PILLAR-1: Safety and Efficacy of RAD001 in Participants With Mantle Cell Lymphoma Who Are Refractory or Intolerant to Velcade® Therapy

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00702052
• Collaborator: (none)
• Enrollment: 58
• Locations: 31
• Arm: 1
• Actual Duration (Months): 43.9
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study was to evaluate the safety and efficacy of a daily, oral dose of 10 mg RAD001 in participants with Mantle Cell Lymphoma who were refractory or intolerant to Velcade® therapy and who had received at least one prior antineoplastic agent other than Velcade®, either separately or in combination with Velcade® (see inclusion criteria). Intolerance to Velcade® therapy was determined by the study investigator based on clinical evaluations. Participants were considered refractory to Velcade® if they have documented radiological progression on or within 12 months of the last dose of Velcade® when given alone or, on or within 12 months of the last dose of the last component of a combination therapy which included Velcade®.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Mantle- Cell	Drug: Everolimus	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Single-Arm, Phase II Study of RAD001 in Patients With Mantle Cell Lymphoma Who Are Refractory or Intolerant to Velcade® (Bortezomib)
• Actual Study Start Date: Aug 22, 2008
• Actual Primary Completion Date: Apr 20, 2012
• Actual Study Completion Date: Apr 20, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.	Drug: Everolimus; Everolimus tablets; Other Names: RAD001

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate (ORR) [From date of enrollment up to disease progression or death (approximately 3.8 years)]

   Overall response rate was defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in the sum of the product of diameter (SPD) of all index nodal and extranodal lesions.

Secondary Outcome Measures

1. Disease Control Rate (DCR) [From date of start of treatment up to disease progression or death (approximately up to 3.8 years)]

   Disease Control Rate was defined as the percentage of participants with best overall disease response of CR or PR or stable disease (SD). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions. SD was defined failure to attain the criteria needed for CR or PR and failure to fulfill the criteria for at least a 50% increase in the SPD of all index nodal and extranodal (including splenic and/or hepatic nodules) lesions, taking as reference the smallest sum of the product of the diameters of all index lesions recorded at or after baseline.

2. Duration of Response [From date of start of treatment up to disease progression or death (approximately up to 3.8 years)]

   Duration of response was defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to lymphoma. CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions.

3. Progression Free Survival (PFS) [From date of start of treatment up to disease progression or death (approximately up to 3.8 years)]

   PFS was defined as the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause.

4. Overall Survival [From date of start of treatment up to disease progression or death (approximately up to 3.8 years)]

   Overall survival was defined as the time from the date of start of study treatment to the date of death due to any cause.

5. Number of Participants With At Least One Adverse Event (AE) and Serious Adverse Event (SAE) [From the start of the study and 28 days after study drug discontinuation (approximately up to 18 months)]

   An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult participants (≥18 years old) with Mantle Cell Lymphoma that has been confirmed by central pathology review (archival diagnostic tumor specimen required).

• Participants with mantle cell lymphoma who have documented refractory disease to Velcade® (bortezomib) or who have documented intolerance to Velcade® therapy. Intolerance to Velcade® is determined by the study investigator based on clinical evaluations. Participants are considered refractory to Velcade® if they have documented radiological progression on or within 12 months of last dose of Velcade® when given alone or, on or within 12 months from the last dose of the last component of a combination therapy which included Velcade®. Participants are considered refractory to Velcade®, if Velcade® is part of a combination treatment for the disease.

• Participants must have received at least one prior antineoplastic agent, other than Velcade® either separately or in combination with Velcade® (bortezomib).

• At least one site of measurable nodal disease at baseline >2.0 cm in the longest transverse diameter and clearly measurable in at least two perpendicular dimensions, as determined by computer tomography (CT) scan (or magnetic resonance imaging (MRI), only if CT scan can not be performed).

• Eastern Cooperative Oncology Group (ECOG) performance status = 0, 1 or 2.

• Life expectancy ≥3 months.

• Adequate bone marrow, liver and renal function.

• Platelets ≥75 x 10^9/L (untransfused platelets).

Exclusion Criteria:

• Participants who are currently receiving anticancer therapies or have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation, antibodies, targeted therapy etc.) are not eligible.

• Previous treatment with mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, sirolimus, temsirolimus, etc).

• Participants with prior allogeneic stem cell transplant.

• Grade 3 or 4 unresolved toxicity from prior antineoplastic therapies.

• Currently taking other investigational agents or received other investigational drugs within 4 weeks of the start of study drug.

• Participants with central nervous system (CNS) lymphoma are not eligible; head magnetic resonance imaging (MRI) (or computer tomography (CT) if MRI is not available) is required prior to study entry.

