Study of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma

Metastatic Renal Cell Carcinoma Clinical Trial

Official title:

An Open-label, Randomized, Multi-center, Phase III Study to Compare the Safety and Efficacy of Dovitinib Versus Sorafenib in Patients With Metastatic Renal Cell Carcinoma After Failure of Anti-angiogenic (VEGF-targeted and mTOR Inhibitor) Therapies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01223027
• Other study ID #: CTKI258A2302
• Secondary ID: 2009-015459-25
• Status: Completed
• Phase: Phase 3
• First received: September 30, 2010
• Last updated: November 5, 2015
• Start date: March 2011
• Est. completion date: June 2014

Study information

• Verified date: November 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health CanadaIsrael: Ministry of HealthSaudi Arabia: Ministry of HealthBrazil: Ministry of HealthColumbia: National Institutes of HealthArgentina: Ministry of HealthThailand: Food and Drug Administration (KFDA)Australia: Department of Health and Ageing Therapeutic Goods AdministrationAustria: Agency for Health and Food SafetyBelgium: Federal Agency for Medicinal Products and Health ProductsCzech Republic: State Institute for Drug ControlFrance: Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santéGermany: Federal Institute for Drugs and Medical DevicesGreece: Ministry of Health and WelfareHungary: National Institute of PharmacyItaly: The Italian Medicines AgencyJapan: Pharmaceuticals and Medical Devices AgencySouth Korea: Korea Food and Drug Administration (KFDA)Netherlands: Medicines Evaluation Board (MEB)Norway: Norwegian Medicines AgencyPoland: Ministry of HealthSlovakia: State Institute for Drug ControlSpain: Agencia Española de Medicamentos y Productos SanitariosSweden: Medical Products AgencySwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

This study will evaluate the safety and efficacy of Dovitinib versus sorafenib in patients with metastatic renal cell cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 564
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with metastatic renal cell carcinoma (mRCC) with histological or cytological confirmation of clear cell carcinoma or a component of clear cell

• Patients must have received one and only one prior VEGF-targeted therapy and one and only one prior mTOR inhibitor therapy in the metastatic setting. One VEGF targeted therapy (e.g. sunitinib, or pazopanib, or axitinib, or tivozanib or bevacizumab) and one prior mTOR inhibitor therapy (everolimus, or temsirolimus or ridaforolimus)

• Prior cytokines therapy and prior vaccines in the adjuvant setting is permitted.

• Patients must have had disease progression on or within 6 months of stopping the last therapy.

• Patients must have at least one measurable lesion at baseline (by RECIST Criteria Guidelines v1.1) assessed by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI).

• Karnofsky performance status = 70%

• Patients must have the following laboratory values:

• Absolute Neutrophil Count (ANC) = 1.5 x 109/L

• Platelets = 100 x 109/L

• Hemoglobin (Hgb) > 9 g/dL

• Serum total bilirubin: = 1.5 x ULN

• ALT and AST = 3.0 x ULN (Patients with known liver metastases: AST and ALT = 5.0 x ULN)

• Serum creatinine = 1.5 x ULN

Exclusion Criteria:

• Patients who have previously received sorafenib therapy in the neoadjuvant, adjuvant or metastatic setting.

• Patients who have previously received Dovitinib or brivanib in the neoadjuvant, adjuvant or metastatic setting.

• Patients with brain metastases. Radiological imaging (e.g. CT or MRI scan) of the brain is required at screening/baseline

• Patients with another primary malignancy within 3 years prior to starting study treatment, with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix

• Patients who have received the last administration of an anticancer targeted small molecule therapy = 2 weeks prior to starting study treatment (e.g. sunitinib, pazopanib, axitinib, everolimus, temsirolimus), or who have not recovered from the side effects of such therapy

• Patients who have received the last administration of nitrosurea or mitomycin-C = 6 weeks prior to starting study treatment, or who have not recovered from the side effects of such therapy

• Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic) = 4 weeks prior to starting study treatment or who have not recovered from side effects of such therapy

