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NCT00260689

Three Immunosuppressive Treatment Regimens for Severe Aplastic Anemia

Completed Phase 2 Results posted Last updated 8 June 2017
What this trial tests

Phase 2 trial testing Anti-thymocyte globulin (rabbit) in Immunosuppresion in 136 participants. Completed in 4 May 2016.

Timeline
28 November 2005
Primary endpoint
4 May 2016
4 May 2016

Quick facts

Lead sponsorNational Heart, Lung, and Blood Institute (NHLBI)
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment136
Start date28 November 2005
Primary completion4 May 2016
Estimated completion4 May 2016
Sites1 location across United States

Drugs / interventions tested

Conditions studied

Sponsor

National Heart, Lung, and Blood Institute (NHLBI)

Who can join

2 and older, any sex, with Immunosuppresion or Thrombocytopenia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Hematologic Response Primary · 3 months

Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

GroupValue95% CI
Horse ATG/CsA Taper38
Rabbit ATG/CsA20
Alemtuzumab3
Hematologic Response Primary · 6 months

Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

GroupValue95% CI
Horse ATG/CsA Taper41
Rabbit ATG/CsA22
Alemtuzumab3
Hematologic Response Primary · 12 months

Hematologic response is defined as subjects having blood counts no longer meeting the standard ("Camitta") criteria for severe pancytopenia in Severe Aplastic Anemia, equivalent to 2 of the following values obtained on 2 serial blood count measurements at least one week apart at landmark time points (3, 6 and 12 months) * Absolute neutrophil count \> 500/ μL * Platelet count \> 20,000/ μL * Reticulocyte count \> 60,000/ μL Improvement in counts that are dependent upon exogenously administered growth factors or transfusion will not be considered as fulfilling response criteria.

GroupValue95% CI
Horse ATG/CsA Taper40
Rabbit ATG/CsA18
Alemtuzumab2

Adverse events — posted to ClinicalTrials.gov

Time frame: 5 years. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Horse ATG/CsA Taper
Serious: 7/60 (12%)
Deaths: 11/60
Rabbit ATG/CsA
Serious: 11/60 (18%)
Deaths: 18/60
Alemtuzumab
Serious: 6/16 (38%)
Deaths: 7/16

Serious adverse events (13 terms)

ReactionSystemHorse ATG/CsA TaperRabbit ATG/CsAAlemtuzumab
Infection (documented clinically or microbiologically with grade 3 or 4 neutropenia)Infections and infestations
Serum sicknessImmune system disorders
CNS hemorrhage/bleedingBlood and lymphatic system disorders
Edema: limbBlood and lymphatic system disorders
Cardiac troponin ICardiac disorders
HypertensionCardiac disorders
Supraventricular arrhythmiaCardiac disorders
Serum sickness/InfectionImmune system disorders
Infection without neutropeniaInfections and infestations
Creatinine (grade 2)Metabolism and nutrition disorders
HypokalemiaMetabolism and nutrition disorders
Arthralgia (joint pain)Musculoskeletal and connective tissue disorders
SeizuresNervous system disorders
Other adverse events (169 terms — click to expand)

ReactionSystemHorse ATG/CsA TaperRabbit ATG/CsAAlemtuzumab
Labeled infusion relatedImmune system disorders
HeadacheGeneral disorders
HypertensionCardiac disorders
Elevated LFT'sHepatobiliary disorders
diarrheaGastrointestinal disorders
feverGeneral disorders
Elevated t. biliHepatobiliary disorders
rigorsGeneral disorders
Serum sicknessImmune system disorders
Gingival hyperplasiaGastrointestinal disorders
NauseaGastrointestinal disorders
h creatinineMetabolism and nutrition disorders
Edema, lower legsCardiac disorders
h BPCardiac disorders
hypotensionCardiac disorders
HeartburnGastrointestinal disorders
vomitingGastrointestinal disorders
neutropenic feverGeneral disorders
C. diff colitisInfections and infestations
GingivitisInfections and infestations
Mouth soresInfections and infestations
Edema, anklesCardiac disorders
fluid overloadCardiac disorders
TachycardiaCardiac disorders
abdominal painGastrointestinal disorders
nausea + vomitingGastrointestinal disorders
abdominal painGeneral disorders
chest painGeneral disorders
weight gainGeneral disorders
h LFTMetabolism and nutrition disorders
HyperglicemiaMetabolism and nutrition disorders
hyperkalemiaMetabolism and nutrition disorders
i magnesiumMetabolism and nutrition disorders
InsomniaNervous system disorders
sobRespiratory, thoracic and mediastinal disorders
RashSkin and subcutaneous tissue disorders
edemaBlood and lymphatic system disorders
edema - mild lower extremityBlood and lymphatic system disorders
gingival hypertrophyBlood and lymphatic system disorders
HemolysisBlood and lymphatic system disorders

