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Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

Primary Purpose

Graft vs Host Disease

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Atorvastatin calcium

About this trial

This is an interventional prevention trial for Graft vs Host Disease focused on measuring Graft vs Host Disease, GVHD, Allogeneic hematopoietic stem cell transplantation, HSCT, Atorvastatin

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with a history of a hematological malignancy or bone marrow failure syndrome suitable for allogeneic stem cell transplantation in the opinion of treating transplant physician.
Patients aged 18-75 years of age are eligible. Patients with age > 18 and ≤ 50 years will be eligible for myeloablative conditioning (MAC), while patients > 50 years of age, or those with previous history of autologous transplantation, high hematopoietic cell transplant comorbidity index (HCT-CI) score (>2), and baseline diagnosis of hodgkin's lymphoma, chronic lymphocytic leukemia and follicular lymphoma will be suitable for reduced intensity conditioning (RIC) transplantation (however intensity of conditioning regimen will remain at the discretion of treating physician).
All patients must have at least one suitable human leukocyte antigen (HLA)-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate sibling donor).
Patient must provide informed consent.
Left ventricular ejection fraction ≥ 40%.
Bilirubin ≤ 2 x the upper limit of normal (ULN) and aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 3 x ULN; and absence of hepatic cirrhosis. For patients with Gilbert's syndrome, bilirubin ≤ 3 x ULN is permitted.
Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation.
Carbon monoxide diffusing capacity (DLCOcor) corrected for hemoglobin or forced expiratory volume at one second (FEV1) or DL/VA ≥ 40% of predicted (a pulmonary function test).
Karnofsky performance status > 70.
A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.
Patients with positive HIV serology are eligible.
Patients who have previously been taking atorvastatin or any other statin drug will be eligible as long as there is no contraindication to switch to atorvastatin (40mg/day) in the opinion of the treating physician.
Method of stem-cell collection from the sibling donor will be at the discretion of the treating physician. Although it is anticipated that majority of sibling donors will undergo Granulocyte colony-stimulating factor(G-CSF) induced stem cell mobilization; however donors undergoing bone marrow harvest or stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for the study.

Exclusion Criteria:

Uncontrolled arrhythmias or uncontrolled New York Heart Association class III-IV heart failure.
Evidence of active bacterial, viral or fungal infection at the time of transplant conditioning.
History of intolerance or allergic reactions with atorvastatin will not be eligible.
Undergoing a T-cell depleted allogeneic transplantation
Receiving conditioning regimens containing anti-thymocyte globulin, and/or campath

Sites / Locations

West Virginia University Hospitals Mary Babb Randolph Cancer Center
Froedtert Hospital and the Medical College of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Atorvastatin calcium (Lipitor)

Unrelated Donor

Arm Description

Atorvastatin will be administered at a dose of 40 mg orally daily starting on day -14, to permit an approximately 1-week observation period to rule out any acute atorvastatin-induced side effects before the initiation of transplant conditioning. Patients will receive atorvastatin until +180 days or until the patient develops grade II-IV acute GVHD, extensive chronic GVHD, or any grade 3-4 toxicity related to atorvastatin.

Outcomes

Primary Outcome Measures

Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD).

The number of subjects in the matched sibling cohort who develop grades II-IV acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched unrelated donors are not included in this analysis.

Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD.

The number of subjects in the matched unrelated donor cohort who develop grade II-IV acute GVHD. Acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched related donors are not included in this analysis.

Secondary Outcome Measures

Matched Related Transplants Who Develop Grade II-IV Chronic GVHD.

