, in patients with moderate to very severe aplastic anemia.
Time Frame	Between weeks 1-12.

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome variable.

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Measure Participants	0

3. Secondary Outcome

Title	Hematology Labs
Description	Association between eltrombopag use and response in hemoglobin, hematocrit, total white blood cell count, and absolute neutrophil count to be evaluate by maximal hemoglobin, hematocrit, total white blood cell count, and absolute neutrophil counts achieved in patients with moderate to very severe aplastic anemia
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome variable.

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Measure Participants	0

4. Secondary Outcome

Title	Number of Patients With AE to Measure Toxicity, Using NCI CTCAE
Description	Evaluated weekly, up to 12 weeks. Association between eltrombopag use, dose, and tolerability in patients with moderate to very severe aplastic anemia
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome variable.

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Measure Participants	0

5. Secondary Outcome

Title	Characterization of the PK Profile of Eltrombopag in Patients With Moderate to Very Severe Aplastic Anemia. Evaluated With AUC, Cmax, Cmin, Tmax.
Description	Samples will for PK analysis will collected as a trough level weeks 2, 6 and 12, prior to dose of eltrombopag. Additional PK level drawn at 2, 4 and 6 hours post-dose at the scheduled week 2 visit.
Time Frame	Weeks 2, 6 and 12

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome variable.

Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
Measure Participants	0

Adverse Events

Time Frame	Approximately 3 years.
Arm/Group Title	Eltrombopag
Arm/Group Description	Single arm study. Dose Escalation. Eltrombopag: Oral eltrombopag 150mg/day by mouth starting on Day 1 with dose modification over 12 weeks to a maximum of 300mg/day determined by platelet count
All Cause Mortality
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)
Serious Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	3/13 (23.1%)
Cardiac disorders
congestive heart failure	1/13 (7.7%)	1
Hepatobiliary disorders
cholecystitis	1/13 (7.7%)	1
Nervous system disorders
syncope	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Eltrombopag
	Affected / at Risk (%)	# Events
Total	13/13 (100%)
Blood and lymphatic system disorders
anemia	3/13 (23.1%)	13
petechiae	11/13 (84.6%)	18
transfusion reaction	1/13 (7.7%)	1
Cardiac disorders
arrhythmia	1/13 (7.7%)	1
chest pain	1/13 (7.7%)	2
Eye disorders
opacity	1/13 (7.7%)	1
scleral icterus	2/13 (15.4%)	2
Gastrointestinal disorders
abdominal pain	1/13 (7.7%)	2
constipation	1/13 (7.7%)	1
diarrhea	2/13 (15.4%)	4
dry mouth	1/13 (7.7%)	1
nausea	2/13 (15.4%)	3
rectal hemorrhage	1/13 (7.7%)	2
General disorders
aches/pains	2/13 (15.4%)	2
chills	1/13 (7.7%)	1
edema	4/13 (30.8%)	10
fatigue	7/13 (53.8%)	8
night sweats	1/13 (7.7%)	1
pain	5/13 (38.5%)	7
port leak	1/13 (7.7%)	1
Hepatobiliary disorders
spelnomegaly	1/13 (7.7%)	1
Infections and infestations
gum hypertrophy	1/13 (7.7%)	1
gum lesions	1/13 (7.7%)	1
otitis externa	1/13 (7.7%)	1
urinary tract infection	2/13 (15.4%)	3
Injury, poisoning and procedural complications
bruising	3/13 (23.1%)	5
Investigations
decreased lymphocyte count	3/13 (23.1%)	22
decreased neutrophil count	3/13 (23.1%)	17
thrombocytopenia	6/13 (46.2%)	24
Alkaline phosphatase increased	1/13 (7.7%)	1
elevated ALT	3/13 (23.1%)	10
elevated AST	3/13 (23.1%)	5
elevated bilirubin	4/13 (30.8%)	7
elevated creatinine	3/13 (23.1%)	8
hypoalbunemia	1/13 (7.7%)	1
weight gain	4/13 (30.8%)	4
Metabolism and nutrition disorders
dehydration	1/13 (7.7%)	1
hyperglycemia	1/13 (7.7%)	2
hypocalcemia	2/13 (15.4%)	5
hyponatremia	2/13 (15.4%)	5
Musculoskeletal and connective tissue disorders
back pain	2/13 (15.4%)	3
cramps	2/13 (15.4%)	2
Nervous system disorders
dizziness	1/13 (7.7%)	1
dysgeusia	2/13 (15.4%)	3
headache	1/13 (7.7%)	1
sciatica	1/13 (7.7%)	1
tremor	1/13 (7.7%)	1
Psychiatric disorders
anxiety	1/13 (7.7%)	1
confusion	1/13 (7.7%)	1
insomnia	2/13 (15.4%)	2
Renal and urinary disorders
dysuria	1/13 (7.7%)	1
pyelonephritis	1/13 (7.7%)	1
renal insufficiency	2/13 (15.4%)	2
Reproductive system and breast disorders
menorrhagia	2/13 (15.4%)	3
Respiratory, thoracic and mediastinal disorders
epistaxis	2/13 (15.4%)	2
hypoxia	2/13 (15.4%)	2
nasal congestion	2/13 (15.4%)	2
respiratory infection	1/13 (7.7%)	1
shortness of breath	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
purpura	5/13 (38.5%)	8
bronzing of the skin	2/13 (15.4%)	3
dry skin	1/13 (7.7%)	3
ecchymosis	2/13 (15.4%)	2
erythema	1/13 (7.7%)	1
facial hair growth	1/13 (7.7%)	1
jaundice	2/13 (15.4%)	2
mouth sores	2/13 (15.4%)	2
pallor	3/13 (23.1%)	3
rash	3/13 (23.1%)	4
thrush	1/13 (7.7%)	1
Vascular disorders
hematoma	1/13 (7.7%)	1
hot flashes	1/13 (7.7%)	1
hypertension	2/13 (15.4%)	2

Limitations/Caveats

Certain data regarding the primary outcome and adverse events were inadvertently not captured during the clinical investigation resulting in insufficient data for statistical analysis and publication.

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.