Eltrombopag With Standard Immunosuppression for Severe Aplastic Anemia
Study Details
Study Description
Brief Summary
Background:
-
Severe aplastic anemia is a rare and serious blood disorder. It happens when the immune system starts to attack the bone marrow cells. This causes the bone marrow to stop making red blood cells, platelets, and white blood cells. Standard treatment for this disease is horse-ATG and cyclosporine, which suppress the immune system and stop it from attacking the bone marrow. However, this treatment does not work in all people. Some people still have poor blood cell counts even after treatment.
-
Eltrombopag is a drug designed to mimic a protein in the body called thrombopoietin. It helps the body to make more platelets. It may also cause the body to make more red and white blood cells. Studies have shown that eltrombopag may be useful when added to standard treatment for severe aplastic anemia. It may help improve poor blood cell counts.
Objectives:
- To test the safety and effectiveness of adding eltrombopag to standard immunosuppressive therapy for severe aplastic anemia.
Eligibility:
- Individuals at least 2 years of age who have severe aplastic anemia that has not yet been treated.
Design:
-
Participants will be screened with a physical exam, medical history, and blood tests. Blood and urine samples will be collected.
-
Participants will start treatment with horse-ATG and cyclosporine. Treatment will be given according to the standard of care for the disease.
-
Cohort 1: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 6 months.
-
Cohort 2: After 14 days, participants will start taking eltrombopag. They will take eltrombopag for up to 3 months.
-
Cohort 3 and Extension Cohort: Participants will start taking eltrombopag on Day 1. They will take eltrombopag for up to 6 months.
-
Participants may receive other medications to prevent infections during treatment.
-
Treatment will be monitored with frequent blood tests. Participants will also fill out questionnaires about their symptoms and their quality of life.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic bone marrow transplantation offers the opportunity for cure in younger patients, but most are not suitable candidates for transplantation due to advanced age or lack of a histocompatible donor. Comparable long-term survival in SAA is attainable with immunosuppressive treatment with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA). However, of those patients treated with h-ATG/CsA, one quarter to one third will not respond, and 30-40% of responders relapse. The majority of the hematologic responses observed following initial h-ATG/CsA are partial, with only a few patients achieving normal blood counts. Furthermore, analysis of our own extensive clinical data suggests that poor blood count responses to a single course of ATG (non-robust responders), even when transfusion-independence is achieved, predicts a worse prognosis than when robust hematologic improvement is achieved (protocol 90-H-0146). The explanation for partial recovery and relapse are not fully understood, but incomplete elimination of auto-reactive T cells and insufficient stem cell reserve are both possible. Furthermore, 10-15% of SAA patients treated with standard immunosuppression will develop an abnormal karyotype in follow-up, with monosomy 7 being most common, which portends progression to myelodysplasia and leukemia. In contrast, malignant clonal evolution is rare in complete responders to immunosuppression. Although horse ATG/CsA represented a major advance in the treatment of SAA, refractoriness, incomplete responses, relapse, and clonal evolution limit the success of this modality. Thus, newer regimens are needed to address these limitations, and provide a better alternative to stem cell transplantation.
One approach to augment the quality of hematologic responses is to improve underlying stem cell function. Previous attempts to improve responses in SAA with hematopoietic cytokines including erythropoietin, G-CSF, and stem cell factor, have failed. Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. In addition, TPO also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. Eltrombopag (Promacta ), an oral 2nd generation small molecule TPO-agonist, is currently approved for treatment of chronic immune thrombocytopenic purpura (ITP), chronic hepatitis C-associated thrombocytopenia, and severe aplastic anemia who have had an insufficient response to immunosuppressive therapy. Eltrombopag increases platelets in healthy subjects and in thrombocytopenic patients with chronic ITP and hepatitis C virus (HCV) infection. Our Branch recently completed a pilot study of eltrombopag in refractory SAA. We saw encouraging clinical results in a cohort of patients who have failed on average two prior immunosuppressive regimens (Olnes et al. ASH Annual Meeting Abstracts, San Diego, CA, 2011, oral presentation and N Engl J Med 2012;367:11-9.1). Of the twenty-five SAA patients treated with eltrombopag by mouth for three months, eleven (44%) patients met protocol criteria of clinically meaningful hematologic responses, without significant toxicity. Nine patients demonstrated an improvement in thrombocytopenia (>20k/ L increase or transfusion independence), hemoglobin improved in two patients (>1.5g/dL or achieved transfusion independence, and four patients had a significant response in their neutrophil count. When responders continued the drug beyond three months, the hematologic response to eltrombopag increased; a trilineage response was observed in four patients, and a bilineage response occurred in another four, with median follow-up of 13 months. These results suggest that stem cell depletion, a major component of the pathophysiology of SAA, might be directly addressed by eltrombopag administration. The aim of the current study would be to improve the hematologic response rate and its quality, as well as prevent late complications such as relapse and clonal progression, by addition of eltrombopag to standard immunosuppressive therapy.
