Clinical trial NCT01665677
Conditions: Graft vs Host Disease
Keywords: Graft vs Host Disease GVHD Allogeneic hematopoietic stem cell transplantation HSCT Atorvastatin
Sponsor: Mehdi Hamadani
Start date: 2014-01-20; Completion date: 2021-07-09
Enrollment: 69 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: 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. arm 2: 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.
Interventions: intervention 1: Atorvastatin calcium
Intervention descriptions: intervention 1: 40 mg PO daily

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 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 
 
NCT Number:  NCT01665677 
 
Date:  07/03/2014 


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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. 
 
 
 
Principal Investigator: 
Mehdi Hamadani, MD 
 
Associate Professor of Medicine,  
 
 
Division of Hematology and Oncology 
 
Froedtert Hospital and the Medical College of Wisconsin 
 
9200 W. Wisconsin Ave. 
 
Milwaukee, WI 53226 
 
Co-Investigators: 
Parameswaran Hari, MD 
 
Mary M. Horowitz, MD 
 
William Drobyski, MD 
 
Timothy S. Fenske 
 
Douglas Rizzo, MD 
 
Marcelo Pasquini, MD 
 
 
 
Wael Saber, MD 
 
Michael Craig, MD 
 
Abraham Kanate, MD 
 
William Petros, PharmD 
 
Aaron Cumpston, PharmD 
 
Scot C. Remick, MD 
 
 
 
Statistician: 
 
 
Alexis Visotcky, MS 
 
Biostatistician II 
 
Division of Biostatistics 
 
Institute for Health and Society 
 
avisotcky@mcw.edu 
 
 
  
 
 


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Study Coordinator: 
For Medical College of Wisconsin: 
Barbara Davies 
Division of Hematology and Oncology 
Froedtert Hospital and the Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-805-8926  
Fax: 414-805-0596 
Email: bdavies@mcw.edu  
 
For West Virginia University: 
 
Pam Bunner, MT, CRCC 
Clinical Research Specialist 
Osborn Hematopoietic Malignancy and Bone Marrow Transplant Service 
Mary Babb Randolph Cancer Center 
PO Box 8110 
One Medical Center Drive 
Morgantown, WV 26506 
Phone:  (304) 598-4511 
Fax:  (304) 598-4519 
Email:  bunnerp@wvuhealthcare.com  
 
Pharmacists 
 
Angela Urmanski, Pharm D. 
Froedtert Hospital 
Inpatient Pharmacy 
Attn: Senad Novic 
9200 W Wisconsin Ave 
Milwaukee,  WI 53226 
 
 
Lisa-Giblin Sutton, Pharm D.,  
Investigational Drug Pharmacist 
West Virginia University Hospitals Pharmaceutical Services 
PO Box 8045  
One Medical Center Drive 
Morgantown, WV 26506 
Phone:  (304) 598-4000 x73760 
Fax:  (304) 598-4073 
Email:  giblinl@wvuhealthcare.com  
 
 


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Schema 
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. 
 
PRIMARY OBJECTIVES: 
1. Determine the efficacy of an atorvastatin/tacrolimus/methotrexate regimen in preventing 
grade II-IV acute GVHD in patients undergoing allogeneic hematopoietic stem cell 
transplantation (HSCT).  
2. Assess the safety of an atorvastatin/tacrolimus/methotrexate regimen in patients 
undergoing allogeneic HSCT. 
 
SECONDARY OBJECTIVES: 
1. To assess rates of chronic GVHD. 
2. To assess rates of late onset acute GVHD at days +180 and +365. 
3. To assess rates of grade III-IV acute GVHD at days +100, +180 and +365. 
4. To assess non-relapse mortality at 100 days post-HSCT. 
5. To assess time to successful neutrophil engraftment. 
6. To assess time to successful platelet engraftment. 
7. To assess incidence of primary and secondary graft failure. 
8. To assess incidence of primary and secondary graft rejection. 
9. To assess relapse rate of the primary hematological malignancy.  
10. To assess lineage specific chimerism kinetics in patients at days +28, +100, +180 and 
+365. 
11. To assess immune reconstitution following transplantation at days +28, +100, +180, and 
+365. 
12. To assess 1 year progression free survival (PFS) and overall survival (OS) following 
transplantation.  
13. To evaluate biologic and genomic markers potentially associated with GVHD and/or 
atorvastatin. 
 
 
STUDY DESIGN: 
This is a phase II study of atorvastatin for the prophylaxis of acute GVHD in patients undergoing 
allogeneic HSCT. The study will have two separate arms: (a) Matched sibling transplants, and 
(b) Matched unrelated donors transplants. Both arms will be enrolled, and analyzed separately.  
 
 
 
 
 


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PATIENT ELIGIBILITY CRITERIA: 
1. 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. 
2. 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). 
3. All patients must have at least one suitable HLA-matched sibling or unrelated donor 
according to transplant center’s guidelines (for selection of appropriate donor). 
4. Patient must provide informed consent.  
5. Left ventricular ejection fraction ≥ 40%. No uncontrolled arrhythmias or uncontrolled 
New York Heart Association class III-IV heart failure. 
6. Bilirubin ≤ 2 x the ULN and AST, and ALT ≤ 3 x ULN; and absence of hepatic cirrhosis. 
For patients with Gilbert’s syndrome, bilirubin ≤ 3 x ULN is permitted.  
7. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal 
calculated by Cockcroft-Gault equation. 
8. DLCOcor (corrected for hemoglobin) or FEV1 or DL/VA ≥ 40% of predicted.  
9. Karnofsky performance status > 70.  
10. A negative pregnancy test will be required for all women of child bearing potential. 
Breast feeding is not permitted.  
11. Patients with positive HIV serology are eligible.  
12. No evidence of active bacterial, viral or fungal infection at the time of transplant 
conditioning. 
13. Patients with history of intolerance or allergic reactions with atorvastatin will not be 
eligible.  


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14. 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. 
15. Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. 
16. Patients receiving conditioning regimens containing antithymocyte globulin, and/or 
campath will not be eligible.  
17. Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of donors will undergo 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Patient Treatment Plan 
 
 
 
 
 
 
 
 
Step1
•Registration
•Baseline evaluations (H&P, vital signs, CBC+differential, 
chemisteries, β-HCG, HIV, KPS, infectious disease titers, 
LVEF, DLCO, BMBx, chimerism specimens, Correlative 
specimens)
Step2
• Start atorvastatin 40mg/day orally on Day -14
• Acceptable MAC Regimens are BuCy2; CY/TBI; TBI/VP:16
• Acceptable RIC Regimens are Flu/Bu; Flu/Mel, Flu/TBI
Step3
•Continue atorvastatin until: (1) Day +180 or until patient 
is off IST, (2) patient develop grade II-IV acute GVHD, (3) 
patient develops extensive chronic GVHD, or (4) patient 
develops any grade 3-4 toxicity related to atorvastatin
•Follow patient for survival until day +365


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Table of Contents 
 
1. 
INTRODUCTION: ............................................................................................................................................ 9 
1.1. 
Graft versus Host Disease: ......................................................................................................................... 9 
1.2. 
HMG-CoA Reductase Inhibitors: ............................................................................................................... 9 
1.3. 
Immunomodulatory effects of Statins: ....................................................................................................... 9 
1.4. 
Pathophysiology of GVHD: ..................................................................................................................... 10 
1.5. 
Statins and Murine Acute GVHD: ............................................................................................................ 10 
1.6. 
Statins and Clinical GVHD: ..................................................................................................................... 11 
1.7. 
Clinical Trial Data for Statin use for preventing acute GVHD: ............................................................... 13 
1.8. 
Inclusion of Women and Minorities: ........................................................................................................ 14 
2. 
OBJECTIVES: ................................................................................................................................................. 14 
2.1. 
Primary Objectives: .................................................................................................................................. 14 
2.2. 
Secondary Objectives: .............................................................................................................................. 15 
3. 
ELIGIBILITY CRITERIA: ............................................................................................................................ 15 
3.1. 
Patient Eligibility Criteria: ........................................................................................................................ 15 
4. 
REGISTRATION PROCEDURE: ................................................................................................................. 17 
4.1.1. 
Registration for collaborating institution(s): ........................................................................................ 17 
5. 
TREATMENT PLAN: ..................................................................................................................................... 17 
5.1. 
Administration schedule to Patients (Transplant recipients) .................................................................... 18 
5.2. 
Dose modification .................................................................................................................................... 19 
5.3. 
Duration of therapy ................................................................................................................................... 19 
5.4. 
Data Safety Monitoring Plan .................................................................................................................... 20 
6. 
MEASUREMENT OF EFFECT: ................................................................................................................... 20 
6.1. 
Visit Schedule:.......................................................................................................................................... 20 
*After 12months, patients will be followed at least yearly for survival, relapse and cause of death for 5 years post 
transplantation. ........................................................................................................................................................ 21 
6.2. 
GVHD Assessment: .................................................................................................................................. 21 
6.3. 
Engraftment Assessment: ......................................................................................................................... 22 
7. 
STUDY PARAMETERS (STUDY CALENDAR): ....................................................................................... 22 
7.1. 
Patient Study Calendar: ............................................................................................................................ 22 
8. 
DRUG FORMULATION AND PROCUREMENT ...................................................................................... 25 
8.1. 
Atorvastatin (Lipitor® Pfizer) ................................................................................................................... 25 
8.1.1. 
Drug description .................................................................................................................................. 25 
8.1.2. 
Pharmacodynamics .............................................................................................................................. 25 
8.1.3. 
Pharmacokinetics ................................................................................................................................. 26 
8.1.4. 
Contraindications ................................................................................................................................. 26 
8.1.5. 
Drug Interactions ................................................................................................................................. 26 
8.1.6. 
Adverse Events: ................................................................................................................................... 28 
8.2. 
How supplied and Storage/Handling ........................................................................................................ 29 
8.3. 
Methods of procurement ........................................................................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS: .......................................................................................................... 30 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 32 
DEFINITIONS ........................................................................................................................................................... 32 


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11. 
PATIENT CONSENT AND PEER REVIEW STATEMENT ..................................................................... 36 
11.1. 
Subject Information and Informed Consent .............................................................................................. 36 
12. 
REFERENCES: ............................................................................................................................................... 38 
13. 
APPENDIX A ASSESSMENT OF ACUTE GVHD...................................................................................... 41 
14. 
APPENDIX B GRADING OF CHRONIC GVHD (NIH CRITERIA) ........................................................ 43 
 
 
 


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1. Introduction:   
 
1.1. Graft versus Host Disease: 
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.  
 
1.2. HMG-CoA Reductase Inhibitors:  
HMG-CoA reductase inhibitors (statins), the cholesterol-lowering drugs that are prescribed 
worldwide to prevent and treat atherosclerosis (5), are increasingly being recognized to exhibit a 
variety of immunomodulatory properties (6). The mechanism of action of statins involves 
binding to HMG-CoA reductase and displacement of its natural substrate, HMG-CoA, leading to 
inhibition of mevalonate and cholesterol biosynthesis (5).  
 