The number of subjects who develop grade II-IV chronic GVHD. Chronic GVHD diagnosis and grading I to IV will be according to National Institutes of Health (NIH) Criteria rating progressively intense symptoms involving: skin (asymptomatic to deep sclerosis, impaired mobility, ulceration, or pruritus), oral cavity (asymptomatic to symptoms limiting oral intake), eyes (asymptomatic to severe dry eye, inability to work, or loss of vision due to keratoconjunctivitis), gastrointestinal tract (asymptomatic to significant weight loss [>15%] or esophageal dilation), liver (normal function to bilirubin or enzymes >5 times ULN), lungs (asymptomatic to severe shortness of breath requiring supplemental oxygen), joints and fascia (asymptomatic to contractures with reduced range of motion and limited ability to perform daily care), and genital tract (asymptomatic to strictures and severe pain). Subjects in the matched unrelated donors are not included in this analysis.

Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD.

Full Information

NCT ID

NCT01665677

First Posted

August 13, 2012

Last Updated

April 20, 2023

Sponsor

Mehdi Hamadani

Collaborators

West Virginia University

1. Study Identification

Unique Protocol Identification Number

NCT01665677

Brief Title

Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

Official Title

Phase II Study of Atorvastatin, Micro-dose Methotrexate and Tacrolimus Administered Only to Transplant Recipients for the Prophylaxis of Acute Graft-versus-host Disease Following Allogeneic Hematopoietic Cell Transplantation

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

January 20, 2014 (Actual)

Primary Completion Date

July 9, 2021 (Actual)

Study Completion Date

July 9, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Mehdi Hamadani

Collaborators

West Virginia University

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Hematopoietic stem cell transplantation is a procedure in which a person receives blood forming stem cells from a person called a "donor." The stem cells can be obtained from the hollow part of the hip bone or from blood. A serious problem with this treatment is graft-versus-host disease (GVHD). This happens when stem cells from the donor attack normal cells of the recipient. Currently, there is no universal standard of care in the United States to prevent GVHD. This study is being done to see if a medicine that is used to lower cholesterol can also help in reducing GVHD. Patients will receive atorvastatin daily by mouth starting 14 days before stem cell transplant. They will continue to take atorvastatin until 180 days after transplant. This medicine may be stopped earlier if there is a bad side effect or a severe GVHD. Patients will also receive standard treatment to prevent GVHD. Patients will undergo many tests that are standard for their treatment at West Virginia University (WVU), including blood tests to check blood counts, kidney function and HIV status; blood test to check for pregnancy; Multi Gated Acquisition Scan (MUGA scan)or echocardiogram to test heart function; lung function testing; and bone marrow aspirate or biopsy. Patients will also have the option to provide blood samples for optional research related to the study.

Detailed Description

Acute graft-versus-host disease (GVHD) is one of the most frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT).(1) It develops in 30-75% of recipients of allogeneic HSCT depending on the degree of histocompatibility between the donor and the recipient, number of T-cells in the graft, recipient's age and GVHD prophylactic regimen used. (2-4) Novel strategies designed to effectively prevent the development of this life threatening complication of allogeneic transplantation are urgently needed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Graft vs Host Disease

Keywords

Graft vs Host Disease, GVHD, Allogeneic hematopoietic stem cell transplantation, HSCT, Atorvastatin

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

69 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Atorvastatin calcium (Lipitor)

Arm Type

Experimental

Arm Description

Arm Title

Unrelated Donor

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Atorvastatin calcium

Other Intervention Name(s)

Lipitor

Intervention Description

40 mg PO daily

Primary Outcome Measure Information:

Title

Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD).

Description

Time Frame

Day 100

Title

Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD.

Description

Time Frame

Day 100

Secondary Outcome Measure Information:

Title

Matched Related Transplants Who Develop Grade II-IV Chronic GVHD.

Description

Time Frame

1 year

Title

Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD.

