Safety & Efficacy of Atorvastatin for Prophylaxis of Acute Graft Versus Host Disease in Patients With Hematological Malignancies HLA- Donor Hematopoietic Stem Cell Transplantation

• Sponsor: Ohio State University Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01491958
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Actual Duration (Months): 54.6
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Phase II trial evaluating the safety & efficacy of Atorvastatin for prophylaxis of Acute Graft Versus Host Disease (GVHD) in patients with hematological malignances undergoing human leukocyte antigen (HLA)-Matched Related Donor Hematopoietic Stem Cell Transplant (HSCT).

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Myelodysplastic Syndrome	Drug: atorvastatin; Drug: Tacrolimus; Drug: methotrexate	Phase 2

Detailed Description

The study is a single-arm phase II single institutional trial evaluating the safety and efficacy of atorvastatin for the prophylaxis of acute GVHD in patients with hematological malignancies undergoing HLA matched related donor HSCT. This study will explore a two-pronged acute GVHD prophylaxis strategy, consisting of pre-treating consenting related donors with atorvastatin before stem cell mobilization and collection, followed by atorvastatin plus methotrexate/tacrolimus-based GVHD prophylaxis in transplant recipient patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Phase II Trial Evaluating the Safety and Efficacy of Atorvastatin for the Prophylaxis of Acute Graft Versus Host Disease(GVHD) in Patients With Hematological Malignancies Undergoing HLA-Matched Related Donor Hematopoietic Stem Cell Transplantation (HSCT)
• Actual Study Start Date: Dec 10, 2011
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jun 27, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Donor Related donors will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration.	Drug: atorvastatin; donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first.; Other Names: Lipitor
Experimental: Patient Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.	Drug: atorvastatin; donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first.; Other Names: Lipitor ; Drug: Tacrolimus; beginning on Day -2 through approximately Day +180 (that is, approximately 6 months after Day 0); Other Names: Prograf ; Drug: methotrexate; Day +1, +3, and +6 and +11; Other Names: Amethopterin MTX

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration [Up through day 100 following transplant]

   The incidence of grades II to IV aGVHD at day +100 of atorvastatin administration. The grading of aGVHD and cGVHD were done using the Consensus Conference criteria.

Secondary Outcome Measures

1. Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities. [Patients: Baseline, weekly for 9 weeks and then on days 84, 91-100, 180 and 365. Donors: at apheresis and then 30 days later.]

   Adverse events and toxicities were monitored in patients using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.

2. Time to Neutrophil and Platelet Engraftment [weekly for 12 weeks, 100 days, 6 months, and 12 months]

   Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 0.5 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.

3. Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD) [up 1 year post transplant]

   cGVHD occurring anytime after day 100 post transplant will be termed chronic GVHD, and evaluated in patients who were followed for at least 100 days without early progression or death. Grading of cGVHD was done using the National Institutes of Health Consensus Development Project Criteria

4. Non Relapse Mortality (NRM) at One Year [up to 12 months post transplant]

   Cumulative incidence of NRM will be calculated as the time from transplant until death not related to disease, where the competing risk for NRM was death due to disease. Patients who had not died were censored at last follow up.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Donor Eligibility Criteria

• The donor must be at least 18 years of age, and willing/able to provide informed consent. Complete medication list will be reviewed for potential negative interaction with atorvastatin.

• The donor must be an HLA-matched sibling or relative.

• Syngeneic donors are not eligible.

• Female donors of child-bearing potential should have a negative pregnancy test, and must not be breast feeding.

• Bilirubin, AST and ALT must be < 2 x normal; and absence of hepatic fibrosis/cirrhosis.

• Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation.

• Adequate cardiac function with no history of congestive heart failure, uncontrolled atrial fibrillation or ventricular tachyarrhythmias.

Patient Eligibility Criteria

• Have hematologic malignancy requiring allogeneic HSCT, have adequate organ function, a serologic (or higher resolution) 6/6 class I human leukocyte antigen (HLA)-A and B and molecular class II DRB1 matched related donor, and are able to give informed consent.