1.3. Immunomodulatory effects of Statins: 
In addition to lowering lipid concentrations, statins have recently been shown to possess 
potent immunomodulatory and anti-inflammatory properties that are relevant not only in the 
context of atherosclerosis-associated inflammation but also in autoimmune diseases such as 
multiple sclerosis and rheumatoid arthritis (7-9). Reduced mevalonate production by statins, not 
only inhibits the synthesis of cholesterol but also that of key isoprenoid intermediate molecules 
required for the isoprenylation of GTP-binding cell signaling proteins such as Ras, Rho and Rac 
(5). By inhibiting this posttranslational modification, statins affect intracellular signaling 
pathways and cellular functions such as differentiation, motility, secretion and proliferation 
(7,10).  Inhibiting Ras leads to a bias towards T helper type 2 (Th-2) cell development, and 
inhibition of pro-inflammatory Th-1 driven responses (7,11). This change in intracellular 
signaling can also affect the development of regulatory T (Treg) cells, as exposure of human 
CD4+ T cells to atorvastatin in vitro increases expression of forkhead box P3 (FOXP3) (12). In 
fact increased numbers of circulating FOXP3+ Treg cells are present in dyslipidemic patients 


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taking statins for 4-6 weeks (12). Mira et al. demonstrated statin mediated increases in the 
migration of Treg cells to inflammatory foci in skin by increased the expression of CCL1, the 
ligand for CCR8, a chemokine receptor that is highly expressed on Th-2 cells and FOXP3+ Treg 
cells (13). In addition to direct effects on T cells, statins can also indirectly decrease T-cell 
activation by inhibiting interferon-γ–induced expression of major histocompatibility complex 
class (MHC) II and by blocking up-regulation of a variety of co-stimulatory molecules and 
cytokines in antigen presenting cells (APCs) (7). Hence statins appear to suppress T cell–
dependent immune responses at many levels and hold promise as a new class of 
immunomodulatory drugs, with potential role in preventing acute GVHD. 
 
 
1.4. Pathophysiology of GVHD: 
Acute GVHD is initiated when donor T cells encounter host APCs in lymphoid tissues and 
become activated (14). This T-cell activation process requires co-stimulation via CD80 and 
CD86, which are up-regulated on APCs during the early phase of  acute GVHD. Activation is 
enhanced by local tissue damage due to the conditioning regimen. Local proinflammatory 
cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interferon (IFN)-
gamma, promote Th-1 differentiation of donor-derived T cells and enhance their proliferation 
and reactivity against host tissues (15). Massive cytokine release related to the Th-1 phenotype 
predicts the incidence and severity of acute GVHD in both murine models and humans, whereas 
patients with high IL-10 production are less at risk for GVHD development (16-18).  
 
 
1.5. Statins and Murine Acute GVHD: 
Zeiser and colleagues (19) reported protective effects of atorvastatin against acute GVHD in 
a MHC mismatched mouse model. In a series of elegant experiments, the authors demonstrated 
reduced risk of lethal acute GVHD by pre-treating the donor mice with atorvastatin. T-cells 
derived from these atorvastatin pre-treated mice not only showed reduced proliferation potential, 
but also displayed (both in-vivo and in-vitro) reduced Th-1 cytokine (TNF, IFN-gamma) and 
increased Th-2 cytokine (IL-10, IL-4) production. Zeiser and colleagues also investigated the 
impact of atorvastatin administration to recipient mice. Atorvastatin when given to recipient 


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mice only translated into acute GVHD protection with a long-term survival of 50%, compared 
with 0% survival in control animals. Recipient APCs derived from liver, spleen, and lymph 
nodes of recipient mice getting atorvastatin or PBS were analyzed at different time points after 
transplantation. Surface expression of CD80, CD86, CD40, and MHC class II was decreased in 
animals treated with the atorvastatin as compared with PBS-treated recipients. Interestingly pre-
treating both donor and recipient mice with atorvastatin produced synergistic protective effects, 
when compare with survival of only donor or recipient pre-treated groups. Perhaps the most 
significant finding was that atorvastatin pretreatment did not interfere with perforin-mediated 
cytolysis or Fas–Fas-ligand interaction–mediated killing. In summary these key experiments 
highlight the potential of atorvastatin in protecting against acute GVHD, while preserving the 
graft-versus-leukemia (GVL) effects.  
 
These landmark experiments hold great translational potential for clinical benefit in the 
field of allogeneic SCT. In humans, elevated IL-10 production by peripheral blood mononuclear 
cells before allogeneic SCT is associated with a subsequent low incidence of acute GVHD and 
transplant-related mortality (20,21), whereas low IL-10 promoter activity predicts an increased 
risk for GVHD (19). Shimada and colleagues have shown Th-2 polarization in adult patients with 
acute coronary syndrome after treatment with atorvastatin (22). A number of other publications 
in humans have reported similar findings (23-26)., which highlight the fact that the reduced 
GVHD reported by Zeiser et al (19) by pre-treating donors with atorvastatin in murine models, 
can be translated into real clinical benefit in allogeneic transplant recipients. In humans and 
murine models statins also inhibit the expression of T-bet, a transcription factor critically 
involved in Th-1 cell differentiation (25,27,28). Lastly the down regulation of co-stimulatory 
molecules and MHC-II expression in recipient mice demonstrated by Zeiser et al (19), has also 
been described in humans treated with statin drugs (25,29) 
 
 
1.6. Statins and Clinical GVHD: 
 
Prompted by these tantalizing data, we therefore asked whether statin use at the time of 
allogeneic SCT would result in reduced acute GVHD while sparing GVL activity (30). Sixty-
seven consecutive patients with acute leukemia underwent T-cell replete allogeneic SCT 
between June 2002 and October 2006 at The Ohio State University. Patients taking statins 


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(defined as any HMG-CoA reductase inhibitor) at ≥40mg/day for at least 1month before and 
3months after allogeneic SCT (n=10) were compared to those without a history of statin use 
(n=57). The median age was 43 years (range 20-73yrs). Diagnosis included acute myeloid 
leukemia (AML) (n=49) and acute lymphoblastic leukemia (ALL) (n=18). The two groups had 
similar baseline characteristics. Acute GVHD was scored according to modified consensus 
criteria (31). The rate of grade II-IV acute GVHD was 10% (n=1) in the statin group compared to 
40% (n=23) in the no-statin group (p-value=0.08). 56 patients were evaluable for chronic 
GVHD. No difference in the incidence of chronic GVHD was seen in patients using statins 
(55%) compared to those in no-statin group (57%) (p-value=0.9). No patient in either group 
experience primary or secondary engraftment failure. On subgroup analysis of patients with 
AML only (n=49), a significantly reduced incidence of grade II-IV acute GVHD was seen in 
statin group (0%) compared to 43% (n=18) in the no-statin group (p-value=0.02). Rates of 
chronic GVHD were 43% and 58% in similar order (p-value=0.68). We further explored to see if 
statin use, while reducing acute GVHD, mitigated the GVL effect in patients with AML. Kaplan-
Meier estimates of progression free survival (PFS) at 3years in AML patients with or without 
statin use were 54% and 28% respectively (p-value=0.17) respectively (Figure 1). This non 
significant trend of improved PFS indicates that the GVL is preserved in patients using statins at 
the time of allografting.  
 
 
Figure 1. KM estimates of PFS following allogeneic SCT in patients with AML. 
 


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Rotta et al. retrospectively analyzed outcomes among 567 patients with hematologic 
malignancies who had hematopoietic cell transplantation from human leukocyte antigen-
identical sibling donors between 2001 and 2007 for a correlation between statin use and risk of 
GVHD. Compared to allografts where neither the donor nor recipient was treated with a statin at 
the time of transplantation (n = 464), statin use by the donor was associated with a decreased risk 
of grade 3-4 acute GVHD (multivariate hazard ratio, 0.28; 95% confidence interval, 0.1-0.9). 
Statin use by both donor and recipient (n = 12) was suggestively associated with a decreased risk 
of grade 3 or 4 acute GVHD (multivariate hazard ratio, 0.00; 95% confidence interval, 
undefined). Risks of chronic GVHD, recurrent malignancy, nonrelapse mortality, and overall 
mortality were not significantly affected by donor or recipient statin exposure. Statin-associated 
GVHD protection was restricted to recipients with cyclosporine-based postgrafting 
immunosuppression and was not observed among those given tacrolimus (P = .009). These 
results suggest that donor statin treatment may be a promising strategy to prevent severe acute 
GVHD without compromising immunologic control of the underlying malignancy. 
In summary these limited but encouraging retrospective studies, and the extensive pre-
clinical and clinical data suggest that the observations made by Zeiser and colleagues (19) in a 
murine model may have clinical relevance and hints at the potential of statins in reducing acute 
GVHD.  
 
1.7. Clinical Trial Data for Statin use for preventing acute GVHD: 
Based on these data our group, opened a single-arm phase-II study evaluating the safety 
and efficacy of atorvastatin for the prophylaxis of acute graft-versus-host disease in patients with 
hematological malignancies undergoing HLA-matched sibling donor hematopoietic SCT (WVU 
protocol #11010; study registered www.clinicaltrials.gov NCT01175148). To date (September 
26, 2013) 30 donor/patient pairs have been enrolled on this protocol WVU 11010. All healthy 
donors have tolerated atorvastatin with no significant side effects. No statin related grade 3-5 
toxicity in donors was seen. Similarly all patients so far have tolerated atorvastatin well, with no 
study drug related grade 3-5 toxicity. No liver function abnormalities or cases of myopathy were 
seen. In terms of the primary outcome of WVU11010 (i.e. rates of grade II-IV acute GVHD at 
day +100 post transplantation), only one patient experienced grade II acute GVHD before day 
100. In the current protocol, we will evaluate the role of atorvastatin in addition to methotrexate 


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and tacrolimus for the prophylaxis of acute GVHD when administered to transplant recipient 
alone, to assess if routine administration of atorvastatin to healthy sibling donors is warranted. 
This protocol will also include patients undergoing unrelated donor transplantation to see if 
atorvastatin can maintain GVHD rates, seen in transplants using ATG. While some retrospective 
studies (31), but not all (30), suggest that statin-mediated benefit for preventing acute GVHD is 
limited to patients receiving cyclosporine-based GVHD prophylaxis, in our study use of 
cyclosporine prophylaxis is not permitted for two reasons: 1) Our prior study has shown 
excellent safety and efficacy profile of atorvastatin/tacrolimus/methotrexate combination 
[Hamadani M et al. Journal of Clinical Oncology. Accepted manuscript in press], and 2) strong 
drug interaction between cyclosporine and atorvastatin (please see section 8.1.5). 
 
