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Alpha 1 Anti-Trypsin (AAT) in Treating Patients With Acute Graft-Versus-Host Disease GVHD)

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ClinicalTrials.gov Identifier: NCT01523821
Recruitment Status : Completed
First Posted : February 1, 2012
Results First Posted : October 30, 2018
Last Update Posted : October 30, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Tracking Information
First Submitted Date  ICMJE January 23, 2012
First Posted Date  ICMJE February 1, 2012
Results First Submitted Date  ICMJE May 10, 2018
Results First Posted Date  ICMJE October 30, 2018
Last Update Posted Date October 30, 2018
Actual Study Start Date  ICMJE October 11, 2013
Actual Primary Completion Date January 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 29, 2018)
Number (Percentage) of Patients at Each Dosing Cohort Who Experience no Toxicity and in Whom Graft Versus Host Disease (GVHD) is Stable or Improved [ Time Frame: Adverse events were reported through 15 days after the last dose of AAT. GVHD response assessed at study day 28. ]
Toxicity and adverse events were assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. All adverse events were reported regardless of attribution to alpha 1 anti-trypsin (AAT). GVHD response was defined per standard criteria for improvement, no change or progression of signs/symptoms in skin rash (% body surface area), GI (nausea, vomiting, anorexia, diarrhea, GI bleeding, abdominal cramping) and hepatic function (serum bilirubin levels). For this outcome measure, the requirement for additional GVHD treatment beyond AAT was not included in the criteria for response (i.e patients who may have required additional GVHD treatment before study day 28 were not automatically categorized as non-responders or as having progressive GVHD).
Original Primary Outcome Measures  ICMJE
 (submitted: January 30, 2012)
  • Achievement of targeted alpha 1 anti-trypsin plasma concentrations [ Time Frame: After dose 1 (24 or 48 hour interval) ]
    Alpha 1 anti-trypsin target concentrations indicated are based on pilot data and the intended suppression of pro-inflammatory cytokines by >= 50%. Stool concentrations of AAT will be measured to determine the effect of IV administered AAT on the expected healing of the intestinal mucosa and the loss of AAT in the stool.
  • Achievement of targeted alpha 1 anti-trypsin plasma concentrations [ Time Frame: After dose 2 (24 or 48 hour interval) ]
    Alpha 1 anti-trypsin target concentrations indicated are based on pilot data and the intended suppression of pro-inflammatory cytokines by >= 50%. Stool concentrations of AAT will be measured to determine the effect of IV administered AAT on the expected healing of the intestinal mucosa and the loss of AAT in the stool.
  • Achievement of targeted alpha 1 anti-trypsin plasma concentrations [ Time Frame: After dose 3 (24 or 48 hour interval) ]
    Alpha 1 anti-trypsin target concentrations indicated are based on pilot data and the intended suppression of pro-inflammatory cytokines by >= 50%. Stool concentrations of AAT will be measured to determine the effect of IV administered AAT on the expected healing of the intestinal mucosa and the loss of AAT in the stool.
  • Achievement of targeted alpha 1 anti-trypsin plasma concentrations [ Time Frame: After dose 6 (24 or 48 hour interval) ]
    Alpha 1 anti-trypsin target concentrations indicated are based on pilot data and the intended suppression of pro-inflammatory cytokines by >= 50%. Stool concentrations of AAT will be measured to determine the effect of IV administered AAT on the expected healing of the intestinal mucosa and the loss of AAT in the stool
Change History Complete list of historical versions of study NCT01523821 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 29, 2018)
  • Number (Percentage) of Patients at Each Dosing Cohort Experiencing an Unexpected Serious Adverse Event (SAE) [ Time Frame: SAEs were reported through 30 days after the last dose of alpha 1 anti-trypsin (AAT). ]
    Serious adverse events included death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/ incapacity, or congenital anomaly/birth defect. Significant events that do not meet these criteria may be considered serious if they jeopardize the patient and require a medical intervention to prevent one of the outcomes above. An "unexpected" adverse event is defined as an event that is not identified in nature, severity or frequency in the current investigator brochure/package insert/product information.
  • Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Suspected Serious Adverse Reactions (Infusion Related Reactions) [ Time Frame: Within 48 hours after each infusion ]
    Serious adverse reactions were assessed by the NCI CTCAE v4.0.
  • Number (Percentage) of Patients at Each Dosing Cohort Who Experience One or More Thrombotic or Thrombo-embolic Events [ Time Frame: Events were reported through 15 days after the last dose of AAT. ]
    Events were assessed using the NCI CTCAE v4.0.
  • Number (Percentage) of Patients at Each Dosing Cohort With Occurrence of Infections [ Time Frame: Infections were reported through 15 days after the last dose of AAT. ]
    Infections were assessed using NCI CTCAE v4.0.
  • Number (Percentage) of Patients at Each Dosing Cohort With Progression of GVHD [ Time Frame: GVHD responses were assessed on day 28 after starting AAT therapy or at time of death if patient died before study day 28. ]
    GVHD responses were assessed using criteria established by the Center for International Blood and Marrow Transplant Research and criteria from the Acute GVHD Activity Index. Patients who required additional systemic GVHD treatment beyond AAT before study day 28 were defined as having progressive GVHD.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2012)
  • Suppression of levels of pro-inflammatory cytokines by > 50% [ Time Frame: After doses 1, 2, 3, and 6 and at completion of study treatment ]
  • Infections when treating GVHD with alpha 1 anti-trypsin [ Time Frame: Through 30 days after completion of study treatment ]
  • Progression of GVHD [ Time Frame: At 4 weeks after starting therapy ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Alpha 1 Anti-Trypsin (AAT) in Treating Patients With Acute Graft-Versus-Host Disease GVHD)
Official Title  ICMJE Treatment of Steroid Non-responsive Acute GVHD With Alpha 1 Antitrypsin (AAT). A Phase I/II Study
Brief Summary This phase I/II trial evaluates the efficacy and adverse effects of alpha 1 anti-trypsin (AAT) for the treatment of acute graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation.
Detailed Description