Most-reported serious reactions: Infection (documented clinically or microbiologically with grade 3 or 4 neutropenia), Serum sickness, CNS hemorrhage/bleeding, Edema: limb, Cardiac troponin I, Hypertension, Supraventricular arrhythmia, Serum sickness/Infection.

Data from ClinicalTrials.gov NCT00260689 adverse events section.

Sponsor's own 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 70% of patients, but most patients are not suitable candidates for hematopoietic stem cell transplantation (HSCT) due to advanced age or lack of a histocompatible donor. For these patients, comparable long term survival is attainable with immunosuppressive treatment with anti-thymocyte globulin (ATG) and cyclosporine (CsA). However, of those patients treated with horse ATG(h-ATG)/CsA, one quarter to one third will not respond, and about 50% of responders relapse. Auto-reactive T cells may be resistant to the effect of ATG/CsA (non-responders), while in others residual auto-reactive T cells expand post-treatment, leading to hematopoietic stem cell destruction and recurrent pancytopenia (relapse). As long term survival is correlated to response rates and robustness of hematopoietic recovery, novel immunosuppressive regimens that can achieve hematologic response and decrease relapse rates are needed. This trial will compare the effectiveness of three immunosuppressive regimens as first line therapies in patients with SAA with early hematologic response as the primary endpoint, as well as assess the role of extended CsA treatment after h-ATG in reducing numbers of late events of relapse and clonal evolution. Randomization is employed to obtain an equal distribution of subject to each arm; comparisons of early hematologic responses will be made among the rates observed among the three concurrent arms (rabbit-ATG \[r-ATG\] versus standard h-ATG; alemtuzumab vs standard h-ATG). For long course CSA, comparison of primary end points will be to well established historic relapse rate of 38% at 2-3 years and a cumulative rate of clonal evolution of 15%.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia.
    Scheinberg P, Nunez O, Weinstein B, Scheinberg P, et al · · 2011 · cited 368× · PMID 21812672 · DOI 10.1056/nejmoa1103975
  2. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study.
    Patel BA, Groarke EM, Lotter J, Shalhoub R, et al · · 2022 · cited 97× · PMID 34525188 · DOI 10.1182/blood.2021012130
  3. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia.
    Scheinberg P, Nunez O, Weinstein B, Scheinberg P, et al · · 2012 · cited 76× · PMID 22067384 · DOI 10.1182/blood-2011-05-352328
  4. Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia.
    Calado RT, Cooper JN, Padilla-Nash HM, Sloand EM, et al · · 2012 · cited 76× · PMID 22005790 · DOI 10.1038/leu.2011.272
  5. Calcineurin-NFAT signalling in myeloid leucocytes: new prospects and pitfalls in immunosuppressive therapy.
    Bendickova K, Tidu F, Fric J. · · 2017 · cited 52× · PMID 28606994 · DOI 10.15252/emmm.201707698
  6. Eltrombopag added to immunosuppression for children with treatment-naïve severe aplastic anaemia.
    Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, et al · · 2021 · cited 50× · PMID 33410523 · DOI 10.1111/bjh.17232
  7. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag.
    Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, et al · · 2022 · cited 44× · PMID 33910334 · DOI 10.3324/haematol.2021.278413
  8. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia.
    Groarke EM, Patel BA, Shalhoub R, Gutierrez-Rodrigues F, et al · · 2022 · cited 43× · PMID 35896822 · DOI 10.1038/s41375-022-01636-8

Verify or expand the search:

Other trials of Anti-thymocyte globulin (rabbit)

Trials testing the same drug.

Other recruiting trials for Immunosuppresion

Currently open trials in the same condition.

Other National Heart, Lung, and Blood Institute (NHLBI) trials

Trials by the same sponsor.

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