1.8. Inclusion of Women and Minorities:  
 
It is the policy of the Mary Babb Randolph Cancer Center to strive for gender and 
minority patient participation that represents the population of West Virginia in all clinical 
investigations. Between January 1st 2009 and December 31st 2009, 125 patients were enrolled 
onto Phase I/II/III trials at the Mary Babb Randolph Cancer Center.  Of these patients 73% 
percent were female (n=92) and 2.4 percent were members of minority ethnic groups.  It is 
anticipated that a similar or greater proportion of patients on this study will be female and/or 
members of ethnic minorities.    
 
 
2. Objectives:  
 
2.1. Primary Objectives: 
 
1. Determine the efficacy of an atorvastatin/tacrolimus/methotrexate regimen in preventing 
grade II-IV acute GVHD in patients undergoing allogeneic hematopoietic stem cell 
transplantation (HSCT).  
2. Assess the safety of an atorvastatin/tacrolimus/methotrexate regimen in patients 
undergoing allogeneic HSCT. 
 


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2.2. Secondary Objectives: 
 
1. To assess rates of chronic GVHD. 
2. To assess rates of late onset acute GVHD at days +180 and +365. 
3. To assess rates of grade III-IV acute GVHD at days +100, +180 and +365. 
4. To assess non-relapse mortality at 100 days post-HSCT. 
5. To assess time to successful neutrophil engraftment. 
6. To assess time to successful platelet engraftment. 
7. To assess incidence of primary and secondary graft failure. 
8. To assess incidence of primary and secondary graft rejection. 
9. To assess relapse rate of the primary hematological malignancy.  
10. To assess lineage specific chimerism kinetics in patients at days +28, +100, +180 and 
+365. 
11. To assess immune reconstitution following transplantation at days +28, +100, +180, and 
+365. 
12. To assess 1 year progression free survival (PFS) and overall survival (OS) following 
transplantation.  
13. To evaluate biologic and genomic markers potentially associated with GVHD and/or 
atorvastatin. 
 
3. Eligibility Criteria: 
 
3.1. Patient Eligibility Criteria: 
 
1. 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. 
2. 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 


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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). 
3. All patients must have at least one suitable HLA-matched sibling or unrelated donor 
according to transplant center’s guidelines (for selection of appropriate donor). 
4. Patient must provide informed consent.  
5. Left ventricular ejection fraction ≥ 40%. No uncontrolled arrhythmias or uncontrolled 
New York Heart Association class III-IV heart failure. 
6. Bilirubin ≤ 2 x the ULN and AST, and ALT ≤ 3 x ULN; and absence of hepatic 
cirrhosis. For patients with Gilbert’s syndrome, bilirubin ≤ 3 x ULN is permitted.  
7. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal 
calculated by Cockcroft-Gault equation. 
8. DLCOcor (corrected for hemoglobin) or FEV1 or DL/VA ≥ 40% of predicted.  
9. Karnofsky performance status > 70.  
10. A negative pregnancy test will be required for all women of child bearing potential. 
Breast feeding is not permitted.  
11. Patients with positive HIV serology are eligible.  
12. No evidence of active bacterial, viral or fungal infection at the time of transplant 
conditioning. 
13. Patients with history of intolerance or allergic reactions with atorvastatin will not be 
eligible.  
14. 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. 
15. Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. 
16. Patients receiving conditioning regimens containing antithymocyte globulin, and/or 
campath will not be eligible.  
17. Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of donors will undergo G-CSF 
induced stem cell mobilization; however donors undergoing bone marrow harvest or 


Version Date 07/03/14 
17 
 
stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for 
the study.  
 
4. Registration Procedure: 
 
4.1. Registration  
 
• 
All source documents that support eligibility including a signed informed 
consent/HIPAA and signed eligibility checklist, should be available review and 
eligibility verification.   
• 
At the point of registration, the research nurse or data manager will register the patient in 
the electronic database, including demographic, consent and on-study information.  The 
patient will be assigned a unique sequence number for the study. 
4.1.1. 
Registration for collaborating institution(s): 
• 
The collaborating institution (e.g. WVU) must contact Study Coordinator at MCW prior 
to registering a patient.  After speaking with the Study Coordinator, the following 
documents should be faxed to 414-805-9025 to begin the registration process: 
 The dated and signed informed consent 
 A physician signed eligibility checklist 
 All source documents that validate eligibility 
 The demographic form 
• 
Written confirmation (via email to study coordinator at WVU) will be sent to the site 
once the patient has been enrolled into the study to issue the unique patient identifier and 
cohort as applicable. 
 
5. Treatment Plan: 
 
This is a phase II study of atorvastatin for the prophylaxis of acute GVHD in patients undergoing 
allogeneic HSCT. The study will have two separate arms: (a): Matched sibling transplants, and 
(b): Matched unrelated donors transplants. Both arms will be enrolled and analyzed separately. 
 


Version Date 07/03/14 
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5.1. Administration schedule to Patients (Transplant recipients) 
1. Atorvastatin will be administered at dose of 40mg 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.  
2. 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.  
3. Patients undergoing myeloablative conditioning (MAC) matched sibling or unrelated 
donor allogeneic transplantation can receive one of following three conditioning 
regimens: 
a) Busulfan ≥0.8 mg/kg/dose (16 doses given every 6 hours, IV on days –7 to –4), 
and cyclophosphamide 60 mg/kg/dose (2 doses given every 24hours, IV on days –
3 and –2). Monitoring busulfan levels with this regimen, per institutional practice, 
is recommended. Oral busulfan is not permitted.  
b) Total body irradiation (>500cGy) and cyclophosphamide as above.  
c) Total body irradiation (>1200cGy) and etoposide. 
d) Other ablative regimens will be permitted after consultation with study PI. 
4. Patients undergoing reduced-intensity conditioning (RIC) matched sibling or unrelated 
donor allogeneic transplantation will receive one of following three regimens: 
 
a) Fludarabine and IV busulfan-based regimen (Flu/Bu2 or Flu/Bu4).  
b) Fludarabine and low dose total body irradiation (200-400cGy) 
c) Fludarabine and melphalan (<140mg/m2) 
d) Other RIC will be permitted after consultation with study PI. 
In addition to atorvastatin, standard GVHD prophylaxis will consist of:Tacrolimus (0.015 
mg/kg I.V every 12 hours or 0.03 mg/kg/day PO; starting day -2) and mini-dose 
methotrexate (5mg/m2 on days +1, +3, +6 and +11). Tacrolimus will be monitored to keep 
levels between 5-12 ng/ml for matched sibling and between 8-12 ng/ml for unrelated donor 
HCT. In absence of acute GVHD, renal insufficiency and disease relapse/progression it is 
recommended that tacrolimus taper SHOULD NOT commence before day +100. The goal 
of tapering is the complete discontinuation of immunosuppressive medications by (but not 
before) day +180. Tacrolimus should be tapered every two to three weeks. Attempt should be 


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19 
 
made to apply similar reductions in dosages at each tapering event, to allow complete 
discontinuation of immunosuppression by day +180. It is recommended by not required that 
tacrolimus dose be reduced by no more than 25% at each tapering event. 
5. Administration of cyclosporine (because of associated risk of myopathy with 
atorvastatin), mycophenolate mofetil, monoclonal (e.g. campath) or polyclonal antibodies 
(e.g. antithymocyte globulin) will not be permitted for GVHD prophylaxis. 
6. Antibiotic prophylaxis will be given according to institutional guidelines. 
7. Temporary interruption (≤10-14days) of atorvastatin is permitted in patients unable to 
tolerate oral intake secondary to severe nausea, vomiting, mucositis etc. Administration 
of atorvastatin via feeding tubes is permitted. In case atorvastatin therapy is interrupted, 
the time interval should be recorded. 
8. Toxicity will be evaluated according to CTCAE v4.0. 
9. Progression free survival (PFS) and overall survival (OS) following transplantation will 
be recorded. 
 
5.2. Dose modification 
1. Patients experiencing a grade 3-4 hematological or non-hematological toxicity (as 
specified in CTCAE v4.0) thought to be related to atorvastatin will be removed from the 
study permanently. No dose modifications for atorvastatin are permitted. 
2.  Decision to hold atorvastatin in patients developing grade 3-4 liver function 
abnormalities (bilirubin, AST and ALT) post-HSCT will be at the discretion of treating 
physician. In such patients if liver function abnormalities are thought not be related to the 
study drug, then atorvastatin prophylaxis can be restarted at time of resolution of hepatic 
transaminases (to grade 1 or less) after consulting with principal investigator. 
 
5.3. Duration of therapy 
        Atorvastatin will be continued until one of the following criteria is met: 
- 
Patient is no longer on immunosuppressive medications or until day +180 after 
transplantation, whichever occurs first. 
- 
Patient develops grade II-IV acute GVHD.  
- 
Patient develops severe chronic GVHD. 


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20 
 
- 
Patient develops any grade 3-4 toxicity related to atorvastatin use. 
Patients experiencing a disease relapse (before day +180) can continue atorvastatin at the 
discretion of treating physician, provided the patient has not been tapered off of tacrolimus.  
 
5.4. Data Safety Monitoring Plan 
At West Virginia University: This protocol will adhere to the policies of the Mary Babb 
Randolph Cancer Center Data and Safety Monitoring Plan, guidelines in accordance with 
NCI regulations. The Data and Safety Toxicity Committee (DSTC) will review all 
serious adverse events and toxicity reports as well as continuing reviews.  This study is 
designated as a moderate risk level and requires quarterly summary reporting to the 
DSTC. 
 
At Medical College of Wisconsin: The Medical College of Wisconsin Cancer Center 
Data Safety Monitoring Committee (DSMC) is responsible for monitoring data quality 
and subject safety for all cancer center investigator initiated clinical trials.  A six to eight 
member Data and Safety Monitoring Committee will complete a review of protocol-
specific data safety monitoring reports, to provide recommendations on trial continuation, 
suspension or termination.  The DSMC will review these reports no less than bi-annually.  
A summary of the DSMC activities are as follows 
• Review the clinical trials for data integrity and safety 
• Review all adverse events requiring expedited reporting as defined per protocol 
• Review all DSM reports 
• Submit a summary of any recommendations related to study conduct 
• Terminate the study if deemed unsafe for patients 
6. Measurement of Effect: 
 
6.1. Visit Schedule: 
The schedule for the study is shown in the table below. 
Study Visit  
Target Day Post-
Transplant  
1 week  
7 ± 3 days  
2 week  
14 ± 3 days  


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3 week  
21 ± 7 days  
4 week  
28 ± 7 days  
5 week  
35 ± 7 days  
6 week  
42 ± 7 days  
7 week  
49 ± 7 days  
8 week  
56 ± 7 days  
9 week  
63 ± 7 days  
10 week  
70 ± 7 days  
11 week  
77 ± 7 days  
12 week  
84 ± 7 days  
100 day  
100± 7 days  
6 month  
180 ± 28 days  
12 month* 
365 ± 28 days  
 
 
 
*After 12months, patients will be followed at least yearly for survival, relapse and cause of 
death for 5 years post transplantation. 
 
