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Preemptive Therapy of GVHD

This study has suspended participant recruitment.
(Toxicity concern upon preliminary analysis, requiring putting study on hold and re-doing the preliminary analysis with longer follow up.)
Sponsor:
Collaborators:
University of Alberta
Alberta Health Services
Information provided by (Responsible Party):
Jan Storek, University of Calgary
ClinicalTrials.gov Identifier:
NCT01994824
First received: November 20, 2013
Last updated: October 28, 2016
Last verified: October 2016
  Purpose
Graft-vs-host disease (GVHD) causes substantial mortality, morbidity and poor quality of life after blood or marrow transplantation (BMT). In Alberta, we use antithymocyte globulin (ATG, given on days -2, -1 and 0) in addition to methotrexate and cyclosporine for GVHD prophylaxis. In spite of that, ~40% patients develop significant GVHD (grade 2-4 acute GVHD or chronic GVHD needing systemic immunosuppressive therapy). ATG at the dose we typically use (4.5 mg/kg) is relatively non-toxic. At higher doses, ATG could increase the likelihood of posttransplant infections or relapse. Thus an extra dose of ATG (on top of the routine 4.5 mg/kg) might be justified only for patients at high risk of developing significant GVHD. In our experience, low serum level of interleukin-15 (IL15) and high serum level of interleukin-2 receptor alpha (IL2Ra) on day 7 predict development of significant GVHD. Here we will test whether, compared to historical/concurrent controls, an extra dose of ATG (3 mg/kg on day 8) given to patients with low IL15 or high IL2Ra on day 7 reduces the incidence of significant GVHD, and improves survival free of relapse and GVHD, and quality of life.

Condition Intervention Phase
Graft-vs-host Disease Drug: rabbit antithymocyte globulin Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Preemptive Therapy of Graft-vs-Host Disease Using Rabbit Antithymocyte Globulin

Resource links provided by NLM:


Further study details as provided by Jan Storek, University of Calgary:

Primary Outcome Measures:
  • Cumulative incidence of significant GVHD [ Time Frame: 2 years ]

Secondary Outcome Measures:
  • Survival free of relapse and significant GVHD [ Time Frame: 2 years ]
  • Quality of life [ Time Frame: 2 years ]

Estimated Enrollment: 160
Study Start Date: January 2014
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Intervention arm

Transplant recipients will have IL15 and IL2Ra measured on day 7. If at risk for significant GVHD, the patient will get rabbit antithymocyte globulin, 3 mg/kg on day 8.

Patients from this intervention/experimental arm will be compared to historical and concurrent controls (no ATG on day 8).

Drug: rabbit antithymocyte globulin
Thymoglobulin, 3 mg/kg, will be given on day 8 posttransplant to patients at high risk of significant GVHD per day 7 IL15 and IL2Ra levels.
Other Name: Thymoglobulin

Detailed Description:

Blood for IL15 and IL2Ra determination will be drawn in the morning of day 7 (10 ml red top tube). IL15 and IL2Ra levels will be measured in Storek/Khan Lab by enzyme-linked immunosorbent assay (ELISA) as described (Pratt LM et al: BMT 2013). Storek/Khan Lab staff will report the IL15 and IL2Ra levels to the Bone Marrow Transplant ward (Unit 57, Foothills Medical Centre) no later than in the morning of day 8. If the IL15 level is <31 ng/L or the IL2Ra level is >4500 ng/L, the physician caring for the patient on the ward will order Thymoglobulin, 3 mg/kg intravenously, to be infused over 4-8 hours on day 8. The dose is based on actual body weight, and is rounded to the nearest vial (Thymoglobulin is supplied in 25 mg vials) except if the rounding would result in >5% difference from the calculated dose. Unit 57 standard practice will be followed for the infusion of ATG (see Standard Operation Procedure BMTS40153 ["ATG Administration"]). Premedication for ATG will include methylprednisolone 40 mg IVPB, acetaminophen 1000 mg PO and diphenhydramine 50 mg IVPB. Acetaminophen 1000 mg PO and diphenhydramine 50 mg IVPB can be repeated in 4-6 hours PRN flu-like symptoms/fever/chills. Meperidine 25-50 mg IVPB every 4 hours will be given PRN for rigors.

EVALUATIONS For the endpoint of the incidence of significant GVHD, patients will be followed per standard practice of the Alberta Blood and Marrow Transplant Program for the development of acute and chronic GVHD (www.albertahealthservices.ca/hp/if-hp-cancer-guide-bmt-manual.pdf). Per this standard practice, acute GVHD is graded according to Consensus criteria (Przepiorka D: BMT 1995) and chronic GVHD is diagnosed and graded according to NIH criteria (Filipovich AH: BBMT 2005). Significant GVHD is defined as grade 2-4 acute GVHD or chronic GVHD needing systemic immunosuppressive therapy.

For the endpoint of survival free of significant GVHD and relapse, relapse will be defined by standard criteria (eg, >5% marrow blasts by morphology in case of acute leukemia).

For the endpoint of quality of life at 2 years (21-27 months) posttransplant, Short Form 36 will be used.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. First allogeneic hematopoietic cell transplantation (second transplants are rare, typically performed for relapse of leukemia, in which case the likelihood of relapse is high, and there is the theoretical risk of increasing the likelihood further with ATG).
  2. Conditioning including ATG 4.5 mg/kg (the predictive value of IL15 and IL2Ra levels was determined in patients whose conditioning included 4.5 mg/kg or ATG).
  3. Age >17 (the predictive value of IL15 and IL2Ra levels has not been studied in children).

Exclusion Criteria:

  1. Nonmyeloablative conditioning (possible risk of ATG increasing relapse).
  2. Active viral infection (risk of worsening of the viral infection with ATG).
  3. Neutropenic fever with hypotension. In such case, the ATG can be given on day 9 (instead of day 8) if patient no longer has hypotension.
  4. Hypoxemia. In such case, the ATG can be given on day 9 (instead of day 8) if patient no longer has hypoxemia.
  5. History of anaphylactic reaction to Thymoglobulin or another rabbit blood protein.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01994824

Locations
Canada, Alberta
Alberta Health Services-CancerControl / University of Calgary / University of Alberta (Edmonton)
Calgary, Alberta, Canada, T2N 4N1
Sponsors and Collaborators
University of Calgary
University of Alberta
Alberta Health Services
Investigators
Principal Investigator: Jan Storek, MD, PhD University of Calgary
  More Information

Responsible Party: Jan Storek, Professor of Medicine, University of Calgary
ClinicalTrials.gov Identifier: NCT01994824     History of Changes
Other Study ID Numbers: PreemptiveATG
Study First Received: November 20, 2013
Last Updated: October 28, 2016

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Antilymphocyte Serum
Immunologic Factors
Physiological Effects of Drugs
Immunosuppressive Agents

ClinicalTrials.gov processed this record on June 22, 2017