• Patients with a history of pulmonary embolism (PE), or untreated deep venous thrombosis (DVT) within the past 6 months

• Patients with concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Renal Cell
• Metastatic Renal Cell Carcinoma

Intervention

Drug:
• Dovitinib
Dovitinib is formulated as an oral gelatin capsule of 100 mg strength and was dosed on a flat scale of 500 mg on a 5 days on/2 days off dosing schedule. Medication labels complied withthe legal requirements of each country and were printed in the local language.
• Sorafenib
Sorafenib is formulated as a round, oral, biconvex, red film-coated tablet that contains 200 mg of sorafenib (tosylate). Sorafenib was administered twice daily without food at least 1 hour before or 2 hours after a meal. Sorafenib was supplied according to local practice.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Sante Fe
Australia	Novartis Investigative Site	Footscray	Victoria
Australia	Novartis Investigative Site	Heidelberg	Victoria
Australia	Novartis Investigative Site	South Brisbane	Queensland
Australia	Novartis Investigative Site	St. Leonards	New South Wales
Australia	Novartis Investigative Site	Westmead	New South Wales
Australia	Novartis Investigative Site	Woodville	South Australia
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Gent
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liège
Brazil	Novartis Investigative Site	Porto Alegre	RS
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Edmonton	Alberta
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Saskatoon	Saskatchewan
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Colombia	Novartis Investigative Site	Bogota
Czech Republic	Novartis Investigative Site	Brno
Czech Republic	Novartis Investigative Site	Olomouc
Czech Republic	Novartis Investigative Site	Praha 5
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Caen Cedex
France	Novartis Investigative Site	Clermont-Ferrand
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Nice Cedex 2
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris Cedex 13
France	Novartis Investigative Site	Rennes Cedex
France	Novartis Investigative Site	Saint Priest en Jarez Cedex
France	Novartis Investigative Site	Saint-Herblain Cédex
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Suresnes
France	Novartis Investigative Site	Toulouse Cedex 9
France	Novartis Investigative Site	Vandoeuvre-Les-Nancy Cede
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Aschaffenburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Chemnitz
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Greifswald
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	München
Germany	Novartis Investigative Site	Nuernberg
Germany	Novartis Investigative Site	Ulm
Germany	Novartis Investigative Site	Weiden
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Thessaloniki	GR
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szolnok
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Ramat Gan
Israel	Novartis Investigative Site	Zrifin
Italy	Novartis Investigative Site	Arezzo	AR
Italy	Novartis Investigative Site	Candiolo	TO
Italy	Novartis Investigative Site	Cremona	CR
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Chiba
Japan	Novartis Investigative Site	Fukuoka-city	Fukuoka
Japan	Novartis Investigative Site	Hidaka	Saitama
Japan	Novartis Investigative Site	Hiroshima-city	Hiroshima
Japan	Novartis Investigative Site	Kitaadachi-gun	Saitama
Japan	Novartis Investigative Site	Kobe-city	Hyogo
Japan	Novartis Investigative Site	Kobe-city	Hyogo
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Kyoto-city	Kyoto
Japan	Novartis Investigative Site	Matsumoto	Nagano
Japan	Novartis Investigative Site	Minato-ku	Tokyo
Japan	Novartis Investigative Site	Nagoya-city	Aichi
Japan	Novartis Investigative Site	Obihiro	Hokkaido
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	OsakaSayama	Osaka
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Shinjuku-ku	Tokyo
Japan	Novartis Investigative Site	Suita-city	Osaka
Japan	Novartis Investigative Site	Takatsuki-city	Osaka
Japan	Novartis Investigative Site	Toon-city	Ehime
Japan	Novartis Investigative Site	Yamagata
Japan	Novartis Investigative Site	Yokohama	Kanagawa
Japan	Novartis Investigative Site	Yokohama-city	Kanagawa