This trial will evaluate the safety and efficacy of combining eltrombopag with standard hATG/CSA as first line therapy in patients with SAA. The primary endpoint will be the rate of complete hematologic response at six months. Secondary endpoints are relapse, robust hematologic blood count recovery at 3, 6, and 12 months, survival, clonal evolution to myelodysplasia and leukemia, marrow stem cell content and hematological response of relapse patients that re-start treatment.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1: hATG, CsA, EPAG Day 14 to Month 6 Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6 |
Drug: Cohort 1: hATG, CsA, EPAG Day 14 to Month 6
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6
Other Names:
|
| Experimental: Cohort 2: hATG, CsA, EPAG Day 14 to Month 3 Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3 |
Drug: Cohort 2: hATG, CsA, EPAG Day 14 to Month 3
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3
Other Names:
|
| Experimental: Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6 Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6 |
Drug: Cohort 3: hATG, CsA (dose reduced), EPAG day 1 to month 6
hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6
Other Names:
|
| Experimental: Extrension Cohort Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6 |
Drug: Extension Cohort
Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18 months, and receive eltrombopag day 1 to month 6
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Rate of Complete Hematologic Response [6 months]
Rate of complete hematologic response at six months for cohorts 1, 2 and 3.
Secondary Outcome Measures
- Rate of Response at 3 and 12 Months Then Yearly; Rate of Relapse; Rate of Clonal Evolution to PNH, MDS and AML; Rate of Survival; Rate of Response for Relapse Subjects That Re-start Treatment and Effects of CsA Dose Starting at Month 6 to Month 24. [3 months to 5 years]
Secondary endpoints will also be evaluated for the study to include: (a) hematological response at 3 and 12 months and yearly thereafter; (b) relapse (c) clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia; (d) survival; (e) health-related quality of life; (f) hematological response of relapse subjects that re-start treatment; and (g) affects of a 2.0mg/kg/day CsA dose starting month 6 for 18 months until month 24 on the rate of relapse of subjects deemed responders at month 6.
Eligibility Criteria
Criteria
-INCLUSION CRITERIA:
- Severe aplastic anemia characterized by Bone marrow cellularity less than 30 percent (excluding lymphocytes)
AND
At least two of the following:
-
Absolute neutrophil count less than 500/microL
-
Platelet count less than 20,000/microL
Absolute reticulocyte count less than 60,000/microL
-
Age greater than or equal to 2 years old
-
Weight greater than 12 kg
EXCLUSION CRITERIA:
-
Known diagnosis of Fanconi anemia
-
Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry. Patients with super severe neutropenia (ANC less than 200 /microL) will not be excluded initially if cytogenetics are not available or pending. If evidence of a clonal disorder consistent with myelodysplasia is later identified, the patient will go off study.
-
Prior immunosuppressive therapy with any ATG, alemtuzumab, or high dose cyclophosphamide
-
SGOT or SGPT >5 times the upper limit of normal
-
Subjects with known liver cirrhosis in severity that would preclude tolerability of cyclosporine and eltrombopag as evidenced by albumin < 35g/L
-
Hypersensitivity to eltrombopag or its components
-
Infection not adequately responding to appropriate therapy
-
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
-
Potential subjects with cancer who are on active chemotherapeutic treatment or who take drugs with hematological effects will not be eligible
-
Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during the course of this study
-
Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent.
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)
- Novartis
Investigators
- Principal Investigator: Neal S Young, M.D., National Heart, Lung, and Blood Institute (NHLBI)
Study Documents (Full-Text)
More Information
Additional Information:
Publications
- Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017 Apr 20;376(16):1540-1550. doi: 10.1056/NEJMoa1613878.
- 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.
