Patients Treated for Wiskott-Aldrich Syndrome (WAS) Since 1990

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Collaborators:
Primary Immune Deficiency Treatment Consortium (PIDTC)
Rare Diseases Clinical Research Network (RDCRN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT02064933
First received: February 13, 2014
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

Wiskott - Aldrich syndrome (WAS) is a rare serious medical condition that causes problems both with the immune system and with easy bruising and bleeding. The immune abnormalities cause patients with WAS to be very susceptible to infections. Depending on the specific type of primary immune deficiency diseases, there are effective treatments, including antibiotics, cellular therapy and gene therapy, but studies of large numbers of patients are needed to determine the full range of causes, natural history, or the best methods of treatment for long term success.

This multicenter study combines retrospective, prospective and cross-sectional analyses of the transplant experiences for patients with WAS who have already received HCT since 1990, or who will undergo Hematopoietic cell transplant (HCT) during the study period. The retrospective and prospective portions of the study will address the impact of a number of pre and post-transplant factors on post-transplant disease correction and ultimate benefit from HCT and the cross-sectional portion of the study will assess the benefit of HCT 2 years post-HCT in consenting surviving patients.


Condition
Wiskott-Aldrich Syndrome

Study Type: Observational
Study Design: Observational Model: Cohort
Official Title: Analysis of Patients Treated for Wiskott-Aldrich Syndrome Since January 1, 1990 (RDCRN PIDTC-6904)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Longitudinal Analysis: Overall Survival From Time of HCT/Gene Therapy [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    The event analyzed is death from any cause. The time to this event is the time from HCT/gene therapy to death or last follow-up.

  • Cross-Sectional Analysis: Proportion of Participants Achieving Full T Cell Reconstitution [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]

    Full T cell reconstitution is defined by all of the following:

    • CD3 cell count within normal range for age.
    • CD4 cell count within normal range for age.
    • CD8 cell count within normal range for age
    • Donor T cell chimerism > 95%
    • Lymphocyte proliferation to PHA. Proliferative responses to PHA within the normal range (at or above the lower limit of normal).

    When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory; alternatively, the lower limit of normal controls for the day may be used


  • Cross-Sectional Analysis: Proportion of Participants Achieving Full B Cell Reconstitution [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]

    Full B cell reconstitution is defined by all of the following:

    • Quantitative immunoglobulins (IgG, IgM, and IgA) within normal range; each immunoglobulin level will be assessed separately.
    • Serologic confirmation of post immunization tetanus titer in protective range.
    • Serologic confirmation of post immunization pneumococcal titers in protective range (protective titers for > 50% of the serotypes contained in the vaccine) following immunization

  • Cross-Sectional Analysis: Proportion of Participants Achieving Resolution of thrombocytopenia [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Resolution of thrombocytopenia defined by Platelets ≥ 150,000/microliter (transfusion independent for at least 7 consecutive days)

  • Cross-Sectional Analysis: Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL is defined as the first day of at least 3 different days the ANC is measured as 500 / uL or greater

  • Cross-sectional Analysis: Day of Recovery of Platelet Count to 20,000 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Platelet Count to 20,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 20,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day.

  • Cross-sectional Analysis: Day of Recovery of Platelet Count to 50,000 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Platelet Count to 50,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 50,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day.


Secondary Outcome Measures:
  • Longitudinal Analysis: Proportion of Participants Achieving Hematologic Reconstitution [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]

    Hematologic Reconstitution is defined as attainment of each of the following lab test values:

    • Hemoglobin within normal range for age
    • WBC count within normal range for age
    • Absolute neutrophil count (ANC) within normal range for age
    • Platelet count ≥ 150,000/microL and without transfusion for at least 7 consecutive days

  • Longitudinal Analysis: Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Absolute Neutrophil Count (ANC) to 500 / uL is defined as the first day of at least 3 different days the ANC is measured as 500 / uL or greater.

  • Longitudinal Analysis: Day of Recovery of Platelet Count to 20,000 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Platelet Count to 20,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 20,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day.