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of AAT in patients with steroid non-responsive acute GVHD.

II. Characterize pharmacodynamic effects of AAT on pro-inflammatory cytokines, heparan sulfate, and the spectrum of peripheral blood T cells.

III. Determine clinical responses of GVHD to AAT in patients with steroid non-responsive acute GVHD.

OUTLINE: This is a phase I/II dose-escalation study of AAT.

Patients will receive AAT intravenously (IV) on study days 1, 3, 5, and 7. Patients who experience no toxicity and in whom GVHD is stable or improved after the day 7 dose can continue therapy with AAT on days 9, 11, 13 and 15 for a total of 8 doses.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
The study will have three escalating alpha 1 anti-trypsin (AAT) dose cohorts with six patients in each cohort (Phase I). Based on response and toxicity, an additional six patients will be enrolled in the optimal dose (Phase II).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Graft-Versus-Host Disease (GVHD) Acute on Chronic
Intervention  ICMJE Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia] at various levels over different days
Study Arms  ICMJE
  • Cohort 1 (30 mg/kg)
    Alpha 1 anti-trypsin (AAT) will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 30mg/kg (maintenance dose) every other day (QOD) on days 3, 5, 7, 9, 11, 13 & 15.
    Intervention: Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
  • Cohort 2 (60 mg/kg)
    AAT will be administered intravenously at a dose of 90 mg/kg (loading dose) on day 1 followed by 60 mg/kg (maintenance dose) QOD on days 3, 5, 7, 9, 11, 13 & 15.
    Intervention: Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
  • Cohort 3 (90 mg/kg)
    AAT will be administered intravenously at a dose of 90 mg/kg on days 1, 3, 5, 7, 9, 11, 13 & 15.
    Intervention: Drug: Alpha 1-Proteinase Inhibitor, Human 1 MG [Glassia]
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 Completed
Actual Enrollment  ICMJE
 (submitted: October 29, 2018)
20
Original Estimated Enrollment  ICMJE
 (submitted: January 30, 2012)
24
Actual Study Completion Date  ICMJE January 15, 2017
Actual Primary Completion Date January 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients transplanted from related or unrelated, human leukocyte antigen (HLA) matched or mismatched donors
  • Patients transplanted with hematopoietic stem cells from any source
  • Patients receiving calcineurin inhibitors as part of graft versus host disease (GVHD) prophylaxis
  • Patients with acute GVHD grades II-IV developing despite GVHD prophylaxis
  • Patients who have not shown a satisfactory response to methylprednisolone-equivalent doses at 2 mg/kg/day, based on adjusted body weight
  • Signed and dated informed consent

Exclusion Criteria:

  • Patients who have received any systemic agents in addition to steroids for treatment of GVHD
  • Patients unable to give informed consent
  • Patients with manifestations of classic chronic GVHD
  • Patients with evidence of recurrent malignancy
  • Patients with acute/chronic GVHD overlap syndrome
  • Patients whose GVHD developed after donor lymphocyte infusion (DLI)
  • Patients with severe organ dysfunction, defined as

    • On dialysis
    • Requiring oxygen (O2) at more than 2 l/min
    • Uncontrolled arrhythmia or heart failure
    • Veno-occlusive disease (sinusoidal obstruction syndrome)
  • Patients with uncontrolled infections
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01523821
Other Study ID Numbers  ICMJE 2571.00
NCI-2011-03805 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2571
2571.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01HL036444 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: H. Joachim Deeg Fred Hutch/University of Washington Cancer Consortium
PRS Account Fred Hutchinson Cancer Research Center
Verification Date October 2018

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