• Use of chronic, systemic corticosteroids or another immunosuppressive agent, except prednisone ≤20 mg daily (or equivalent) for adrenal insufficiency (must have been on a stable dosage regimen for ≥4 weeks prior to the first treatment with RAD001).

• HIV positive participants are not eligible; (human immunodeficiency virus (HIV) testing is not required for study entry; review of previous medical records is required).

• Uncontrolled hyperlipidemia (≥Grade 3 hyperlipidemia despite optimal supportive medical therapy).

• Active, bleeding disorders or major surgery within 4 weeks of starting study drug.

• Severe and/or uncontrolled medical conditions such as symptomatic congestive heart failure (New York Heart Association Class III or IV), unstable angina, myocardial infarction within 6 months or study start, severely impaired lung function, cirrhosis, chronic active/persistent hepatitis.

• History of another primary malignancy ≤3 years prior to study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic - Arizona Mayo Clinic - Scottsdale	Multiple Locations	Arizona	United States	85259
2	Highlands Oncology Group DeptofHighlandsOncologyGrp(2)	Fayetteville	Arkansas	United States	72703
3	Bay Area Cancer Research Dept.ofBayAreaCancerResearch	Concord	California	United States	94520
4	City of Hope National Medical Center Dept.ofCityofHopeMedicalCtr(1)	Duarte	California	United States	91010-3000
5	UCLA/ University of California Los Angeles Dept.of Hem/Oncology	Los Angeles	California	United States	90095
6	University of California Davis Cancer Center Dept. of UC Davis Cancer (4)	Sacramento	California	United States	95817
7	Rocky Mountain Cancer Centers RMCC - Denver-Midtown	Greenwood Village	Colorado	United States	80121
8	Advanced Medical Specialties Medical Onc Hem	Miami	Florida	United States	33176
9	Georgia Health Sciences University Dept. of MCG	Augusta	Georgia	United States	30912
10	Northwestern University	Chicago	Illinois	United States	60611
11	St. Francis Cancer Research Foundation Dept.ofSt.FrancisCancerRes.(2)	Beech Grove	Indiana	United States	46107
12	Central Indiana Cancer Centers CICC - East (2)	Indianapolis	Indiana	United States	46227
13	University of Michigan Comprehensive Cancer Center Dept of Michigan Cancer Center	Ann Arbor	Michigan	United States	48109-0944
14	Mayo Clinic - Rochester Hematology	Rochester	Minnesota	United States	55905
15	Washington University School Of Medicine-Siteman Cancer Ctr Medical Oncology	Saint Louis	Missouri	United States	63110
16	Hackensack University Medical Center Dept ofHackensackUniversityMC	Hackensack	New Jersey	United States	07601
17	New York University Medical Center NYU Cancer Institute	New York	New York	United States	10016
18	East Carolina University BrodySchool of Medicine	Greenville	North Carolina	United States	27858
19	Northwest Cancer Specialists Vancouver Cancer Center (2)	Portland	Oregon	United States	97210
20	Kaiser Permanente Northwest Dept of Kaiser Northwest (3)	Portland	Oregon	United States	97227
21	Fox Chase Cancer Center Regulatory Contact	Philadelphia	Pennsylvania	United States	19111-2497
22	Western Pennsylvania Cancer Institute /Western Penn Hospital Western Pann. Cancer Inst.	Pittsburgh	Pennsylvania	United States	15224
23	University of Pittsburgh Medical Center Hillman Cancer Center (4)	Pittsburgh	Pennsylvania	United States	15232
24	Cancer Centers of the Carolinas CC of C -Eastside	Greenville	South Carolina	United States	29605
25	Vanderbilt University Medical Center, Clinical Trials Center Dept. of VUMC	Nashville	Tennessee	United States	37212
26	Baylor College of Medicine Dept. of Sammons Cancer (2)	Dallas	Texas	United States	75246
27	University of Texas Southwestern Medical Center DeptofSimmons Cancer Center(2)	Dallas	Texas	United States	75390-8527
28	MD Anderson Cancer Center/University of Texas Dept. of MD Anderson (10)	Houston	Texas	United States	77030-4009
29	Tyler Cancer Center Dept.ofTylerCancerCtr.	Tyler	Texas	United States	75702
30	Cancer Care Northwest CC Northwest- Spokane South(3)	Spokane	Washington	United States	99202
31	West Virginia University/ Mary Babb Randolph Cancer Center	Morgantown	West Virginia	United States	26506

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00702052
• Other Study ID Numbers: CRAD001N2201; 2007-005700-40
• First Posted: Jun 20, 2008
• Last Update Posted: May 25, 2021
• Last Verified: Apr 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Mantle Cell Lymphoma; Lymphoma; B-Cell Lymphoma; Mantle Zone Lymphoma; Refractory Lymphoma; Aggressive Lymphoma; PILLAR-1
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Everolimus