- Young NS, Leonard E, Platanias L. Lymphocytes and lymphokines in aplastic anemia: pathogenic role and implications for pathogenesis. Blood Cells. 1987;13(1-2):87-100. Review.
- Zoumbos NC, Gascón P, Djeu JY, Trost SR, Young NS. Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med. 1985 Jan 31;312(5):257-65.
- 120150
- 12-H-0150
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | Recruitment has yet to be completed for the Extension Cohort, which was added to better assess the secondary endpoints |
| Arm/Group Title | hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 |
|---|---|---|---|
| Arm/Group Description | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6 hATG/CsA /eltrombopag -Cohort 1: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3 hATG/CsA /eltrombopag Cohort 2: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6 hATG/CsA /eltrombopag Cohort 3: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6 |
| Period Title: Overall Study | |||
| STARTED | 30 | 31 | 31 |
| COMPLETED | 13 | 17 | 18 |
| NOT COMPLETED | 17 | 14 | 13 |
Baseline Characteristics
| Arm/Group Title | hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 | Total |
|---|---|---|---|---|
| Arm/Group Description | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6 hATG/CsA /eltrombopag -Cohort 1: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3 hATG/CsA /eltrombopag Cohort 2: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6 hATG/CsA /eltrombopag Cohort 3: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6 | Total of all reporting groups |
| Overall Participants | 30 | 31 | 31 | 92 |
| Age (Count of Participants) | ||||
| <=18 years |
5
16.7%
|
6
19.4%
|
8
25.8%
|
19
20.7%
|
| Between 18 and 65 years |
20
66.7%
|
23
74.2%
|
18
58.1%
|
61
66.3%
|
| >=65 years |
5
16.7%
|
2
6.5%
|
5
16.1%
|
12
13%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
14
46.7%
|
14
45.2%
|
14
45.2%
|
42
45.7%
|
| Male |
16
53.3%
|
17
54.8%
|
17
54.8%
|
50
54.3%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
6
20%
|
2
6.5%
|
9
29%
|
17
18.5%
|
| Not Hispanic or Latino |
24
80%
|
29
93.5%
|
22
71%
|
75
81.5%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
3
10%
|
4
12.9%
|
1
3.2%
|
8
8.7%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
5
16.7%
|
7
22.6%
|
4
12.9%
|
16
17.4%
|
| White |
16
53.3%
|
19
61.3%
|
23
74.2%
|
58
63%
|
| More than one race |
3
10%
|
0
0%
|
3
9.7%
|
6
6.5%
|
| Unknown or Not Reported |
3
10%
|
1
3.2%
|
0
0%
|
4
4.3%
|
| Region of Enrollment (participants) [Number] | ||||
| United States |
30
100%
|
31
100%
|
31
100%
|
92
100%
|
Outcome Measures
| Title | Rate of Complete Hematologic Response |
|---|---|
| Description | Rate of complete hematologic response at six months for cohorts 1, 2 and 3. |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 |
|---|---|---|---|
| Arm/Group Description | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6 hATG/CsA /eltrombopag -Cohort 1: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3 hATG/CsA /eltrombopag Cohort 2: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6 hATG/CsA /eltrombopag Cohort 3: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6 |
| Measure Participants | 30 | 31 | 31 |
| No Response |
3
10%
|
2
6.5%
|
1
3.2%
|
| Partial Response |
14
46.7%
|
19
61.3%
|
11
35.5%
|
| Complete Response |
10
33.3%
|
8
25.8%
|
18
58.1%
|
| Off study/Not Evaluable |
3
10%
|
2
6.5%
|
1
3.2%
|
| Title | Rate of Response at 3 and 12 Months Then Yearly; Rate of Relapse; Rate of Clonal Evolution to PNH, MDS and AML; Rate of Survival; Rate of Response for Relapse Subjects That Re-start Treatment and Effects of CsA Dose Starting at Month 6 to Month 24. |
|---|---|
| Description | Secondary endpoints will also be evaluated for the study to include: (a) hematological response at 3 and 12 months and yearly thereafter; (b) relapse (c) clonal evolution to PNH, clonal chromosomal population in bone marrow, myelodysplasia by morphology, or acute leukemia; (d) survival; (e) health-related quality of life; (f) hematological response of relapse subjects that re-start treatment; and (g) affects of a 2.0mg/kg/day CsA dose starting month 6 for 18 months until month 24 on the rate of relapse of subjects deemed responders at month 6. |
| Time Frame | 3 months to 5 years |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title |
|---|
| Arm/Group Description |
Adverse Events
| Time Frame | 6 months | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 | |||
| Arm/Group Description | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 6 hATG/CsA /eltrombopag -Cohort 1: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 6 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6, and receive eltrombopag day 14 to month 3 hATG/CsA /eltrombopag Cohort 2: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months, eltrombopag (experimental) administered Day 14 to month 3 | Receive horse ATG days 1- 4, receive CsA day 1 to month 6 at higher dose, then reduced dose for 18months, and receive eltrombopag day 1 to month 6 hATG/CsA /eltrombopag Cohort 3: hATG (standard of care) administered for 4 days, CsA (standard of care) administered starting day 1 for 6 months at higher dose, then reduced dose for 18 months, eltrombopag (experimental) administered Day 1 to month 6 | |||
All Cause Mortality |
||||||
| hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/30 (3.3%) | 0/31 (0%) | 0/31 (0%) | |||
Serious Adverse Events |
||||||
| hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 17/30 (56.7%) | 15/31 (48.4%) | 14/31 (45.2%) | |||
| Blood and lymphatic system disorders | ||||||
| Anemia | 0/30 (0%) | 0 | 2/31 (6.5%) | 2 | 0/31 (0%) | 0 |
| Idiopathic Thrombocytopenic Purpura | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Febrile neutropenia | 4/30 (13.3%) | 5 | 5/31 (16.1%) | 8 | 1/31 (3.2%) | 1 |
| Cardiac disorders | ||||||