6.2. GVHD Assessment: 
Following neutrophil engraftment, patients will be monitored for development of acute and 
chronic GVHD at once a week until day +100. After Day 100, patients will be assessed at 
each study visit for the presence of GVHD. Diagnosis of acute GVHD will require biopsy 
confirmation in at least one involved organ. When more than one organ is involved, biopsy 
confirmation of all involved organs is recommended but not necessary. Liver-only GVHD 
must be confirmed by biopsy. Acute GVHD will be assessed by consensus criteria 
(Appendix A) (32) and graded on BMT CTN MOP suggested grading sheets (Appendix A). 
Acute GVHD assessment and grading will be performed by treating physicians. Chronic 
GVHD diagnosis and grading will be according to NIH Criteria. Please see Appendix B (33-
34). 
 
Clinical Grading of Chronic GVHD (According to Appendix B) 
None 
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see below ‡), 
with no clinically significant functional impairment (maximum of score 1 in all affected 
organs or sites) 


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Moderate chronic GVHD involves: (1) at least 1 organ or site with clinically significant 
but no major disability (maximum score of 2 in any affected organ or site) or (2) 3 or more 
organs or sites with no clinically significant functional impairment (maximum score of 1 in 
all affected organs or sites). ‡A lung score of 1 will also be considered moderate chronic 
GVHD. 
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in 
any organ or site). ‡A lung score of 2 or greater will also be considered severe chronic 
GVHD. 
 
 
6.3. Engraftment Assessment: 
Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 500 x 
109/L post-conditioning regimen induced nadir. Similarly platelet engraftment is defined as 
first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days. 
Lineage specific chimerism analysis (CD3 and CD33 subsets), quantitative 
immunoglobulins and immune reconstitution will be performed on days +28, +100, +180 
and +365. 
 
7. Study Parameters (Study Calendar): 
 
7.1. Patient Study Calendar:  
 
The table below summarizes the patient clinical assessments over the course of the study. 


Version Date 07/03/14 
23 
 
 
Study Assessment 
 
Baseline1 
 
Day-14 
 
Day0 
Days Post-Transplantation 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
100 
180 
36515 
Informed consent and H & PE2 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Vital signs3 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Karnofsky performance status 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
CBC/differential & platelet count 
X 
 
X 
X4 
X4 
X4 
X4 
 
 
 
 
X 
 
 
 
X 
X 
X 
Serum chemistries panel5 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Infectious disease titer6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVEF7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV quantitative PCR 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bone marrow aspirate/biopsy8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Β-HCG serum pregnancy test 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins10 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Peripheral blood for chimerism 
X13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Immune reconstitution panel11 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
CD34/CD3 cell dose infused 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute/chronic GVHD assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research specimens (voluntary)12 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
ANC and platelet recovery14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Notes 
H & PE= history and physical examination 
1Baseline refers to the period prior to conditioning. Assessments should be made within 4 weeks prior to day of conditioning. 
2History is only required at baseline. 
3Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
4Daily during the post-infusion period while hospitalized (recommended) and once weekly after discharge until Day 28. 
5Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, LDH, albumin. Electrolytes to include 
sodium, potassium, chloride, carbon dioxide, and calcium. 
6Infectious disease titers: Cytomegalovirus (CMV) antibody test, hepatitis panel (Hepatitis B including HBsAg, HBcAb; Hepatitis C Ab), HIV 
including HIV testing, syphilis, Epstein-Barr Virus (EBV) IgG and IgM, herpes simplex virus (HSV) IgG and IgM  
7To be determined by MUGA or echocardiogram. 
8Required at baseline. On Days +100, +180 and +365, bone marrow biopsy will be performed if clinically indicated. Other tests and/or 
imaging studies for response assessment will be performed as clinically indicated. 
9Females of reproductive potential only. 
10IgG, IgM and IgA. 
11Peripheral blood flow cytometry to assess recipient immune reconstitution. 
12Peripheral blood specimens: draw 15 mL in  purple top  (EDTA containing) tubes AND 5 mL in blue top (citrate containing) tubes at 
indicated time points and send to the Biospecimen Processing Core at WVU. At MCW voluntary research specimens will not be collected.  
13Chimersim testing to be performed prior to study from BOTH donor and recipient at any time point. Chimerism testing should be sorted 
(lineage specific) to assess myeloid and lymphoid cell chimerism.  
14Record time to neutrophil engraftment defined as first of three consecutive days with ANC ≥ 500 x 109/L, and platelet engraftment defined 
as first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days. 
15After day 365, patients will be followed at least yearly for survival, relapse and cause of death for a total of 5 years post transplantation.


Version Date 07/03/14 
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8. Drug Formulation and Procurement 
 
8.1. Atorvastatin (Lipitor® Pfizer)  
8.1.1. 
Drug description 
LIPITOR is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the 
conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol 
biosynthesis. Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5- 
(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, 
calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is 
(C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.42. Its structural formula 
is: Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in 
aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in 
distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and 
freely soluble in methanol. LIPITOR Tablets for oral administration contain 10, 20, 40, 
or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate, USP; 
candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, cellulose, 
NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium 
dioxide); polysorbate 80, NF; simethicone emulsion. 
 
 
8.1.2. 
Pharmacodynamics 
LIPITOR, as well as some of its metabolites, are pharmacologically active in humans. 
The liver is the primary site of action and the principal site of cholesterol synthesis and 


Version Date 07/03/14 
26 
 
LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better 
with LDL-C reduction.  
 
8.1.3. 
Pharmacokinetics 
Absorption: LIPITOR is rapidly absorbed after oral administration; maximum plasma 
concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to 
LIPITOR dose. The absolute bioavailability of atorvastatin (parent drug) is 
approximately 14% and the systemic availability of HMG-CoA reductase inhibitory 
activity is approximately 30%. The low systemic availability is attributed to presystemic 
clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food 
decreases the rate and extent of drug absorption by approximately 25% and 9%, 
respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether 
LIPITOR is given with or without food.  
 
8.1.4. 
 Contraindications  
Active Liver Disease which may include Unexplained Persistent Elevations of Hepatic 
Transaminase Levels 
Hypersensitivity to any Component of this Medication 
Pregnancy 
Nursing Mothers 
 
8.1.5. 
 Drug Interactions 
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis include 
the following. 
Interacting Agents                                 
Prescribing Recommendations 
Cyclosporine 
Atorvastatin is a substrate of the OATP1B1 
transporter. Inhibitors of the OATP1B1 (e.g., 
cyclosporine) can significantly increase the 
bioavailability of atorvastatin. Concomitant 
administration of atorvastatin and cyclosporine is 
not permitted on the protocol. 
Clarithromycin, itraconazole, HIV protease inhibitors 
Caution when exceeding doses 


Version Date 07/03/14 
27 
 
(ritonavir plus saquinavir or lopinavir plus ritonavir) 
> 20mg atorvastatin daily. The 
lowest dose necessary should be used. 
Atorvastatin is metabolized by cytochrome P450 3A4. 
Concomitant administration of atorvastatin with 
inhibitors of cytochrome P450 3A4 can potentially lead 
to increased plasma atorvastatin concentrations.  
Use of strong inhibitors of cytochrome P450 3A4 
(erythromycin, clarithromycin, protease 
inhibitors, diltiazem, or itraconazole), with 
atorvastatin should be done with caution.  
Grapefruit juice 
: Contains one or more components that inhibit 
CYP 3A4 and can increase plasma concentrations 
of atorvastatin, especially with excessive 
grapefruit juice consumption (>1.2 liters per 
day). 
Gemfibrozil 
Due to an increased risk of 
myopathy/rhabdomyolysis when HMG-CoA 
reductase inhibitors are co-administered with 
gemfibrozil, concomitant administration of 
LIPITOR with gemfibrozil should be avoided 
Digoxin 
Digoxin concentrations are unaffected 
by atorvastatin doses of <80mg/day 
Rifampin or other Inducers of Cytochrome P450 3A4: 
Concomitant administration of LIPITOR with 
inducers of cytochrome P450 3A4 (e.g., 
efavirenz, rifampin) can lead to variable 
reductions in plasma concentrations of 
atorvastatin. Due to the dual interaction 
mechanism of rifampin, simultaneous co-
administration of LIPITOR with rifampin is 
recommended, as delayed administration of 
LIPITOR after administration of rifampin has 
been associated with a significant reduction in 
atorvastatin plasma concentrations. 
                                               
 
 
 
 


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8.1.6. 
 Adverse Events: 
Skeletal Muscle 
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have 
been reported with LIPITOR and with other drugs in this class. A history of renal 
impairment may be a risk factor for the development of rhabdomyolysis. Such patients 
merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, 
occasionally causes myopathy, defined as muscle aches or muscle weakness in 
conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The 
concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine 
and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease 
inhibitors) increases the risk of myopathy/rhabdomyolysis. Myopathy should be 
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or 
marked elevation of CPK. Patients should be advised to report promptly unexplained 
muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 
LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or 
myopathy is diagnosed or suspected. 
Liver Dysfunction 
Statins, like some other lipid-lowering therapies, have been associated with biochemical 
abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal 
[ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of 
patients who received LIPITOR in clinical trials. The incidence of these abnormalities 
was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively 
Endocrine Function 
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or 
gonadal steroid production. Clinical studies have shown that LIPITOR does not reduce 
basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on 
male fertility have not been studied in adequate numbers of patients. The effects, if any, 
on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be 
exercised if a statin is administered concomitantly with drugs that may decrease the 
levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, 
and cimetidine. 


Version Date 07/03/14 
29 
 
CNS Toxicity 
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain 
hemorrhage and optic nerve vacuolation were seen in another female dog that was 
sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. 
The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human 
plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human 
dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one 
treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions 
have been observed in mice after chronic treatment for up to 2 years at doses up to 400 
mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times 
(mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum 
recommended human dose of 80 mg/day. 
Other adverse reactions reported in placebo-controlled studies include: Body as a 
whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, 
hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck 
pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver 
function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase 
increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin 
and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: 
white blood cells urine positive. 
 