• Patients > 18 and ≤ 65 years with comorbidity score ≤ 3 will be eligible for myeloablative conditioning (MAC), while patients > 65 years of age, those with previous history of autologous transplantation, or high comorbidity index (>3) will be eligible for reduced intensity conditioning (RIC) transplantation .

• All patients must have at least one 6/6 HLA-matched sibling donor.

• Patient must provide informed consent

• Patients must have left ventricular ejection fraction > 30%, no uncontrolled arrhythmias or New York Heart Association class III-IV heart failure.

• Bilirubin must be < 2 x normal; and absence of hepatic fibrosis/cirrhosis.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be <2 x normal; and absence of hepatic fibrosis/cirrhosis.

• Serum creatinine clearance of ≥40% of normal calculated by Cockcroft-Gault equation.

• Forced expiratory volume in one second (FEV1)and diffusion capacity; corrected for hemoglobin(DLCO) ≥ 50% and 40% of predicted respectively.

• Karnofsky performance status > 70.

• A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.

• No HIV infection. Patients with immune dysfunction are at a significantly higher risk of toxicities from intensive immunosuppressive therapies.

• No evidence of active bacterial, viral or fungal infection at the time of transplant conditioning.

• No active alcohol or substance abuse within 6 months of study entry.

• Prior allogeneic transplant is acceptable.

• No history of intolerance or allergic reactions with atorvastatin or other statins.

• Patients who have previously been taking atorvastatin or any other statin will be eligible as long as there is no contraindication to switch to atorvastatin 40mg/day in the opinion of the treating physician.

Exclusion Criteria:

• Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible.

• Patients receiving another investigational drug are not eligible unless cleared by Principal Investigator. Patients with prior malignancies except resected basal cell carcinoma, treated carcinoma in-situ, or other hematologic diseases for which allogeneic HSCT is a treatment strategy, are not eligible. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Principal Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Ohio State University Comprehensive Cancer Center

Investigators

• Principal Investigator: Yvonne Efebera, MD, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Jamesline

Publications

None provided.

• Responsible Party: Yvonne Efebera, Principal Investigator, Ohio State University Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT01491958
• Other Study ID Numbers: OSU-11004; NCI-2011-03590
• First Posted: Dec 14, 2011
• Last Update Posted: Jan 23, 2018
• Last Verified: Jan 1, 2018

• Keywords provided by Yvonne Efebera, Principal Investigator, Ohio State University Comprehensive Cancer Center: Leukemia; AML; ALL; MDS
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myelodysplastic Syndromes; Graft vs Host Disease; Methotrexate; Atorvastatin; Tacrolimus

Study Results

Participant Flow

Recruitment Details	Patients who are candidates for HSCT using HLA matched related donors were eligible to be enrolled in the study.

Arm/Group Title	Patients	Donors
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.	Related donors will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration.
Period Title: Overall Study
STARTED	40	40
COMPLETED	40	40
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Patients	Donor	Total
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.	Related donors will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration.	Total of all reporting groups
Overall Participants	40	40	80
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51	50	51
Sex: Female, Male (Count of Participants)
Female	20 50%	20 50%	40 50%
Male	20 50%	20 50%	40 50%
Region of Enrollment (patients) [Number]
United States	40	40	80

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration
Description	The incidence of grades II to IV aGVHD at day +100 of atorvastatin administration. The grading of aGVHD and cGVHD were done using the Consensus Conference criteria.
Time Frame	Up through day 100 following transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.
Measure Participants	40
Number (95% Confidence Interval) [percentage of patients]	30

2. Secondary Outcome

Title	Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities.
Description	Adverse events and toxicities were monitored in patients using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.
Time Frame	Patients: Baseline, weekly for 9 weeks and then on days 84, 91-100, 180 and 365. Donors: at apheresis and then 30 days later.