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 26 investigative sites in the United States from 22 August 2008 to 20 April 2012.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Period Title: Overall Study
STARTED	58
COMPLETED	0
NOT COMPLETED	58

Baseline Characteristics

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Overall Participants	58
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.29 (7.991)
Sex: Female, Male (Count of Participants)
Female	13 22.4%
Male	45 77.6%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate (ORR)
Description	Overall response rate was defined as the percentage of participants with a best overall disease response of complete response (CR) or partial response (PR). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in the sum of the product of diameter (SPD) of all index nodal and extranodal lesions.
Time Frame	From date of enrollment up to disease progression or death (approximately 3.8 years)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) included all participants who received at least one dose of the study drug.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	58
Number (90% Confidence Interval) [percentage of participants]	8.6 14.8%

2. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	Disease Control Rate was defined as the percentage of participants with best overall disease response of CR or PR or stable disease (SD). CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions. SD was defined failure to attain the criteria needed for CR or PR and failure to fulfill the criteria for at least a 50% increase in the SPD of all index nodal and extranodal (including splenic and/or hepatic nodules) lesions, taking as reference the smallest sum of the product of the diameters of all index lesions recorded at or after baseline.
Time Frame	From date of start of treatment up to disease progression or death (approximately up to 3.8 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received at least one dose of the study drug.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	58
Number (90% Confidence Interval) [percentage of participants]	69.0 119%

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to lymphoma. CR was defined as complete disappearance of all extranodal lesions. PR was defined as at least a 50% decrease in SPD of all index nodal and extranodal lesions.
Time Frame	From date of start of treatment up to disease progression or death (approximately up to 3.8 years)

Outcome Measure Data

Analysis Population Description

We have exhausted all efforts to locate this data and it has since been destroyed, therefore no data is available to report for this outcome measure.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	0

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of start of treatment to the date of event defined as the first documented progression or death due to any cause.
Time Frame	From date of start of treatment up to disease progression or death (approximately up to 3.8 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received at least one dose of the study drug.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	58
Median (95% Confidence Interval) [months]	4.40

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from the date of start of study treatment to the date of death due to any cause.
Time Frame	From date of start of treatment up to disease progression or death (approximately up to 3.8 years)

Outcome Measure Data

Analysis Population Description

The FAS included all participants who received at least one dose of the study drug.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	58
Median (95% Confidence Interval) [months]	16.85

6. Secondary Outcome

Title	Number of Participants With At Least One Adverse Event (AE) and Serious Adverse Event (SAE)
Description	An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important.
Time Frame	From the start of the study and 28 days after study drug discontinuation (approximately up to 18 months)

Outcome Measure Data

Analysis Population Description

The safety set included all participants who received at least one dose of the study drug with a valid post-baseline assessment.

Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
Measure Participants	58
AE	58 100%
SAE	29 50%