  • Longitudinal Analysis: Day of Recovery of Platelet Count to 50,000 / uL [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Day of Recovery of Platelet Count to 50,000 / uL is defined as the first day of at least 3 laboratory values obtained on different days where the platelet count was measured as 50,000 / uL or greater, AND without platelet transfusions for at least 7 consecutive days immediately preceding this day.

  • Longitudinal Analysis: Proportion of Participants Achieving Full T Cell Immune Reconstitution [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    • Absolute CD3 T cell count within normal range for age
    • Absolute CD4 T cell count within normal range for age
    • Absolute CD8 T cell count within normal range for age
    • Proliferative responses to PHA within the normal range (at or above the lower limit of normal).
    • When possible the proliferation to PHA should be calculated as a percentage of the lower limit of normal controls for that laboratory; alternatively, the lower limit of normal controls for the day may be used.

  • Longitudinal Analysis: Proportion of Participants Achieving Full B Cell Immune Reconstitution [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    • Quantitative immunoglobulins (IgG, IgM, and IgA) within normal range for age; each immunoglobulin level will be assessed separately.
    • Serologic confirmation of post immunization tetanus titer in protective range.
    • Serologic confirmation of post immunization pneumococcal titers in protective range (protective titers for > 50% of the serotypes contained in the vaccine) following immunization.
    • Patients who remain on IVIG will be considered not B cell reconstituted.
    • Normalization of isohemagglutinin titers.

  • Longitudinal Analysis: State of Lineage Specific Chimerism (HCT Stratum) [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Peripheral blood chimerism will be assessed by FISH XX/XY, STRs, or WASP expression.

  • Longitudinal Analysis: Definition of Graft Failure / Rejection [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    • Less than 5% of donor cells in all lineages or in whole blood by 100 days post-HCT using standard PCR based or in situ hybridization techniques OR
    • Second transplant by 100 days post-HCT (unless > 5% CD3 and purpose is to boost immune recovery).

    Failure to achieve ≥5% donor cells in all lineages or in whole blood by 100 days post-HCT will be defined as graft failure/rejection. Patients who receive a second transplant by day 100 will be considered graft failure.


  • Longitudinal Analysis: Severe bleeding episodes [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Any severe bleeding episode requiring platelet and/or RBC transfusion(s)

  • Longitudinal Analysis: Malignancy [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    New onset or relapse of lymphoid malignancy confirmed by relevant pathologic and genetic features.

  • Longitudinal Analysis: Growth [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Z score of weight and height pre-HCT/gene therapy and post-HCT/gene therapy.

  • Longitudinal Analysis: Incidence of Acute GVHD [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of Grades IIIV or grades III-IV acute GVHD1 are considered events. Death is a competing risk, and patients alive without acute GVHD will be censored at the time of last follow-up.

  • Longitudinal Analysis: Incidence of Chronic GVHD [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Chronic GVHD will be graded as limited or extensive.2 Occurrence of symptoms in any organ system that meet the criteria of chronic GVHD will be recorded. Death is a competing risk, and patients alive without chronic GVHD will be censored at time of last follow-up.

  • Longitudinal Analysis: Autoimmunity disorders [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Incidence of documented autoimmunity disorders

  • Longitudinal Analysis: Infections / blood borne infections [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    1. Clinical resolution of any pre-HCT opportunistic infections including but not limited to CMV, HSV1, adenovirus, EBV, and VZV. Approximate time to resolution (clinically well, off treatment, and/or negative culture/PCR assay) will be measured from the day of HCT.
    2. Incidence of documented severe (requiring hospitalization or resulting in death) and/or recurrent bacterial, viral or fungal infection post HCT. These will be reported by site of disease, organism, date of onset post HCT, and whether or not the infection resolved.
    3. Presence and resolution of severe warts (verruca vulgaris, flat warts) from the day of HCT. Whether the subject had complete resolution, partial resolution, persistent or recurrent warts will be recorded.
    4. New episodes of infections due to meningococcus, pneumococcus or hemophilus.
    5. Lymphoproliferative disease due to EBV.