Outcome Measure Data

Analysis Population Description

Only patients with evaluable data reported

Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.
Measure Participants	36
Grade 2 elevated liver enzymes	2
Grade 4 elevated liver enzymes	1

3. Secondary Outcome

Title	Time to Neutrophil and Platelet Engraftment
Description	Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 0.5 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.
Time Frame	weekly for 12 weeks, 100 days, 6 months, and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.
Measure Participants	40
Neutrophil engraftment	18
Platelet engraftment	14

4. Secondary Outcome

Title	Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD)
Description	cGVHD occurring anytime after day 100 post transplant will be termed chronic GVHD, and evaluated in patients who were followed for at least 100 days without early progression or death. Grading of cGVHD was done using the National Institutes of Health Consensus Development Project Criteria
Time Frame	up 1 year post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.
Measure Participants	34
Number (95% Confidence Interval) [percentage of patients]	43

5. Secondary Outcome

Title	Non Relapse Mortality (NRM) at One Year
Description	Cumulative incidence of NRM will be calculated as the time from transplant until death not related to disease, where the competing risk for NRM was death due to disease. Patients who had not died were censored at last follow up.
Time Frame	up to 12 months post transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered. atorvastatin: donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive
Measure Participants	40
Number (95% Confidence Interval) [percentage of patients]	5.5

