A Phase 2 interventional study of Anti-thymocyte globulin (rabbit) and Anti-thymocyte globulin (horse) in Immunosuppresion, Thrombocytopenia and Pancytopenia, sponsored by National Heart, Lung, and Blood Institute (NHLBI). Completed at 1 site in United States. Open to participants aged 2 Years and older. Per ClinicalTrials.gov, last updated 2017-06-08.
Sponsored by National Heart, Lung, and Blood Institute (NHLBI) · Phase 2, Interventional, and Treatment
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%.
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%.
In the original design subjects were randomized to one of three different regimens: h-ATG + 6 months CsA followed by an 18 month CsA taper; r-ATG + 6 months CsA; or alemtuzumab (Campath). Subjects failing to respond to r-ATG will be crossed over to alemtuzumab (Campath), and subjects failing alemtuzumab (Campath) will be crossed over to r-ATG. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath) as salvage therapy.
The Campath arm was closed to new accrual for lack of efficacy on 4/10/2008. Subsequently, new accruals will be randomized to h-ATG + 6 months CsA followed by an 18 month CsA taper or r-ATG + 6 months CsA. Subjects failing to respond to h-ATG + CsA taper will go off study and be evaluated for eligibility for a second course of immunosuppression on companion protocol 03-H-0249, which similarly randomizes subjects between r-ATG and alemtuzumab (Campath ) as salvage therapy. Subjects who fail to respond to r-ATG + 6 months CsA will be offered treatment with h-ATG as salvage therapy or will go off-study to alternative treatments or stem cell transplant (from sibling or unrelated donor).
The primary endpoint will be hematologic response, defined as no longer meeting criteria for SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at 6 months, response at 3 and 12 months, survival, clonal evolution to PNH, myelodysplasia and acute leukemia. Long-course CSA will be assessed separately for its efficacy in reducing late events of relapse and evolution by comparison to historical control data.
482 studies on the registry are indexed under Thrombocytopenia; 100 are open to participants now.
This study's enrollment of 136 is above the median of 54 across 334 interventional studies indexed under Thrombocytopenia.
Browse Thrombocytopenia studies →National Heart, Lung, and Blood Institute (NHLBI) is the lead sponsor of 1,143 studies on the registry; 71 are open to participants now.
Of its 58 completed or terminated interventional studies of FDA-regulated products, 51 (88%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Severe aplastic anemia characterized by bone marrow cellularity less than 30% (excluding lymphocytes) and at least two of the following:
EXCLUSION CRITERIA:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Absolute neutrophil count (ANC)
The number of neutrophils, white blood cells that help fight infection, in a given amount of blood. Too few raises the risk of infection.
It is a count, not a percentage of the white cells. Limits are written in units that mean the same: ≥ 1.5 × 10⁹/L is ≥ 1,500 per mm³ (µL). Each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Platelets
Blood cells that help blood clot. Too few raises the risk of bleeding and bruising. A usual adult range is about 150–400 × 10⁹/L (150,000–400,000 per µL); each lab has its own reference range.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Immunosuppression
A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.
Read whether the line is about a condition or about medicines, and which medicines and doses it means.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
HIV
The human immunodeficiency virus, which weakens the immune system.
Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
h-ATG (Anti-thymocyte globulin (horse)) + 6 months CsA (Cyclosporine) followed by an 18 month CsA taper
Biological: Anti-thymocyte globulin (horse) · Drug: Cyclosporine
r-ATG (Anti-thymocyte globulin (rabbit)) + 6 months CsA (Cyclosporine)
Biological: Anti-thymocyte globulin (rabbit) · Drug: Cyclosporine
Alemtuzumab administered for 10 days
Drug: Alemtuzumab
Also known as: Campath
Hematologic Response
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.
Time frame: 3 months
Hematologic Response
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.
Time frame: 6 months
Hematologic Response
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.
