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出境医 / 临床实验 / A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia: (FluCAB-Prime)

A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia: (FluCAB-Prime)

Study Description
Brief Summary:
Severe and very severe aplastic anemia are life threatening disorders for which allogeneic stem cell transplant is only curative treatment. However, matched sibling donor (MSD) is available in only 25-35% cases. Pakistan has a population of around 203 million but there is no donor registry available so there is no option available for matched unrelated donor (MUD) transplants . Haploidentical transplant represents only curative option for patients lacking MSD. Protocols involving post transplant cyclophosphamide require Total body irradiation (TBI) and utilize peripheral blood stem cell(PBSC) as graft source. TBI is not available in most of transplant centres across Pakistan due to lack of availability , cost and lack of expertise. The investigators have conceived a novel TBI free conditioning regimen to be used for haplo-identical Hemtopoeitic stem cell transplant in acquired aplastic anemia patients

Condition or disease Intervention/treatment Phase
Aplastic Anemia Idiopathic Drug: Haploidentical HSCT using TBI free regimen, ''ATG'' with ''Post transplant cyclophosphamide'' Phase 2

Detailed Description:
Aplastic anemia is considered to be a rare and heterogenous disease with incidence of 1-2 per million in western countries. Data from Asian studies show a 3-4 fold higher incidence.Majority of newly diagnosed aplastic anemia patients are younger and in Armed forces bone marrow transplant cohort of 1324 patients 64 % patient are younger than 24 years of age and 87% patients younger than 40 years (unpublished data).There is no donor registry in Pakistan and patients lacking sibling match donor cannot proceed to stem cell transplant due lack of matched unrelated donors. Horse antithymocyte globulin is not available currently in Pakistan and response to Rabbit antithymocyte globulin is dismal as shown in number of international studies. So haploidentical stem cell transplant remains only curative option for patients lacking Matched sibling donor. Currently there are 2 major platforms used for haplo-identical stem cell transplant. Post transplant cyclophosphamide based using TBI and haplo regimen of Peking university. TBI is not available for most of our patients in Pakistan due to cost,non-availability and lack of expertise. The investigators have formulated a novel TBI free regimen incorporating Busulphan, antithymocyte globulin and using co-primed bone marrow and peripheral blood harvest to minimize graft-versus-host disease and facilitate engraftment. Post transplant cyclophosphamide, Cyclosporine and mycophenolate mofetil will be used for graft-versus-host disease prophylaxis
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Novel TBI Free Conditioning Protocol for Haploidentical Hematopoeitic Stem Cell Transplant in Acquired Aplastic Anemia
Actual Study Start Date : July 12, 2018
Estimated Primary Completion Date : December 30, 2020
Estimated Study Completion Date : June 30, 2021
Arms and Interventions
Arm Intervention/treatment
Experimental: TBI free Haploidentical HSCT
Recipients will receive a reduced intensity conditioning regimen of ''Fludarabine'' 30 mg/m2 IV daily from day -7 to -3, ''Cyclophosphamide'' 14.5-30 mg/kg IV daily on day -6 and -5 , ''rabbit Antithymocyte globulin'' 5 mg /kg/day from day -6 to day-3; ''Busulphan'' IV 3.2 mg per kg/day in 02 divided doses on day -3 and day-2, ''Granulocyte Colony Stimulating factor primed Bone marrow harvest'' and/OR ''PBSC'' graft on day 0 and day +1 respectively and Graft versus host disease prophylaxis with ''post-transplant cyclophosphamide'' administered at a dose of 50mg/kg/day given daily on days +3 and +5 post-transplant and ''cyclosporine'' from day +5, ''mycophenolate mofetil'' from day+5 to day+35.
 Drug: Haploidentical HSCT using TBI free regimen, ''ATG'' with ''Post transplant cyclophosphamide''
''Busulphan'' will be used in place of ''TBI'' in equivalent myelotoxic dose to facilitate engraftment , ''ATG'' will be used to reduce GVHD and facilitate engraftment while ''combine PBSC'' and/OR ''Bone marrow harvest'' will be used
Other Name: ''Combined BMH'' and ''PBSC harvest''
Outcome Measures
Primary Outcome Measures :
  1. Number of Participants with overall survival [ Time Frame: from the date of transplant to 1 year post transplant ]
    overall survival is defined as the time interval from date of transplant to death or to last follow-up, whichever occurs first.