Adverse Events

Adverse Event Reporting Description	Adverse events were assessed for 36 patients only using the Common Toxicity Criteria for Adverse Events version 4.0 (CTCAE v4.0)
Arm/Group Title	Patients
Arm/Group Description	Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered.
All Cause Mortality
	Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Patients
	Affected / at Risk (%)	# Events
Total	5/36 (13.9%)
Blood and lymphatic system disorders
Febrile Neutropenia	1/36 (2.8%)	1
Gastrointestinal disorders
Abdominal Pain	1/36 (2.8%)	1
Constipation	1/36 (2.8%)	1
Diarrhea	1/36 (2.8%)	1
Nausea	1/36 (2.8%)	1
Vomiting	1/36 (2.8%)	1
General disorders
Chills	1/36 (2.8%)	1
Infections and infestations
Urinary tract infection	1/36 (2.8%)	1
Wound infection	1/36 (2.8%)	1
Investigations
Alanine Aminotransferase increased	1/36 (2.8%)	1
Aspartate Aminotransferase increased	1/36 (2.8%)	1
Creatinine increased	2/36 (5.6%)	2
Neutrophil count decreased	1/36 (2.8%)	1
Weight loss	1/36 (2.8%)	1
Metabolism and nutrition disorders
Anorexia	1/36 (2.8%)	1
Nervous system disorders
Dysgeusia	1/36 (2.8%)	1
Lethargy	1/36 (2.8%)	1
Seizure	1/36 (2.8%)	1
Psychiatric disorders
Confusion	2/36 (5.6%)	2
Vascular disorders
Hypotension	1/36 (2.8%)	1
Other (Not Including Serious) Adverse Events
	Patients
	Affected / at Risk (%)	# Events
Total	36/36 (100%)
Blood and lymphatic system disorders
Anemia	14/36 (38.9%)	16
Febrile Neutropenia	4/36 (11.1%)	4
Cardiac disorders
Palpitations	2/36 (5.6%)	2
Sinus Tachycardia	2/36 (5.6%)	2
Endocrine disorders
Endocrine Disorders	2/36 (5.6%)	3
Eye disorders
Blurred Vision	2/36 (5.6%)	2
Dry eye	4/36 (11.1%)	4
Eye Disorders	2/36 (5.6%)	3
Gastrointestinal disorders
Abdominal Pain	6/36 (16.7%)	7
Constipation	6/36 (16.7%)	6
Diarrhea	19/36 (52.8%)	26
Dry mouth	9/36 (25%)	11
Dyspepsia	2/36 (5.6%)	2
Mucositis oral	20/36 (55.6%)	21
Nausea	24/36 (66.7%)	33
Oral pain	4/36 (11.1%)	5
Vomiting	10/36 (27.8%)	16
General disorders
Edema limbs	7/36 (19.4%)	8
Fatigue	28/36 (77.8%)	34
Fever	10/36 (27.8%)	14
General Disorder	5/36 (13.9%)	6
Localized Edema	2/36 (5.6%)	3
Pain	11/36 (30.6%)	14
Infections and infestations
Infections	15/36 (41.7%)	18
Rhinitis Infective	2/36 (5.6%)	2
Upper Respiratory Infection	3/36 (8.3%)	3
Urinary Tract Infection	8/36 (22.2%)	9
Injury, poisoning and procedural complications
Brusing	2/36 (5.6%)	2
Investigations
Alanine Aminotransferase Increased	26/36 (72.2%)	47
Alkaline Phosphatase Increased	12/36 (33.3%)	15
Aspartate Aminotransferase Increased	26/36 (72.2%)	49
Blood Bilirubin Increased	6/36 (16.7%)	6
Cholesterol High	4/36 (11.1%)	4
Creatinine Increased	25/36 (69.4%)	40
INR Increased	2/36 (5.6%)	2
Investigations-other	2/36 (5.6%)	2
Lymphocyte Count Decreased	2/36 (5.6%)	2
Neutrophil Count Decreased	9/36 (25%)	11
Platelet Count Decreased	12/36 (33.3%)	18
Weight loss	4/36 (11.1%)	4
White Blood Cell Decreased	10/36 (27.8%)	20
Metabolism and nutrition disorders
Anorexia	13/36 (36.1%)	18
Hypercalcemia	5/36 (13.9%)	6
Hyperglycemia	23/36 (63.9%)	35
Hyperkalemia	3/36 (8.3%)	3
Hypermagnesemia	2/36 (5.6%)	3
Hypernatremia	2/36 (5.6%)	2
Hypertriglyceridemia	3/36 (8.3%)	3
Hypoalbuminemia	18/36 (50%)	28
Hypocalcemia	18/36 (50%)	32
Hypokalemia	11/36 (30.6%)	12
Hypomagnesemia	24/36 (66.7%)	50
Hyponatremia	18/36 (50%)	33
Hypophosphatemia	3/36 (8.3%)	4
Metabolism and nutrition disorders	3/36 (8.3%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	4/36 (11.1%)	4
Back pain	4/36 (11.1%)	6
Generalized Muscle Weakness	2/36 (5.6%)	3
Muscleskeletal and Connective Tissues Disorder	2/36 (5.6%)	2
Myalgia	3/36 (8.3%)	3
Pain in Extremity	3/36 (8.3%)	3
Nervous system disorders
Dizziness	3/36 (8.3%)	3
Dysgeusia	5/36 (13.9%)	6
Headache	9/36 (25%)	14
Peripheral Sensory Neuropathy	5/36 (13.9%)	7
Psychiatric disorders
Anxiety	3/36 (8.3%)	3
Confusion	3/36 (8.3%)	3
Insomnia	3/36 (8.3%)	3
Renal and urinary disorders
Acute Kidney Injury	5/36 (13.9%)	5
Chronic Kidney Disease	2/36 (5.6%)	3
Hematuria	2/36 (5.6%)	2
Renal and Urinary disorders	5/36 (13.9%)	9
Urinary Frequency	2/36 (5.6%)	2
Respiratory, thoracic and mediastinal disorders
Cough	5/36 (13.9%)	6
Dyspnea	10/36 (27.8%)	11
Epistaxis	2/36 (5.6%)	3
Nasal congestion	3/36 (8.3%)	3
Sore throat	4/36 (11.1%)	5
Skin and subcutaneous tissue disorders
Erythema Multiforme	3/36 (8.3%)	5
Pruritus	5/36 (13.9%)	8
Rash Acneiform	3/36 (8.3%)	4
Rash Maculo-papular	13/36 (36.1%)	15
Skin and subcutaneous tissue disorder	3/36 (8.3%)	3
Skin hyperpigmentation	2/36 (5.6%)	2
Vascular disorders
Hypertension	7/36 (19.4%)	7
Hypotension	6/36 (16.7%)	6
Thromboembolic event	4/36 (11.1%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.