Adverse Events

Time Frame	From the start of the study and 28 days after study drug discontinuation (approximately up to 18 months)
Adverse Event Reporting Description	The safety set included all participants who received at least one dose of the study drug with a valid post-baseline assessment.
Arm/Group Title	Everolimus
Arm/Group Description	Participants received everolimus tablets, 10 mg, orally, once daily during each 28 day cycle until determination of objective tumor progression or unacceptable toxicity, or death, or consent withdrawal, or discontinuation from the study for any other reason.
All Cause Mortality
	Everolimus
	Affected / at Risk (%)	# Events
Total	7/58 (12.1%)
Serious Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	29/58 (50%)
Blood and lymphatic system disorders
Anaemia	1/58 (1.7%)
Febrile neutropenia	2/58 (3.4%)
Thrombocytopenia	1/58 (1.7%)
Cardiac disorders
Intracardiac thrombus	1/58 (1.7%)
Gastrointestinal disorders
Abdominal pain	1/58 (1.7%)
Diarrhoea	1/58 (1.7%)
Intestinal obstruction	1/58 (1.7%)
Intestinal perforation	1/58 (1.7%)
Vomiting	1/58 (1.7%)
General disorders
Asthenia	1/58 (1.7%)
Multi-organ failure	1/58 (1.7%)
Immune system disorders
Drug hypersensitivity	1/58 (1.7%)
Infections and infestations
Arthritis infective	1/58 (1.7%)
Cellulitis	1/58 (1.7%)
Clostridial infection	1/58 (1.7%)
Diverticulitis	1/58 (1.7%)
Pneumonia	6/58 (10.3%)
Sinusitis	2/58 (3.4%)
Metabolism and nutrition disorders
Dehydration	1/58 (1.7%)
Failure to thrive	1/58 (1.7%)
Hypercholesterolaemia	1/58 (1.7%)
Hyperglycaemia	1/58 (1.7%)
Hypertriglyceridaemia	1/58 (1.7%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/58 (1.7%)
Nervous system disorders
Hydrocephalus	1/58 (1.7%)
Peripheral motor neuropathy	1/58 (1.7%)
Psychiatric disorders
Mental status changes	1/58 (1.7%)
Renal and urinary disorders
Renal failure acute	1/58 (1.7%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/58 (1.7%)
Dyspnoea	2/58 (3.4%)
Pneumonitis	3/58 (5.2%)
Pulmonary embolism	1/58 (1.7%)
Pulmonary haemorrhage	1/58 (1.7%)
Vascular disorders
Deep vein thrombosis	1/58 (1.7%)
Orthostatic hypotension	1/58 (1.7%)
Venous thrombosis limb	1/58 (1.7%)
Other (Not Including Serious) Adverse Events
	Everolimus
	Affected / at Risk (%)	# Events
Total	58/58 (100%)
Blood and lymphatic system disorders
Anaemia	15/58 (25.9%)
Leukopenia	3/58 (5.2%)
Neutropenia	6/58 (10.3%)
Thrombocytopenia	17/58 (29.3%)
Cardiac disorders
Tachycardia	4/58 (6.9%)
Eye disorders
Lacrimation increased	4/58 (6.9%)
Vision blurred	6/58 (10.3%)
Gastrointestinal disorders
Abdominal distension	4/58 (6.9%)
Abdominal pain	11/58 (19%)
Constipation	9/58 (15.5%)
Diarrhoea	26/58 (44.8%)
Dry mouth	7/58 (12.1%)
Dyspepsia	4/58 (6.9%)
Gastrooesophageal reflux disease	3/58 (5.2%)
Haemorrhoids	5/58 (8.6%)
Mouth ulceration	4/58 (6.9%)
Nausea	16/58 (27.6%)
Oral pain	4/58 (6.9%)
Proctalgia	3/58 (5.2%)
Stomatitis	12/58 (20.7%)
Toothache	3/58 (5.2%)
Vomiting	10/58 (17.2%)
General disorders
Asthenia	8/58 (13.8%)
Fatigue	25/58 (43.1%)
Oedema peripheral	16/58 (27.6%)
Pain	4/58 (6.9%)
Pyrexia	12/58 (20.7%)
Infections and infestations
Bronchitis	3/58 (5.2%)
Candidiasis	3/58 (5.2%)
Herpes zoster	3/58 (5.2%)
Nasopharyngitis	4/58 (6.9%)
Pneumonia	5/58 (8.6%)
Sinusitis	4/58 (6.9%)
Upper respiratory tract infection	7/58 (12.1%)
Urinary tract infection	4/58 (6.9%)
Investigations
Aspartate aminotransferase increased	3/58 (5.2%)
Blood alkaline phosphatase increased	3/58 (5.2%)
Blood triglycerides increased	4/58 (6.9%)
Platelet count decreased	4/58 (6.9%)
Weight decreased	8/58 (13.8%)
Metabolism and nutrition disorders
Decreased appetite	13/58 (22.4%)
Dehydration	5/58 (8.6%)
Hypercholesterolaemia	5/58 (8.6%)
Hyperglycaemia	8/58 (13.8%)
Hypertriglyceridaemia	4/58 (6.9%)
Hypocalcaemia	4/58 (6.9%)
Hypokalaemia	4/58 (6.9%)
Hyponatraemia	3/58 (5.2%)
Hypophosphataemia	4/58 (6.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/58 (15.5%)
Back pain	6/58 (10.3%)
Musculoskeletal pain	3/58 (5.2%)
Myalgia	5/58 (8.6%)
Pain in extremity	6/58 (10.3%)
Nervous system disorders
Dizziness	9/58 (15.5%)
Dysgeusia	8/58 (13.8%)
Headache	11/58 (19%)
Hypoaesthesia	3/58 (5.2%)
Psychiatric disorders
Depression	4/58 (6.9%)
Insomnia	6/58 (10.3%)
Respiratory, thoracic and mediastinal disorders
Cough	12/58 (20.7%)
Dyspnoea	12/58 (20.7%)
Dyspnoea exertional	3/58 (5.2%)
Epistaxis	7/58 (12.1%)
Oropharyngeal pain	6/58 (10.3%)
Pleural effusion	3/58 (5.2%)
Pneumonitis	7/58 (12.1%)
Productive cough	3/58 (5.2%)
Skin and subcutaneous tissue disorders
Blister	3/58 (5.2%)
Dry skin	5/58 (8.6%)
Pruritus	4/58 (6.9%)
Rash	16/58 (27.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e. data from all sites) in the clinical trial.