  • Cross-sectional Analysis: Current State of Lineage Specific Chimerism (HCT Stratum) [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Peripheral blood donor chimerism will be assessed by FISH XX/XY, STR, and/or WASP expression

  • Cross-sectional Analysis: Current frequency and severity of infections [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
  • Cross-sectional Analysis: Current Status of Growth [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Current Z score of weight and height pre-HCT/gene therapy and post-HCT/gene therapy.

  • Cross-Sectional Analysis: Graft-versus-host Disease (GvHD) [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Presence of chronic GVHD, current assessment; graded as limited or extensive

  • Cross-Sectional Analysis: Autoimmunity Disorders [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Presence of autoimmunity disorders

  • Cross-sectional Analysis: Severe Bleeding Episodes [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Any severe bleeding episode requiring platelet and/or RBC transfusion(s) during the previous year.

  • Cross-sectional Analysis: fertility [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    Whether the subject has biological offspring will be recorded.

  • Cross-sectional Analysis: malignancy [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: Yes ]
    New onset or relapse of lymphoid malignancy confirmed by relevant pathologic and genetic features.

  • Cross-sectional Analysis: Quality of Life Questionnaire [ Time Frame: an expected average of 5 years ] [ Designated as safety issue: No ]
    Age appropriate testing will be performed at the cross-sectional visit inpatients surviving at least two years post-transplant


Biospecimen Retention:   Samples With DNA

Whole blood and tissue samples


Estimated Enrollment: 541
Study Start Date: June 2014
Estimated Study Completion Date: August 2019
Estimated Primary Completion Date: August 2019 (Final data collection date for primary outcome measure)
Groups/Cohorts
Retrospective Cohort (Longitudinal Analysis)
Participants with WAS treated at consortium centers since 1990 who have received transplant (Stratum A) or gene therapy (Stratum B)
Prospective Cohort (Longitudinal Analysis)
Participants treated at consortium centers since 1990 who will receive transplant (Stratum A) or gene therapy (Stratum B)
Cross-Sectional Cohort (Cross-sectional Analysis)
Living participants with WAS who have received transplant (Stratum A) or gene therapy (Stratum B) at Consortium Centers 1990-Present And >= 2 Years Post-Transplant

  Eligibility

Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Male WAS participants treated at consortium centers Since 1990

Criteria

Inclusion Criteria:

  • WAS participants will be defined as males who have:

    1. thrombocytopenia (< 100K) AND EITHER molecular diagnosis of WAS OR reduced WASP expression; OR
    2. thrombocytopenia (< 100K) AND positive family history consistent with WAS diagnosis; OR
    3. chronic thrombocytopenia (< 100K for minimum of 3 months) AND low mean platelet volume (MPV below normal range for age) AND EITHER recurrent and/or severe infections requiring treatment and/or eczema OR lack of antibody response to polysaccharide antigens or low IgM.
  • Longitudinal Analysis (Retrospective and Prospective)

    1. Stratum A. Participants with WAS who have or will Receive HCT

      • Participants with WAS who have received an HCT since January 1, 1990
    2. Stratum B. Participants with WAS who have or will Receive Gene Transfer

      • Participants in which the intention is to treat with gene transfer with autologous modified cells
  • Cross-Sectional Analysis (Strata A and B) 1. Participants with WAS who are surviving and at least 2 years after the most recent HCT or gene therapy.

Exclusion Criteria:

  • As this is a natural history study, for both the Longitudinal Analysis and the Cross-Sectional Analysis we will not exclude any patients due to race or age who fit the inclusion criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02064933

  Show 32 Study Locations
Sponsors and Collaborators
Primary Immune Deficiency Treatment Consortium (PIDTC)
Rare Diseases Clinical Research Network (RDCRN)
Investigators
Principal Investigator: Lauri M Burroughs, MD University of Washington
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02064933     History of Changes
Other Study ID Numbers: DAIT RDCRN PIDTC-6904
Study First Received: February 13, 2014
Last Updated: June 27, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Wiskott-Aldrich Syndrome
Hematopoietic Stem Cell Transplantation
Genetic Therapy

Additional relevant MeSH terms:
Wiskott-Aldrich Syndrome
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphopenia
Leukopenia
Leukocyte Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Immunologic Deficiency Syndromes
Immune System Diseases

ClinicalTrials.gov processed this record on July 28, 2014