8.2. How supplied and Storage/Handling  
 
40 mg tablets: coded “PD 157” on one side and “40” on the other. 
NDC 0071-0157-23 bottles of 90 
NDC 0071-0157-73 bottles of 500 
NDC 0071-0157-88 bottles of 2500 
NDC 0071-0157-40 10 x 10 unit dose blisters  
Stored at controlled room temperature 20 - 25°C (68 - 77°F). 
 
 


Version Date 07/03/14 
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8.3. Methods of procurement         
 
The Medical College of Wisconsin & West Virginia University Hospitals Departments of 
Pharmacy will order Atorvastatin 40mg and receive drug specifically for this study.  The 
CTRU (at WVU) and CTO (at MCW) will be billed for the cost of the drug which will be 
paid for by study funds.  The drug will be dispensed per patient and labeled according to 
more stringent state or federal law.  Drug accountability and inventory records will be 
created and maintained within the Investigational Drug Services. 
 
9. Statistical Considerations: 
 
The study is a single-arm phase II trial evaluating the safety and efficacy of atorvastatin for 
the prophylaxis of acute GVHD in patients with hematological malignancies undergoing 
HLA-matched HSCT. The primary objective of this study is to evaluate the cumulative 
incidence of grade II-IV acute GVHD by day +100 in patients receiving acute GVHD 
prophylaxis with atorvastatin, tacrolimus and methotrexate. The incidence of grade II-IV 
acute GVHD in patients undergoing MAC or RIC matched sibling allogeneic SCT, and 
receiving GVHD prophylaxis with tacrolimus and methotrexate is approximately 30-40%. 
The respective rates for patients undergoing RIC unrelated donor transplantation with ATG 
are 45-55% and without ATG 50-60%. The sibling and unrelated donor arms of this study 
will be analyzed separately, with aim for separate publications. At the time of publication the 
results of unrelated donor arm of the study will be retrospectively compared against patients 
undergoing unrelated transplantation at our center after conditioning with Flu/Bu2 or 
Flu/Bu4 and receiving GVHD prophylaxis with tacrolimus, MTX and ATG. 
 
For this phase II study, we will use an open-label, minimax two-stage design as specified by 
Simon. We will consider the “experimental” acute GVHD prophylactic regimen of 
atorvastatin/tacrolimus/methotrexate to be no more effective than GVHD prophylaxis with 
tacrolimus/methotrexate alone for matched sibling allogeneic HCT, if the true probability of 
developing grade II-IV acute GVHD is more than 35% (p0). We will also assume that the 
new prophylactic regimen is worthy of further study if the true probability of grade II-IV 


Version Date 07/03/14 
31 
 
acute GVHD is equal or less than 15% (p1). In statistical terms, we are testing the null 
hypothesis H0: p≥0.35, versus the alternate H1: p≤0.15, where p is probability of grade II_IV 
acute GVHD. These figures result in a two-stage design of 25 and 30 patients during stage 1 
and 2 respectively, with an alpha of 0.05 and beta of 0.20. In the first stage, we will enter 25 
patients undergoing matched sibling transplantation. If 6 or more of these patients develop 
grade II-IV acute GVHD, we will stop and conclude in favor of H0: p≥0.35. If only 5 or less 
of the first 25 patients develop grade II-IV acute GVHD, we will enter an additional 5 
patients, for a total of 30 patients. In the final analysis, if 7 or fewer of the 30 patients 
develop grade II-IV acute GVHD we will reject null hypothesis. 
 
 
For the unrelated donor HCT arm of this study we will consider the “experimental” 
acute GVHD prophylactic regimen of atorvastatin/tacrolimus/methotrexate to be no more 
effective than GVHD prophylaxis with tacrolimus/methotrexate alone, if the true probability 
of developing grade II-IV acute GVHD is more than 55% (p0). We will also assume that the 
new prophylactic regimen is worthy of further study if the true probability of grade II-IV 
acute GVHD is equal or less than 40% (p1). In statistical terms, we are testing the null 
hypothesis H0: p≥0.55, versus the alternate H1: p≤0.35, where p is probability of grade II_IV 
acute GVHD. These figures result in a two-stage design of 30 and 39 patients during stage 1 
and 2 respectively, with an alpha of 0.05 and beta of 0.20. In the first stage, we will enter 30 
patients undergoing unrelated donor transplantation. If 14 or more of these patients develop 
grade II-IV acute GVHD, we will stop and conclude in favor of H0: p≥0.55. If only 13 or 
less of the first 30 patients develop grade II-IV acute GVHD, we will enter an additional 9 
patients, for a total of 39 patients. In the final analysis, if 17 or fewer of the 39 patients 
develop grade II-IV acute GVHD we will reject null hypothesis. 
We anticipate that a maximum of 30 each, matched sibling and unrelated donor patients will 
be accrued to the study provided 10 or less patients develop grade II-IV acute GVHD during 
the first stage of the study. Descriptive statistics (i.e. means, standard deviations, 95% 
confidence intervals for continuous variables, and frequencies for discrete data) will be 
computed for all correlative laboratory parameters.  
 
Safety/Stopping Rules: 


Version Date 07/03/14 
32 
 
1. 
Development of grade 3-4 adverse events deemed to be related to atorvastatin in 6 or 
more transplant recipients, will mandate halting further patient accrual until review by 
DSMB. 
2. 
Cumulative incidence of relapse of >50% (with NRM as competing event) observed 
after enrolling at least 20 patients in each cohort, will mandate halting further patient accrual 
until review by DSMB. 
3. 
In patients complaining of grade II or worse muscle pain, weakness or myopathy, a 
serum CPK level will be checked to rule out development of rhabdomyolysis.  
 
Accrual Estimate: 55-69 patients. Patients experiencing mortality within 100 days of 
transplant due to disease relapse/progression, will be replaced to fully assess late onset acute 
GVHD rates. However, all patients will be included in toxicity and survival analysis. 
Accrual Period :  Approximately 24-36 months 
 
 
Follow-Up Period : One year to evaluate incidence of acute and chronic GVHD and relapse 
pattern. Five years for survival outcomes, relapse, and mortality.  
 
10. Adverse Event Reporting Requirements 
 
Definitions 
 
The following are definitions of adverse events as defined by 21CFR312.32. 
 
Types of Adverse Events 
 
Adverse Event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not consider drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction:  An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
 


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Serious adverse event or serious suspected adverse reaction:  An adverse event or suspected 
adverse reaction is considered “serious” if, in the view of the investigator or sponsor, it results in 
any of the following outcomes: 
 
• Death, 
• A life-threatening prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent of the outcomes listed above.   
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse event.  Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction:  An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, it is not consistent with the risk information currently 
described.   
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
 


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Adverse Event Grading 
 
Grade 
Description 
 
0 
No AE (or within normal limits). 
 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing 
cautery) indicated; limiting age-appropriate instrumental activities of 
daily living (ADL). 
 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
 
4 
Life-threatening consequences; urgent intervention indicated. 
 
5 
Death related to AE 
 
 
Adverse Event Attribution 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigationl 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
Reporting of Adverse Events 
Because all of the study transplant recipients will be receiving potentially toxic preparative 
therapy, significant regimen related toxicity is expected.  These risks are listed in the consent 
form.  A study specific toxicity CRF will be designed to capture information regarding these 
expected events.  Transplant is also related to a degree of mortality and this will also be captured 
by a study designed CRF.  Unexpected adverse events will be reported throughout the study. 


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The sub-site (i.e. West Virginia University) must report all serious adverse events to the sponsor-
investigator (SAE FAX-414-805-9025 or Froedtert Hospital and the Medical College of 
Wisconsin Cancer Center Clinical Trials Office 9200 W. Wisconsin Ave. Milwaukee, WI) so that 
the sponsor-investigator can meet his/her foregoing reporting obligations to the required 
regulatory agencies, unless otherwise agreed between the sponsor-investigator and sub-
investigator(s).   
Unexpected Adverse Events 
Grades 3-5 (severe, life threatening, disabling, or fatal) require expedited reporting and will be 
submitted to the DSTC within 24 hours of discovery for review.  If the Grade 3-5 event is 
determined to be an unanticipated problem, the event will be forwarded to the WVU IRB for 
review as required by their policy.  Unexpected adverse events, regardless of severity, will be 
reported to the DSTC and reviewed on a quarterly basis. 
 
Expected Adverse Events 
All fatal (grade 5) expected adverse events require expedited reporting and will be reported to 
the DSTC within 24 hours for review.  Expected adverse events that are being captured on the 
study toxicity form will be reported at the time of the form’s scheduled due date.   
 
All DSTC reports and recommendations will be submitted to the IRB for their review. 
 
Adverse Events Occurring after the End of the Study 
 
Follow-up of AEs 
Any unexpected AEs ongoing at the time of study discontinuation will be followed until 
resolution or stable for at least 2 months.  
 
 
FDA Reporting Procedures  
 
Commercial Agents:    Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source.  In some cases an agent obtained commercially may 


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be used for indications not included in the package label.  The following procedures should be 
followed to determine if an adverse is reportable to the FDA: 
 
Refer to the pharmaceutical section of the protocol to determine if an agent is investigational or 
commercial.   
• 
WHAT TO REPORT:  An unexpected, life-threatening (Grade 4) or unexpected, fatal (Grade 5) 
adverse event with an attribution of possible, probable or definite. 
 
• 
WHEN TO REPORT:  These events should be reported within (7) working days. 
 
 
• 
WHERE TO REPORT:  These adverse events with commercial agents must be reported to the 
FDA using the MedWatch form.  A copy of the MedWatch form can be obtained from theFDA’s 
MedWatch web site at www.fda.gov/medwatch.  You can mail the reports to the address below or 
fax it 1-800-332-0178. 
MedWatch 
 
5600 Fishers Lane 
Rockville, MD 20852-9787 
 
11. Patient Consent and Peer Review Statement 
11.1. 
Subject Information and Informed Consent 
 
Written informed consent must be obtained from the subject prior to study participation. 
 
The informed consent document must be signed and dated by the subject and properly 
witnessed (if applicable) before initiation of any study procedures including any change 
in medication or initiation of study drug dosing.   
 
Subjects must be consented in accordance with all local regulatory and legal 
requirements.  This process must include a verbal explanation of the nature, scope, and 
possible consequences of the study provided in plain language.  The information should 


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be presented by the investigator unless a designee is permitted by local regulations.  The 
potential study subject should be encouraged to ask questions about the study.   
 