Secondary Outcome Measures :
  1. Number of Participants with Disease free survival [ Time Frame: from the date of transplant to 1 year post transplant ]
    from time of transplant to death or last follow up

  2. Time of Neutrophil engraftment [ Time Frame: from the date of transplant to 10 to day 28 post transplant ]
    first of 3 consecutive days with Absolute neutrophil count> 0.5

  3. Frequency of Graft versus host disease [ Time Frame: from the date of transplant to acute upto 100 day post transplant, chronic >100 days post transplant ]
    as per clinical and histopathological diagnosis

  4. Rate of Complications [ Time Frame: from the date of transplant to 1 year from day of transplantation ]
    both infectious and non infectious


Eligibility Criteria
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Ages Eligible for Study:   2 Years to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age >2 years and < 60 years
  • Karnofsky performance status >= 70%

  • Aplastic Anemia that meets the following criteria:

    i. Peripheral Blood (must fulfill 2 of 3): ii. <500 neutrophils iii. <20,000 platelets iv. absolute reticulocyte count <40,000/microL

  • Bone Marrow (must be ): markedly hypocellular (<25% of normal cellularity) with absence of reticulin and abnormal infiltrate

Exclusion Criteria:

  • Presence of donor specific antibodies
  • Fanconi anemia
  • Cytogenetic abnormalities suggestive of myelodysplastic syndrome
  • Prior HSCT
  • Human immunodeficiency virus infection
  • Active Hepatitis B virus infection
  • Active /uncontrolled bacterial, viral , fungal infection or Tuberculosis
  • Psychiatric illness
  • Poor cardiac function (ejection fraction <40%)
  • Poor pulmonary function (Forced vital capacity <50% predicted)
  • Poor liver function (bilirubin >= 2mg/dL)
  • Poor renal function (creatinine >= 2.0mg/dL or creatinine clearance <40)
Contacts and Locations

Contacts
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Contact: Xanab akram 03325346564 xanab.akram@gmail.com