Time frame: 12 months
| Milestone | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Started | 60 | 60 | 16 |
| Completed | 19 | 11 | 1 |
| Not completed | 41 | 49 | 15 |
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.
| Participants | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Hematologic Response | 38 | 20 | 3 |
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.
| Participants | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Hematologic Response | 41 | 22 | 3 |
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.
| Participants | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Hematologic Response | 40 | 18 | 2 |
Collected over 5 years. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Horse ATG/CsA Taper | 11/60 (18.3%) | 7/60 (11.7%) | 36/60 (60%) |
| Rabbit ATG/CsA | 18/60 (30%) | 11/60 (18.3%) | 39/60 (65%) |
| Alemtuzumab | 7/16 (43.8%) | 6/16 (37.5%) | 15/16 (93.8%) |
| Event | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Infection (documented clinically or microbiologically with grade 3 or 4 neutropenia)Infections and infestations | 3/60 | 1/60 | 5/16 |
| Serum sicknessImmune system disorders | 2/60 | 4/60 | 0/16 |
| HypokalemiaMetabolism and nutrition disorders | 0/60 | 0/60 | 1/16 |
| CNS hemorrhage/bleedingBlood and lymphatic system disorders | 0/60 | 1/60 | 0/16 |
| Edema: limbBlood and lymphatic system disorders | 0/60 | 1/60 | 0/16 |
| Cardiac troponin ICardiac disorders | 1/60 | 0/60 | 0/16 |
| HypertensionCardiac disorders | 0/60 | 1/60 | 0/16 |
| Supraventricular arrhythmiaCardiac disorders | 0/60 | 1/60 | 0/16 |
| Serum sickness/InfectionImmune system disorders | 0/60 | 1/60 | 0/16 |
| Infection without neutropeniaInfections and infestations | 0/60 | 1/60 | 0/16 |
| Event | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab |
|---|---|---|---|
| Labeled infusion relatedImmune system disorders | 28/60 | 31/60 | 15/16 |
| Elevated LFT'sHepatobiliary disorders | 9/60 | 9/60 | 5/16 |
| HypertensionCardiac disorders | 8/60 | 9/60 | 3/16 |
| HeadacheGeneral disorders | 10/60 | 6/60 | 1/16 |
| diarrheaGastrointestinal disorders | 5/60 | 8/60 | 0/16 |
| Gingival hyperplasiaGastrointestinal disorders | 2/60 | 4/60 | 2/16 |
| feverGeneral disorders | 6/60 | 5/60 | 0/16 |
| Elevated t. biliHepatobiliary disorders | 5/60 | 6/60 | 0/16 |
| rigorsGeneral disorders | 5/60 | 2/60 | 0/16 |
| Serum sicknessImmune system disorders | 2/60 | 5/60 | 0/16 |
| Age, Categorical(Participants) | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab | Total |
|---|---|---|---|---|
| <=18 years | 14 | 21 | 4 | 39 |
| Between 18 and 65 years | 38 | 35 | 8 | 81 |
| >=65 years | 8 | 4 | 4 | 16 |
| Sex: Female, Male(Participants) | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab | Total |
|---|---|---|---|---|
| Female | 27 | 23 | 4 | 54 |
| Male | 33 | 37 | 12 | 82 |
| Ethnicity (NIH/OMB)(Participants) | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab | Total |
|---|---|---|---|---|
| Hispanic or Latino | 9 | 13 | 7 | 29 |
| Not Hispanic or Latino | 50 | 44 | 9 | 103 |
| Unknown or Not Reported | 1 | 3 | 0 | 4 |
| Race (NIH/OMB)(Participants) | Horse ATG/CsA Taper | Rabbit ATG/CsA | Alemtuzumab | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 | 0 |
| Asian | 5 | 2 | 1 | 8 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 | 0 |
| Black or African American | 15 | 20 | 1 | 36 |
| White | 29 | 24 | 7 | 60 |
| More than one race | 2 | 0 | 0 | 2 |
| Unknown or Not Reported | 9 | 14 | 7 | 30 |
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Studies of the drugs tested here: Thymoglobulin · Antilymphocyte Serum · Cyclosporine · Alemtuzumab
National Heart, Lung, and Blood Institute (NHLBI) →