The informed consent document must be prepared in accordance with GCP guidelines 
and with local regulatory and legal requirements.  A copy of the signed consent form will 
be given to the subject and the original document must be safely archived by the 
investigator so that the forms can be retrieved at any time for monitoring, auditing, and 
inspection purposes. 
 
The informed consent will be updated as appropriate (e.g., due to protocol amendment or 
if significant new safety information that may be relevant to consent of the subjects 
becomes available).  If the informed consent is revised, it is the investigator’s 
responsibility to ensure that an amended consent form is reviewed and signed by all 
subjects subsequently entered into the study and those currently in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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38 
 
12. References: 
 
1. Deeg HJ. How I treat refractory acute GVHD. Blood 2007; 109(10): 4119-4126. 
2. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. 
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; 92(7): 2303-2314. 
3. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. 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; 96(6): 2062-2068. 
4. Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, et al. Sirolimus, tacrolimus, 
and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched 
related donor or unrelated donor transplantation. Blood 2003; 102(5): 1601-1605. 
5. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 
2005;45:89-118. 
6. Broady R, Levings MK. Graft-versus-host disease: suppression by statins. Nat Med. 2008 
Nov;14(11):1155-6. 
7. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from 
protein prenylation to immunomodulation. Nat Rev Immunol. 2006 May;6(5):358-70.  
8. Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in 
inflammatory arthritis. J Immunol 2003; 170:1524–1530. 
9. Youssef S, Stuve O, Patarroyo JC, et al. The HMG-CoA reductase inhibitor, atorvastatin, 
promotes a Th2 bias and reverses paralysis in central nervous system autoimmune 
disease. Nature 2002; 420:78–84. 
10. Greenwood J, Walters CE, Pryce G, et al. Lovastatin inhibits brain endothelial cell Rho-
mediated lymphocyte migration and attenuates experimental autoimmune 
encephalomyelitis. FASEB J 2003; 17:905–907. 
11. Dunn SE, Youssef S, Goldstein MJ, et al. Isoprenoids determine Th-1/Th2 fate in 
pathogenic T cells, providing a mechanism of modulation of autoimmunity by 
atorvastatin. J Exp Med 2006; 203:401–412. 
12. Mausner-Fainberg K, Luboshits G, Mor A, Maysel-Auslender S, Rubinstein A, Keren G, 
George J. The effect of HMG-CoA reductase inhibitors on naturally occurring 
CD4+CD25+ T cells. Atherosclerosis. 2008 Apr;197(2):829-39.  
13. Mira E, León B, Barber DF, Jiménez-Baranda S, Goya I, Almonacid L, Márquez G, 
Zaballos A, Martínez-A C, Stein JV, Ardavín C, Mañes S. Statins induce regulatory T 
cell recruitment via a CCL1 dependent pathway. J Immunol. 2008 Sep 1;181(5):3524-34. 
14. Shlomchik W, Couzens MS, Tang CB, et al. Prevention of graft-versus-host disease by 
inactivation of host antigen-presenting cells. Science 1999; 285:412–415. 
15. Ferrara J and Deeg HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667–674. 
16. Blazar BR, Korngold R, Vallera DA. Recent advances in graft-versus-host-disease 
(GVHD) prevention. Immunol Rev 1997; 157:79–109. 
17. Lin M, Storer B, Martin PJ, et al. Relation of an interleukin-10 promotor polymorphism 
to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl 
J Med 2003; 349:2201–2210.  


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18. Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M. Th1 and Th2 mediate acute graft-
versus-host disease, each with distinct end-organ targets. J Clin Invest 2000; 105:1289–
1298. 
19. Zeiser R, Youssef S, Baker J, et al. Preemptive HMG-CoA reductase inhibition provides 
graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-
leukemia activity. Blood. 2007;110:4588-4598. 
20. Holler E, et al. Prognostic significance of increased IL-10 production in patients prior to 
allogeneic bone marrow transplantation. Bone Marrow Transplant 2000; 25:237–241.  
21. Baker K, et al. High spontaneous IL-10 production in unrelated bone marrow transplant 
recipients is associated with fewer transplant-related complications and early deaths. 
Bone Marrow Transplant 1999; 23:1123–1129. 
22. Shimada K, Miyauchi K, Daida H. Early intervention with atorvastatin modulates 
TH1/TH2 imbalance in patients with acute coronary syndrome: from bedside to bench. 
Circulation. 2004 May 11;109(18):e213-4. 
23. Sellner J, Greeve I, Findling O, Kamm CP, Minten C, Engelhardt B, Grandgirard D, Leib 
SL, Mattle HP. Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in 
multiple sclerosis. Neurochem Int. 2008 Jul;53(1-2):17-21. 
24. Kanda H, Yokota K, Kohno C, Sawada T, Sato K, Yamaguchi M, Komagata Y, Shimada 
K, Yamamoto K, Mimura T. Effects of low-dosage simvastatin on rheumatoid arthritis 
through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol. 2007;17(5):364-8. 
25. Peng X, Jin J, Giri S, Montes M, Sujkowski D, Tang Y, Smrtka J, Vollmer T, Singh I, 
Markovic-Plese S. Immunomodulatory effects of 3-hydroxy-3-methylglutaryl coenzyme-
A reductase inhibitors, potential therapy for relapsing remitting multiple sclerosis. J 
Neuroimmunol. 2006 Sep;178(1-2):130-9.  
26. Cheng X, Liao YH, Zhang J, Li B, Ge H, Yuan J, Wang M, Lu B, Liu Y, Cheng Y. 
Effects of Atorvastatin on Th polarization in patients with acute myocardial infarction. 
Eur J Heart Fail. 2005 Dec;7(7):1099-104. 
27. Arora M, Chen L, Paglia M, Gallagher I, Allen JE, Vyas YM, Ray A, Ray P. Simvastatin 
promotes Th2-type responses through the induction of the chitinase family member Ym1 
in dendritic cells. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7777-82. 
28.  Nath N, Giri S, Prasad R, Singh AK, Singh I. Potential targets of 3-hydroxy-3-
methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy. J Immunol. 
2004 Jan 15;172(2):1273-86. 
29. Shimabukuro-Vornhagen A, Liebig T, von Bergwelt-Baildon M. Statins inhibit human 
APC function: implications for the treatment of GVHD. Blood. 2008 Aug 
15;112(4):1544-5. 
30. Hamadani M, Awan FT, Devine SM. The impact of HMG-CoA reductase inhibition on 
the incidence and severity of graft-versus-host disease in patients with acute leukemia 
undergoing allogeneic transplantation. Blood. 2008 Apr 1;111(7):3901-2. 
31. Rotta M, Storer BE, Storb RF, Martin PJ, Heimfeld S, Peffer A, Maloney DG, Deeg HJ, 
Sandmaier BM, Appelbaum FR, Mielcarek M. Donor statin treatment protects against 
severe acute graft-versus-host disease after related allogeneic hematopoietic cell 
transplantation. Blood. 2010;115:1288-95.  
32. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant. 1995;15:825-828. 


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33. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-
versus-host disease: National Institutes of Health Consensus Development Project on 
Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria    
Working Group report. Biol Blood Marrow Transplant. 2006;12(3):252-66.  
34. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus 
development project on criteria for clinical trials in chronic graft-versus-host disease: I. 
Diagnosis and staging working group report. Biol Blood Marrow Transplant. 
2005;11:945-56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13. Appendix A Assessment of Acute GVHD 
 
 
 
 
 
 


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14. Appendix B Grading of Chronic GVHD (NIH Criteria) 
 
 
 
 
 


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ICF_001.pdf: 
Consent 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 
 
NCT Number:  NCT01665677 
 
Date:  10/20/2014 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
Page 1 of 13 
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10/20/2014 
 
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Medical College of Wisconsin and Froedtert Hospital 
CONSENT TO PARTICIPATE IN RESEARCH 
 
Name of Study Subject: ____________________________ 
 
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 
 
Mehdi Hamadani, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI 53226-0509 
414-805-6800 
 
You are invited to take part in this research study. This form tells you why this research 
study is being done, what will happen in the research study, possible risks and benefits 
to you, your choices, and other important information. If there is anything that you do not 
understand, please ask questions. Then you can decide if you want to join this study or 
not.   
 
A1. INTRODUCTION – WHY ARE WE ASKING YOU ABOUT THIS STUDY? 
 
You are being invited to participate in this research study of the drug Atrovastatin 
(Lipitor®) because you are a patient undergoing a stem cell transplant (SCT) 
(commonly known as a bone marrow transplant) from your donor. 
 
A total of about 55-75 people are expected to participate in this study nationally 
including about 30-45 at the Medical College of Wisconsin/Froedtert Hospital. 
 
The Director of the study is Mehdi Hamadani, MD in the Department of Medicine. A 
study team works with Dr. Hamadani. You can ask who these people are.  
 
This study is being funded by a grant called; Conquer Cancer Foundation of the 
American Society of Clinical Oncology, which is providing the financial support to Dr. 
Hamadani to conduct the study.  Dr. Hamadani is the sponsor of the study. 
 
A2. DO I HAVE TO BE IN THIS STUDY? 
You can decide whether to take part in this study or not. You are free to say yes or no. If 
you say no, your regular medical care will not change. Even if you join this study, you do 
not have to stay in it. You may stop at any time.  
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
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A research study is different from routine medical care in three ways: 1) there are extra 
risks that we will tell you about in this form; 2) you may have some extra medical tests 
and visits; 3) the study procedures, tests and visits follow a set plan that must be kept. 
 
A3. WHY IS THIS RESEARCH STUDY BEING DONE? 
 
Patients who undergo SCT from donors are at risk of suffering a common problem 
called acute graft-versus-host disease (GVHD).  Acute GVHD is a complication where 
the donor cells (graft) received during transplant attacks and damages the patient’s 
(transplant recipient) tissues.  GVHD can cause skin rash, intestinal problems such as 
diarrhea, nausea, vomiting and decrease liver function or liver failure.  These symptoms 
can range from mild to severe and may be life threatening and may be fatal in some 
cases.   
 
The purpose of this study is to learn if prescribing atorvastatin to you starting 
approximately two weeks before your transplant and continuing through the first 180 
days post transplant will help prevent acute graft-versus-host disease.  We also want to 
see if atorvastatin is safe to use in transplant patients. 
 
Atorvastatin (Lipitor®) is currently approved by the Food and Drug Administration to treat 
high cholesterol, but it is not approved for use in patients to prevent GVHD. This means 
that the use of atorvastatin in this study is considered investigational (or experimental).  
The use of methotrexate and tacrolimus in this study is considered part of the 
investigation.  
 
B1. WHAT WILL HAPPEN IF I TAKE PART IN THE STUDY?   
 