| Heart failure | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Myocardial infarction | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Pericardial tamponade | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal pain | 1/30 (3.3%) | 1 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Appendicitis | 2/30 (6.7%) | 2 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Gastritis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Paraesophageal hernia, post elective laparascopic surgery | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Viral gastroenteritis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Colitis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Ileal hemorrhage | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Lower gastrointestinal hemorrhage | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| General disorders | ||||||
| Fever | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Edema limbs | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Pain (heel) | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Infusion related reaction | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Immune system disorders | ||||||
| Anaphylaxis (Red blood cells transfusion reaction) | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Autoimmune Hemolyitic Anemia Disorder | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Infusion related reaction | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Serum sickness | 0/30 (0%) | 0 | 2/31 (6.5%) | 2 | 4/31 (12.9%) | 4 |
| Infections and infestations | ||||||
| Anorectal infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Catheter related infection | 0/30 (0%) | 0 | 2/31 (6.5%) | 2 | 0/31 (0%) | 0 |
| Cellulitis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Stenotrophomanas maltophilia | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Periodontal abscess | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Lung Infection | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 2 |
| Sinusitis (Invasive Fungal Infection: Dematiaceous of nare/sinus) | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Pseudomonas aeruginosa Bacteremia | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Staphylococcus Epidermidis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Lung infection | 1/30 (3.3%) | 1 | 1/31 (3.2%) | 2 | 1/31 (3.2%) | 1 |
| Pneumonia | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Sepsis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Skin infection | 1/30 (3.3%) | 2 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Tooth infection | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Upper Respiratory Infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Upper respiratory infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Urinary tract infection | 0/30 (0%) | 0 | 2/31 (6.5%) | 2 | 0/31 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||
| Humerus and Tibia Fracture | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Hip fracture, left | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Hip fracture | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Investigations | ||||||
| Alanine aminotransferase increased | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Aspartate aminotransferase increased | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Hyperkalemia | 1/30 (3.3%) | 2 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Hypoglycemia | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Muscle weakness lower limb | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Temperomandibular joint disease | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Rhabdomyolisis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Weakness | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Squamous Cell Carcinoma, keratocantoma type | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Basal Cell Carcinoma | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Nervous system disorders | ||||||
| Amnesia | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Dizziness | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Encephalopathy | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Headache | 2/30 (6.7%) | 3 | 1/31 (3.2%) | 2 | 0/31 (0%) | 0 |
| Syncope | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Psychiatric disorders | ||||||
| Depression | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 2 |
| Acute kidney injury | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Renal calculi | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Pulmonary edema | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Cough | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Volume overload | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Acute Hypoxic Respiratory Failure | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Sinusitis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Rash maculo-papular | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Skin ulceration | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Laceration | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Vascular disorders | ||||||
| Hematoma | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Hypertension | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Hypotension | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Thromboembolic event | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| hATG, CsA, EPAG Day 14 to Month 6 | hATG, CsA, EPAG Day 14 to Month 3 | hATG, CsA (Dose Reduced), EPAG Day 1 to Month 6 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 30/30 (100%) | 31/31 (100%) | 31/31 (100%) | |||
| Blood and lymphatic system disorders | ||||||
| Febrile neutropenia | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 5/31 (16.1%) | 5 |
| Cardiac disorders | ||||||
| Atrial fibrillation | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Ear and labyrinth disorders | ||||||
| Fluid in the mastoid and inner ear | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Pressure behind ear | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Ear pain | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| External ear inflammation | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Otitis media | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Eye disorders | ||||||