Description

Time Frame

1 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with a history of a hematological malignancy or bone marrow failure syndrome suitable for allogeneic stem cell transplantation in the opinion of treating transplant physician. Patients aged 18-75 years of age are eligible. Patients with age > 18 and ≤ 50 years will be eligible for myeloablative conditioning (MAC), while patients > 50 years of age, or those with previous history of autologous transplantation, high hematopoietic cell transplant comorbidity index (HCT-CI) score (>2), and baseline diagnosis of hodgkin's lymphoma, chronic lymphocytic leukemia and follicular lymphoma will be suitable for reduced intensity conditioning (RIC) transplantation (however intensity of conditioning regimen will remain at the discretion of treating physician). All patients must have at least one suitable human leukocyte antigen (HLA)-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate sibling donor). Patient must provide informed consent. Left ventricular ejection fraction ≥ 40%. Bilirubin ≤ 2 x the upper limit of normal (ULN) and aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 3 x ULN; and absence of hepatic cirrhosis. For patients with Gilbert's syndrome, bilirubin ≤ 3 x ULN is permitted. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation. Carbon monoxide diffusing capacity (DLCOcor) corrected for hemoglobin or forced expiratory volume at one second (FEV1) or DL/VA ≥ 40% of predicted (a pulmonary function test). Karnofsky performance status > 70. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted. Patients with positive HIV serology are eligible. Patients who have previously been taking atorvastatin or any other statin drug will be eligible as long as there is no contraindication to switch to atorvastatin (40mg/day) in the opinion of the treating physician. Method of stem-cell collection from the sibling donor will be at the discretion of the treating physician. Although it is anticipated that majority of sibling donors will undergo Granulocyte colony-stimulating factor(G-CSF) induced stem cell mobilization; however donors undergoing bone marrow harvest or stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for the study. Exclusion Criteria: Uncontrolled arrhythmias or uncontrolled New York Heart Association class III-IV heart failure. Evidence of active bacterial, viral or fungal infection at the time of transplant conditioning. History of intolerance or allergic reactions with atorvastatin will not be eligible. Undergoing a T-cell depleted allogeneic transplantation Receiving conditioning regimens containing anti-thymocyte globulin, and/or campath

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Craig, MD

Organizational Affiliation

West Virginia University

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Mehdi Hamadani, MD

Organizational Affiliation

Medical College of Wisconsin

Official's Role

Principal Investigator

Facility Information:

Facility Name

West Virginia University Hospitals Mary Babb Randolph Cancer Center

City

Morgantown

State/Province

West Virginia

ZIP/Postal Code

26506

Country

United States

Facility Name

Froedtert Hospital and the Medical College of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

17234737

Citation

Deeg HJ. How I treat refractory acute GVHD. Blood. 2007 May 15;109(10):4119-26. doi: 10.1182/blood-2006-12-041889. Epub 2007 Jan 18.

Results Reference

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PubMed Identifier

9746768

Citation

Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14.

Results Reference

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PubMed Identifier

10979948

Citation

Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, Przepiorka D, Davies S, Petersen FB, Bartels P, Buell D, Fitzsimmons W, Anasetti C, Storb R, Ratanatharathorn V. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000 Sep 15;96(6):2062-8.

Results Reference

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PubMed Identifier

12730113

Citation

Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003 Sep 1;102(5):1601-5. doi: 10.1182/blood-2003-02-0489. Epub 2003 May 1.

Results Reference

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PubMed Identifier

15822172

Citation

Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. doi: 10.1146/annurev.pharmtox.45.120403.095748.

Results Reference

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PubMed Identifier

7581076

Citation

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.

Results Reference

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PubMed Identifier

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Citation

Kanate AS, Hari PN, Pasquini MC, Visotcky A, Ahn KW, Boyd J, Guru Murthy GS, Rizzo JD, Saber W, Drobyski W, Michaelis L, Atallah E, Carlson KS, D'Souza A, Fenske TS, Cumpston A, Bunner P, Craig M, Horowitz MM, Hamadani M. Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2017 Aug;23(8):1295-1302. doi: 10.1016/j.bbmt.2017.04.009. Epub 2017 Apr 12.

Results Reference

result

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Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

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