The Director of this study or a member of the study staff will discuss with you the 
requirements for being in this study.  A healthcare professional will evaluate your ability 
to be in the study. 
 
Before you begin the study: 
 
You will have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests, or procedures are part of regular cancer care and may be 
done even if you do not join the study.  If you have had some of them recently, they may 
not need to be repeated.  This will be up to your study doctor. 
 
Baseline Tests: 
 Medical history and physical examination (includes vital signs, height, 
weight, and current medications) 
 Blood tests to check your blood counts, chemistries, liver function, and 
kidney function 
 Blood tests to check for CMV infection, hepatitis A, hepatitis B, hepatitis C, 
HIV testing, syphilis, EBV infection and herpes simplex virus infection 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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 Blood tests to check your immune system 
 Blood tests to check how many of your blood cells are from your donor 
 A blood test to check for pregnancy for women of childbearing potential 
 Karnofsky Performance Status to see how well you perform daily activities 
 A MUGA scan or echocardiogram to test your heart function 
 Bone marrow aspirate or biopsy 
 A test to check your lung function 
 
During the Study 
 
Prior to receiving your donor’s progenitor cells you will undergo your transplant 
conditioning therapy, which includes chemotherapy and/or radiotherapy.  Transplant 
conditioning is a standard procedure for patients receiving a SCT and it helps prepare 
the body for the transplant.   
 
This study will include patients undergoing SCT from sibling donors or unrelated donors, 
enrolled in two separate cohorts. If you are found to be eligible for the study after the 
baseline tests and procedures are complete you will start atorvastatin (40 milligrams) 
one tablet daily by mouth 14 days before you are scheduled to receive your donor’s 
cells (this is also called Day 0).  
 
There is no universally accepted standard treatment to prevent GVHD, and different 
transplant centers in the country use a variety of treatment to prevent this complication.  
In this study you will also be given two drugs called tacrolimus and methotrexate. You 
will take tacrolimus until your doctor feels it is safe to quit taking it but in most cases it 
will be at least until Day 180 post transplant.  The methotrexate is given at days 1, 3, 6 
and 11 post transplant.  Your study doctor will help you understand the risks involved 
with these drugs as well.  
 
If the exams, tests and procedures show that you can be in the study, and you choose 
to take part, then you will need the following tests and procedures throughout the study. 
 
Study Tests 
While you are on the study the following tests will be completed: 
 Physical examinations (includes vital signs, height, weight, and current 
medications) 
 Blood tests to check your blood counts, chemistries, liver function, kidney 
function 
 Blood tests to check your immune system 
 Blood tests for CMV (virus) infection  
 Blood tests to check how many of your blood cells are from your donor 
 Karnofsky Performance Status to see how well you perform daily activities 
 Bone marrow aspirate or biopsy (only if recommended by your physician) 
 GVHD assessments 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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IRB Protocol Number: PRO00021090    
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 Assessment of any side effects that you may be experiencing  
 
You will need to keep taking atorvastatin (the study drug) until one of the following 
happens: 
 It is 180 days after your transplant or you are done taking the standard GVHD 
prevention treatment described above (tacrolimus)  
 You develop a moderate grade of acute GVHD, which normally occurs within the 
first 100 days of the transplant 
 You developed severe chronic GVHD, which normally occurs beyond 100 days 
of the transplant and can even occur years after the transplant 
 You have a bad side effect or reaction to the study drug (atorvastatin) 
 
We will talk to you about any side effects you may have experienced during this study at 
your normal clinic visits or hospital stays.   
 
Follow-up 
After your transplant we will need to ask you how you are doing and if you are having 
any side effects, so someone from the research team will contact you. Your follow-up 
visits during the first two years is no more frequent than standard for most patients at 
our center (i.e. weekly during the first one hundred days followed by at least every 3-6 
months up to the one year mark post SCT). After 1 year we will continue to follow-up 
yearly about your survival and disease status for five years. 
 
We will talk to you about any side effects you may have experienced during this study at 
your normal clinic visits or hospital stays.   
 
B2. HOW LONG WILL I BE IN THE STUDY? 
 
You will be in this research study for about 5 years after your transplant. 
 
B3. CAN I STOP BEING IN THE STUDY?   
You are free to withdraw from the study at any time. If you leave, your regular medical 
care will not change. If you are thinking about leaving, please tell the study doctor.  
 The doctor can tell you about the effects of stopping, and you and the doctor can talk 
about what follow-up care would help you the most. 
 You might be asked to come back for one more visit to check your health. 
 
The study doctor may take you out of this study at any time. This would happen if: 
 
They think it is in your best interest. 
 
You do not follow the study rules. 
 
The whole study is stopped. 
If this happens, the study doctor will tell you. 
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
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IRB Approval Period: 10/20/2014 – 10/19/2015 
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C1. WHAT HEALTH RISKS OR PROBLEMS CAN I EXPECT FROM THE STUDY? 
There are risks to taking part in any research study. There is a risk that you may get a 
drug, drug combination or dose of a drug that does not help your condition or may make 
it worse.  There also may be problems (side effects) we do not know about yet, from 
drug itself, or how it combines with other drugs you are taking. If we learn about new 
important side effects, we will tell you.  
 
We watch everyone in the study for problems (side effects). You need to tell the study 
doctor or a member of the study team immediately if you experience any 
problems, side effects, or changes in your health.  If you have problems, call Dr. 
Hamadani immediately at 414-805-6800. In an emergency, call 911. 
 
C2. RISKS OF TREATMENT 
The research drug itself may cause problems (side effects).  Side effects may be mild or 
very serious.  Some can last a long time or never go away.   
Many go away soon after you stop taking the drug.  Drugs can affect individuals in 
different ways. . Complications of some of the side effects below may lead to life-
threatening events and possibly death. 
 
Atorvastatin  
 
More likely: 
 
 Diarrhea 
 Upset stomach 
 Muscle and joint pain 
 Changes in laboratory blood tests 
 
Less likely: 
 
 Tiredness 
 Tendon problems (tendons connect your muscles to your bones) 
 
Rare, but serious: 
 
 Muscle problems that can lead to kidney problems, including kidney failure.  You 
have a greater chance of this problem if you take other medicines with 
atorvastatin. 
 Liver problems, including liver failure 
 
 
 
Allergic Reactions 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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Allergic reactions can vary in degrees of severity.  They may cause death in rare cases.  
When a severe allergic reaction develops, it usually occurs at the time the medicine is 
entering the body (during drug infusion).  Allergic reactions may cause trouble 
breathing, very low blood pressure, sudden swelling, and/or hives or rash. 
 
Tacrolimus: This medication is used to try to prevent GVHD.  The immediate side 
effects you may experience include nausea (feeling sick to your stomach) or vomiting 
(throwing up) when the medications are given orally.  Other side effects you may 
experience include high blood pressure (hypertension), shaking of the hands (tremor), 
increased hair growth and possibly an effect on mental function.  If you experience 
these effects they generally go away when the dose of the medication is decreased.  A 
few patients have had a seizure while taking these medications.  You may experience a 
change of liver or kidney function, in which case the medication dose will be reduced or 
possibly even withheld.  In rare cases, the kidney damage caused may require the use 
of an artificial kidney machine (hemodialysis). 
 
Some patients given tacrolimus develop diabetes and must take insulin while taking 
tacrolimus. 
 
Methotrexate: This is also a medication used to try to prevent GVHD.  Methotrexate 
causes damage to cells, and therefore can affect many different tissues of your body.  It 
may cause or can worsen the mouth sores or inflammation of the mouth which you may 
have already developed from the procedures and medications used to prepare you for 
the transplant.  It may also cause nausea (feeling sick to your stomach) and vomiting 
(throwing up).  Methotrexate may slow down the recovery of blood cells after 
transplantation.  Methotrexate can cause kidney damage.  If your kidney is already 
damaged for other reasons, it can worsen kidney function.  If kidney damage does 
occur, the methotrexate dose may be reduced or the mediation may not be given at all. 
 
C3. OTHER RISKS OF THIS RESEARCH STUDY 
 
Other procedures that are part of the study also involve some risks: 
 
The following risks are not specifically related to any one drug or the transplanted donor 
cells, but they are risks that are a part of the transplant procedure. The following applies to 
ALL patients. 
 
Additional Risks and Toxicities Related to the Standard Transplant Procedure 
 
There are certain risks related to a SCT.  There are risks from the medications and/or 
irradiation therapy you will receive as part of the conditioning for the transplant and risks 
related to the transplant itself.  Most of these risks and side effects are listed below, but 
they will vary from person to person. Your doctor will give you medications to lessen 
some of the side effects.  Some of these complications can be serious and may be fatal 


Medical College of Wisconsin & Froedtert Hospital  
 
 
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in some instances.  The risk of death may be as high as 40% depending on individual 
patient related factors.  You will be monitored closely during the transplant for any 
complications that may occur.  
 
Your study doctor will explain the risks of transplant to you further. 
 
Blood Draw:  Although you may require a central venous catheter to donate cells, there 
may be an occasional need to have an intravenous catheter placed in your arm(s) or 
you may need to have blood withdrawn from the veins of your arm(s).  Drawing blood 
from the arm may be associated with bleeding into the skin and may very rarely result in 
an infection. 
 
Central Venous Catheter: A central venous catheter is a flexible sterile tube that can 
be placed into a large vein either under the collar bone or in your groin area so that 
blood can be withdrawn.  This tube is placed under local anesthesia and will be placed 
just prior to receiving the cyclophosphamide/rituximab that is given during the 
cytoreduction process.  Complications include blood clots and infection.  Clotting may 
necessitate removal of the catheter or treatment of the clot by injecting a medicine that 
dissolves blood clots.  If you develop an infection, you will require treatment with 
antibiotics.  If the catheter is placed under the collarbone, other uncommon side effects 
may include swelling of the face and arm and/or lung collapse.  If the lung collapses, it 
may be necessary to place a tube between the ribs to allow the lung to re-expand. 
 
Bleeding: Platelets help your blood to clot.  Your platelets will be low until the new bone 
marrow grows and, as a result, bleeding may occur.  This can be minor bleeding, such 
as nosebleeds or bruising, but more serious, life-threatening bleeding in the lungs, brain 
and other organs can occur if the platelet count remains low.  Usually, there is success 
in preventing major bleeding problems with transfusions of platelets.  However, some 
patients may not respond well to transfused platelets and may be at serious risk for 
bleeding.  
 
Mouth Sores and Diarrhea: The chemotherapy causes irritation in the lining of the 
mouth and intestines.  This can result in painful mouth sores and diarrhea and you may 
need medication to help control the pain.  If your mouth sores are severe you may not 
be able to eat normally until the sores are healed.  Mouth sores get better when the 
white blood count starts to rise. 
 