Locations
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Pakistan
NIBMT Recruiting
Rawalpindi, Punjab, Pakistan, 46000
Contact: Tariq Mehmood Satti, FCPS, MCPS    +92-51-9270076 ext 201    tariqmahmood_satti@yahoo.com   
Contact: FCPS,FACP         
Sub-Investigator: Xanab Akram         
Sponsors and Collaborators
National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
Investigators
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Study Chair: Tariq Mehmood Satti, FCPS NIBMT
Tracking Information
First Submitted Date  ICMJE April 22, 2019
First Posted Date  ICMJE May 20, 2019
Last Update Posted Date August 11, 2020
Actual Study Start Date  ICMJE July 12, 2018
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2019) 		Number of Participants with overall survival [ Time Frame: from the date of transplant to 1 year post transplant ]
overall survival is defined as the time interval from date of transplant to death or to last follow-up, whichever occurs first.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2019)
  • Number of Participants with Disease free survival [ Time Frame: from the date of transplant to 1 year post transplant ]
    from time of transplant to death or last follow up
  • Time of Neutrophil engraftment [ Time Frame: from the date of transplant to 10 to day 28 post transplant ]
    first of 3 consecutive days with Absolute neutrophil count> 0.5
  • Frequency of Graft versus host disease [ Time Frame: from the date of transplant to acute upto 100 day post transplant, chronic >100 days post transplant ]
    as per clinical and histopathological diagnosis
  • Rate of Complications [ Time Frame: from the date of transplant to 1 year from day of transplantation ]
    both infectious and non infectious
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Novel TBI Free Conditioning Protocol for Haploidentical Transplant in Acquired Aplastic Anemia:
Official Title  ICMJE A Novel TBI Free Conditioning Protocol for Haploidentical Hematopoeitic Stem Cell Transplant in Acquired Aplastic Anemia
Brief Summary Severe and very severe aplastic anemia are life threatening disorders for which allogeneic stem cell transplant is only curative treatment. However, matched sibling donor (MSD) is available in only 25-35% cases. Pakistan has a population of around 203 million but there is no donor registry available so there is no option available for matched unrelated donor (MUD) transplants . Haploidentical transplant represents only curative option for patients lacking MSD. Protocols involving post transplant cyclophosphamide require Total body irradiation (TBI) and utilize peripheral blood stem cell(PBSC) as graft source. TBI is not available in most of transplant centres across Pakistan due to lack of availability , cost and lack of expertise. The investigators have conceived a novel TBI free conditioning regimen to be used for haplo-identical Hemtopoeitic stem cell transplant in acquired aplastic anemia patients
Detailed Description Aplastic anemia is considered to be a rare and heterogenous disease with incidence of 1-2 per million in western countries. Data from Asian studies show a 3-4 fold higher incidence.Majority of newly diagnosed aplastic anemia patients are younger and in Armed forces bone marrow transplant cohort of 1324 patients 64 % patient are younger than 24 years of age and 87% patients younger than 40 years (unpublished data).There is no donor registry in Pakistan and patients lacking sibling match donor cannot proceed to stem cell transplant due lack of matched unrelated donors. Horse antithymocyte globulin is not available currently in Pakistan and response to Rabbit antithymocyte globulin is dismal as shown in number of international studies. So haploidentical stem cell transplant remains only curative option for patients lacking Matched sibling donor. Currently there are 2 major platforms used for haplo-identical stem cell transplant. Post transplant cyclophosphamide based using TBI and haplo regimen of Peking university. TBI is not available for most of our patients in Pakistan due to cost,non-availability and lack of expertise. The investigators have formulated a novel TBI free regimen incorporating Busulphan, antithymocyte globulin and using co-primed bone marrow and peripheral blood harvest to minimize graft-versus-host disease and facilitate engraftment. Post transplant cyclophosphamide, Cyclosporine and mycophenolate mofetil will be used for graft-versus-host disease prophylaxis
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Aplastic Anemia Idiopathic
Intervention  ICMJE Drug: Haploidentical HSCT using TBI free regimen, ''ATG'' with ''Post transplant cyclophosphamide''
''Busulphan'' will be used in place of ''TBI'' in equivalent myelotoxic dose to facilitate engraftment , ''ATG'' will be used to reduce GVHD and facilitate engraftment while ''combine PBSC'' and/OR ''Bone marrow harvest'' will be used
Other Name: ''Combined BMH'' and ''PBSC harvest''
Study Arms  ICMJE Experimental: TBI free Haploidentical HSCT
Recipients will receive a reduced intensity conditioning regimen of ''Fludarabine'' 30 mg/m2 IV daily from day -7 to -3, ''Cyclophosphamide'' 14.5-30 mg/kg IV daily on day -6 and -5 , ''rabbit Antithymocyte globulin'' 5 mg /kg/day from day -6 to day-3; ''Busulphan'' IV 3.2 mg per kg/day in 02 divided doses on day -3 and day-2, ''Granulocyte Colony Stimulating factor primed Bone marrow harvest'' and/OR ''PBSC'' graft on day 0 and day +1 respectively and Graft versus host disease prophylaxis with ''post-transplant cyclophosphamide'' administered at a dose of 50mg/kg/day given daily on days +3 and +5 post-transplant and ''cyclosporine'' from day +5, ''mycophenolate mofetil'' from day+5 to day+35.
Intervention: Drug: Haploidentical HSCT using TBI free regimen, ''ATG'' with ''Post transplant cyclophosphamide''
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 16, 2019) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 30, 2021
Estimated Primary Completion Date December 30, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age >2 years and < 60 years
  • Karnofsky performance status >= 70%

  • Aplastic Anemia that meets the following criteria:

    i. Peripheral Blood (must fulfill 2 of 3): ii. <500 neutrophils iii. <20,000 platelets iv. absolute reticulocyte count <40,000/microL

  • Bone Marrow (must be ): markedly hypocellular (<25% of normal cellularity) with absence of reticulin and abnormal infiltrate

Exclusion Criteria:

  • Presence of donor specific antibodies
  • Fanconi anemia
  • Cytogenetic abnormalities suggestive of myelodysplastic syndrome
  • Prior HSCT
  • Human immunodeficiency virus infection
  • Active Hepatitis B virus infection
  • Active /uncontrolled bacterial, viral , fungal infection or Tuberculosis
  • Psychiatric illness
  • Poor cardiac function (ejection fraction <40%)
  • Poor pulmonary function (Forced vital capacity <50% predicted)
  • Poor liver function (bilirubin >= 2mg/dL)
  • Poor renal function (creatinine >= 2.0mg/dL or creatinine clearance <40)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 60 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Xanab akram 03325346564 xanab.akram@gmail.com
Listed Location Countries  ICMJE Pakistan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03955601
Other Study ID Numbers  ICMJE AFBMTC-HAPLO-AA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
Study Sponsor  ICMJE National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Tariq Mehmood Satti, FCPS NIBMT
PRS Account National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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