| Blurred vision | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Conjunctivitis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Eye discoloration | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Subconjunctival hemorrhage eye | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Blindness transient | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Photophobia | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Retinopathy | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Scleral disorder | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Vitreous hemorrhage | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal pain | 2/30 (6.7%) | 2 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Cholecystitis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Colitis, intermittent (C. difficile) | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Constipation | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Diarrhea | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Gastroesophageal reflux disease | 2/30 (6.7%) | 2 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Gallstones | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Mucositis oral | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Nausea | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Oral hemorrhage | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Toothache | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Vomiting | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| General disorders | ||||||
| Edema limbs | 2/30 (6.7%) | 2 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Fever | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Infusion related reaction | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Non-cardiac chest pain | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Immune system disorders | ||||||
| Allergic reaction | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Infections and infestations | ||||||
| Catheter related infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| HSV mucositis: Mouth sore (aphthous ulcer) | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Oral candidiasis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Parainfluenzae virus infection | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Staphylococcus test positive | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Culture stool positive | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Lip infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Lung infection | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Meningitis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Paronychia | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Pharyngitis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Skin infection | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 1/31 (3.2%) | 1 |
| Skin infection (Folliculitis) | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Upper respiratory infection | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Urinary tract infection | 1/30 (3.3%) | 1 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Investigations | ||||||
| Alanine aminotransferase increased | 3/30 (10%) | 3 | 8/31 (25.8%) | 17 | 11/31 (35.5%) | 17 |
| Alanine aminotransferase increased (intermittent) | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Aspartate aminotransferase increased | 2/30 (6.7%) | 2 | 3/31 (9.7%) | 4 | 7/31 (22.6%) | 8 |
| Blood bilirubin increased | 9/30 (30%) | 10 | 9/31 (29%) | 10 | 5/31 (16.1%) | 8 |
| Blood bilirubin increased (intermittent) | 2/30 (6.7%) | 3 | 4/31 (12.9%) | 4 | 1/31 (3.2%) | 1 |
| CPK increased | 1/30 (3.3%) | 1 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Hypokalemia | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 2/31 (6.5%) | 2 |
| Hyponatremia | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Weight gain | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Gout | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Smear cervix abnormal | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Basal Cell Carcinoma | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Squamous Cell Carcinoma | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Nervous system disorders | ||||||
| Headache | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Memory impairment | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Radiculitis | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Seizure | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Psychiatric disorders | ||||||
| Depression | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Insomnia | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Suicidal ideation | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Acute kidney injury | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Urine discoloration | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Reproductive system and breast disorders | ||||||
| Gynecomastia | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Ovarian hemorrhage | 0/30 (0%) | 0 | 1/31 (3.2%) | 1 | 0/31 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Nasal congestion | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Pleural effusion | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Sore throat | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Hirsutism | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Papulopustular rash | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Pruritus | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Rash acneiform | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Actinic keratosis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Actinic elastosis | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 0/31 (0%) | 0 |
| Onychocryptosis | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Skin hyperpigmentation | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 2/31 (6.5%) | 2 |
| Surgical and medical procedures | ||||||
| Debridement of nasal septum | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Vascular disorders | ||||||
| Hypertension | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 3 |
| Hypotension | 1/30 (3.3%) | 1 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
| Thromboembolic event | 0/30 (0%) | 0 | 0/31 (0%) | 0 | 1/31 (3.2%) | 1 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Neal S. Young, M.D, NIH Principal Investigator |
|---|---|
| Organization | National Heart Lung and Blood Institute (NHLBI) |
| Phone | 301-496-5093 |
| youngns@nhlbi.nih.gov |
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