Capillary Leak Syndrome:  This may occur as a result of chemotherapy and radiation 
therapy. The blood vessels may become ‘leaky’ and fluid enters the abdominal cavity, 
lungs, and other tissues.  You may gain water weight and not go to the bathroom as 
often as you normally do. Capillary leak syndrome can be difficult to manage if extra 
fluid enters the lungs and causes difficulty breathing.  You may die if there is continued 
fluid collection in the lungs.  
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
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Unexpected Organ Damage and Other Side Effects:  Although your major organs 
function well, it is possible you may experience unexpected, life-threatening heart, lung, 
kidney, or liver damage as a result of the transplant.  Occasionally, the high doses of 
chemotherapy cause severe lung damage that cannot always be treated. If this 
happens, you may need to use oxygen or even a respirator.  The lung damage can be 
life threatening.  Rarely, multi-organ failure (such as lung and kidney failure) may occur, 
which is often fatal.   
 
Late Effects:  You may experience side effects that occur several months to many 
years after your transplant.  You may experience poor function of the thyroid gland, 
requiring you to take thyroid medication.  It is rare, but your kidneys could be affected, 
causing anemia or high blood pressure.  There is also a 1-3 % risk you may develop a 
second cancer including leukemia as a result of the chemotherapy and/or radiation ,.  If 
secondary cancers occur they generally do not occur until 10 to 15 years after the 
transplant but can occur sometimes within five years after transplant.  The long-term 
effects upon heart, lung, and brain are unknown.  
 
Fluid Build-up: You will receive intravenous fluids during the transplant process and 
you may have difficulty eliminating this fluid.  Furosemide is a drug that is often given to 
help eliminate this excess fluid.  This drug may cause hearing loss and loss of body 
chemicals such as potassium and sodium. 
 
C4. REPRODUCTIVE RISKS 
Risks to women who could become pregnant 
 
The drug in this study might affect a baby, before or after the baby is born. We do not 
know if the drug causes harm to a baby, so we do not want anyone who might be 
pregnant to enter the study. You should not become pregnant or nurse a baby while in 
this study. You must tell the study doctor right away if you think you are pregnant. You 
will be asked to have a pregnancy test to be sure you are not pregnant at the start of the 
study.  
 
Risks of fathering a child 
 
You should not father a baby while taking part in this study because it is unknown if the 
drug in this study could affect a baby. If your partner is able to become pregnant, one or 
both of you must use some form of effective birth control.  You must tell the study doctor 
right away if you think your partner is pregnant. 
 
Birth control methods for all subjects 
 
Check with the study doctor about the birth control methods needed for this study and 
how long to use them. Some methods might not be good enough for this study. If you 
are having sex that could lead to pregnancy, you should use birth control while you are 
in this study.   


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
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This may include: 
 Not having vaginal sex (abstinence) 
 Taking birth control pills orally 
 Having birth control shots or patches such as Depo-Provera 
 Surgical sterilization (hysterectomy or tubal ligation) 
 Use of an intrauterine device (IUD) 
 Use of diaphragm with contraceptive jelly 
 Use of condoms with contraceptive foam 
 Use of diaphragm with condoms (“double barrier”) 
 Limiting sexual activity to a male partner who has had a vasectomy 
 
C5. ARE THERE ANY BENEFITS TO TAKING PART IN THE STUDY? 
 
We don’t know if this study will help you. Your condition may get better but it could stay 
the same or even get worse. We hope the information from this study will help us learn 
how to better prevent acute GVHD. 
 
D1. ARE THERE ANY COSTS TO BEING IN THE STUDY? 
 
Some of / most of the medical care that you will receive in this study is considered 
routine care for your condition and would be recommended whether you join the study 
or not.  Costs for routine care will be billed to you or your insurance carrier.  Activities / 
costs that are part of the study will not be billed to you or your insurance company. 
These are the study drug (Lipitor®). Some insurers will not pay for drugs, tests or 
hospitalization that are part of research studies, so check with your insurer before you 
join this study. If you have questions regarding study costs, please contact Dr. 
Hamadani. 
 
D2. WILL I BE PAID FOR PARTICIPATING IN THE STUDY? 
 
There is no payment for being in this study.  
 
D3. WHAT OTHER HEALTHCARE CHOICES DO I HAVE? 
 
You do not have to join this study. You are free to say yes or no. If you do not join this 
study, your doctor can discuss other healthcare choices with you.  
Your other choices may include: 
 
Routine care for this condition or symptoms 
 
Joining a different research study 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
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MCW Version: 08-10-14 
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10/20/2014 
 
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D4. WILL I BE GIVEN NEW INFORMATION ABOUT THE STUDY? 
 
If we learn any important new information about the drug that might change your mind 
about being in the study, we will tell you about it right away.  You can then decide if you 
want to stay in the study. 
 
D5. WHAT HAPPENS IF I AM HARMED BECAUSE I TOOK PART IN THE STUDY?  
 
No funds have been set aside to pay any costs if you become ill or are harmed because 
of this study. If you think that you have become ill or were harmed because of this 
study, let the study doctors know right away by calling 414-805-6800.  By signing this 
form, you do not give up your right to seek payment for harm you receive while 
participating in this study. 
 
If you think that you have become ill or were harmed because of this study, let the study 
doctors know right away by calling 414-805-6800. 
 
By signing this form, you do not give up your right to seek payment for harm you receive 
while participating in this study. 
 
D6. WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY? 
 
 
If you have more questions about this study at any time, you can call Dr. Hamadani 
at 414-805-6800. 
 
If you have questions about your rights as a study participant, want to report any 
problems or complaints, obtain information about the study, or offer input, you can 
call the MCW/Froedtert Hospital Research Subject Advocate at 414-955-8844  
 
E. PERMISSION TO COLLECT, USE AND SHARE HEALTH INFORMATION 
 
E1. What health information will be collected and used for this study? 
To do this research study, we need your permission to collect and use some of your 
health information, or you cannot be in the study. This information may come from 
questions we ask, forms we ask you to fill out, or your medical record, as described 
below. We will only collect and use information needed for the study.  
 
The health information to be collected and used for this study is:  
All or portions of your medical chart: 
 Hospital/Medical Records 
 Physician/Clinical Records 
 Lab and/or Pathology Reports 
 Radiology Reports 
 Biological Samples 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
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MCW Version: 08-10-14 
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10/20/2014 
 
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E2. Who will see the health information collected for this study? 
The only MCW/Froedtert Hospital employees allowed to handle your health information 
are those on the study team, those on the Institutional Review Board (IRB) and those 
who check on the research activities to make sure the hospital’s rules are followed. 
 
The study team may share your information with people who don’t work at 
MCW/Froedtert Hospital because they planned, pay for, or work with us on this study.  
The federal Privacy Rule may no longer protect your health information once it leaves 
MCW/Froedtert Hospital.  For this study, we plan to share information with those 
doctors, researchers or government representatives working with us on this study at the 
institutions or companies listed here: 
 
U.S. Food and Drug Administration, Rockville, MD 
  
Any Independent ethics committee, which approved this study 
Other Regulatory Agencies and/or Their Designated Representatives   
Those required by law 
 
We may record your research information, including results of tests and procedures 
done for research, in your Froedtert Hospital and/or Medical College of Wisconsin 
medical record.  As a result, this research information may be seen by people allowed 
to see your medical records for healthcare operations or treatment, by those you allow 
to see your medical records by giving written permission, and by others when required 
by law. 
 
We will not use your personal health information for a different study without your 
permission or the permission of a hospital research review board (IRB). Once all 
personal identification is removed, the information might be used or released for other 
purposes without asking you. Results of the study may be presented in public talks or 
written articles, but no information will be presented that identifies you. 
  
E3. What are the risks of sharing this health information? 
One risk of taking part in a research study is that more people will handle your personal 
health information collected for this study. The study team will make every effort to 
protect the information and keep it confidential, but it is possible that an unauthorized 
person might see it. Depending on the kind of information being collected, it might be 
used in a way that could embarrass you or affect your ability to get insurance. If you 
have questions, you can talk to the study doctor about whether this could apply to you.  
 
E4. How long will you keep the health information for this study? 
If you sign this form, we plan to keep your information without any end-date in case we 
need to check it again for this study. 
 
E5. Can I cancel my permission to share this health information? 
If you change your mind later and do not want us to collect or share your health 
information, you need to send a letter to: 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
Page 12 of 13 
MCW Version: 08-10-14 
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10/20/2014 
 
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Mehdi Hamadani, MD 
Froedtert & Medical College of Wisconsin 
Division of Hematology and Oncology 
9200 W. Wisconsin Avenue 
Milwaukee, WI  53226 
 
 The letter must say that you have changed your mind and do not want the researcher 
to collect and share your health information. At that time, we may decide that you 
cannot continue to be part of the study. We may still use the information we have 
already collected.  
 
F1. FOR MORE INFORMATION ABOUT THE STUDY 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
You can look up this study by referring to the ClinicalTrials.gov number (NCT01665677) 
or by asking the study team for a printed copy.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Medical College of Wisconsin & Froedtert Hospital  
 
 
Informed Consent for Research 
Template A - Version: October 1, 2012 
 
IRB Protocol Number: PRO00021090    
IRB Approval Period: 10/20/2014 – 10/19/2015 
Page 13 of 13 
MCW Version: 08-10-14 
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10/20/2014 
 
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CONSENT TO PARTICIPATE IN THE STUDY 
 
By signing my name below, I confirm the following: 
 I have read (or had read to me) this entire consent document.  All of my questions 
have been answered to my satisfaction. 
 The study’s purpose, procedures, risks and possible benefits have been explained to 
me.   
 I agree to let the study team use and share the health information and other 
information gathered for this study. 
 I voluntarily agree to participate in this research study.  I agree to follow the study 
procedures as directed.  I have been told that I can stop at any time. 
 
IMPORTANT: You will receive a signed and dated copy of this consent form.  Please 
keep it where you can find it easily.  It will help you remember what we discussed today. 
 
. 
 
 
 
Subject's Name please print  
Subject's Signature 
Date   
 
 
 
Name of Legally Authorized 
Representative (if applicable)  
please print  
Signature of Legally Authorized 
Representative 
Date 
 
 
 
Name of Witness (if applicable) please 
print  (for short form consent process, or 
consent of blind or illiterate subject) 
Signature of Witness 
 
Date 
 
 
 
* Name of person discussing/ 
obtaining consent please print  
Signature of person 
discussing/obtaining consent
Date 
* A member of the study team trained and authorized by the Principal Investigator to act on her/his behalf 
in obtaining informed consent according to the protocol.  In all research study protocols the Principal 
Investigator is responsible and accountable for the study.