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Breda
Netherlands	Novartis Investigative Site	Dordrecht
Netherlands	Novartis Investigative Site	Maastricht
Netherlands	Novartis Investigative Site	Meerssen	KR
Netherlands	Novartis Investigative Site	Rotterdam
Norway	Novartis Investigative Site	Ålesund
Norway	Novartis Investigative Site	Bergen
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Saudi Arabia	Novartis Investigative Site	Riyadh
Slovakia	Novartis Investigative Site	Bratislava	Slovak Republic
Spain	Novartis Investigative Site	Alcorcon	Madrid
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Benidorm	Comunidad Valenciana
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Spain	Novartis Investigative Site	Las Palmas de Gran Canarias	Las Palmas de Gran Canaria
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Oviedo	Asturias
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Pamplona	Navarra
Spain	Novartis Investigative Site	Sabadell	Barcelona
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Sundsvall
Sweden	Novartis Investigative Site	Umeå
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	St. Gallen
Thailand	Novartis Investigative Site	Bangkok
United Kingdom	Novartis Investigative Site	Bristol	Avon
United Kingdom	Novartis Investigative Site	Colchester
United Kingdom	Novartis Investigative Site	Leicester
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Southampton
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	University of Maryland Medical Center UMMC	Baltimore	Maryland
United States	St. Luke's Hospital and Health Network St Luke's	Bethlehem	Pennsylvania
United States	Medical University of South Carolina -Hollings Cancer Center Med Univ SC	Charleston	South Carolina
United States	University of Virginia Health Systems Univ Virginia	Charlottesville	Virginia
United States	Sarah Cannon Research Institute SC - 3	Chattanooga	Tennessee
United States	Baylor Health Care System/Sammons Cancer Center Dept. of Sammons Cancer (4)	Dallas	Texas
United States	Texas Oncology Texas Onc - Austin	Dallas	Texas
United States	Texas Oncology Texas Oncology - Houston	Dallas	Texas
United States	University of Texas Southwestern Medical Center UTSW	Dallas	Texas
United States	Karmanos Cancer Institute Dept.of KarmanosCancerInst (5)	Detroit	Michigan
United States	Willamette Valley Clinical Studies Williamette Valley Cancer	Eugene	Oregon
United States	Highlands Oncology Group Dept of Highlands Oncology Grp	Fayetteville	Arkansas
United States	Florida Cancer Specialists DeptofFloridaCancerSpecialists	Fort Myers	Florida
United States	Cancer Centers of the Carolinas CC of C -Eastside	Greenville	South Carolina
United States	Rocky Mountain Cancer Centers RMCC	Greenwood Village	Colorado
United States	Moanalua Medical Center. Attn: Oncology Dept	Honolulu	Hawaii
United States	Straub Clinic & Hospital Straub	Honolulu	Hawaii
United States	University of Kansas Cancer Center Univ of KS	Kansas City	Kansas
United States	University of California San Diego - Moores Cancer Center Dept of Moores Cancer Ctr (5)	La Jolla	California
United States	Comprehensive Cancer Centers of Nevada CCC of Nevada (1)	Las Vegas	Nevada
United States	Cedars Sinai Medical Center Cedars Sinai Medical Ctr. (SC)	Los Angeles	California
United States	University of California at Los Angeles UCLA (4)	Los Angeles	California
United States	The West Clinic	Memphis	Tennessee
United States	University of Minnesota Medical Center - Fairview Univ of MN	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center SC	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center Dept. of MSKCC	NY	New York
United States	Utah Cancer Specialists Dept.of Utah Cancer Spec. (3)	Salt Lake City	Utah
United States	Rockwood Clinic Spokane Location	Spokane	Washington
United States	Stanford University Medical Center Cancer Clinical Trials Office	Stanford	California
United States	SUNY - Upstate Medical University Div. of Hematology-Oncology	Syracuse	New York
United States	New York Oncology Hematology, P.C. Dept. of New York Oncology. PC	Troy	New York
United States	CINJ at Cooper University Hospital Cooper	Voorhees	New Jersey
United States	Deke Slayton Cancer Center Deke Slayton Cancer Center (2)	Webster	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Colombia,  Czech Republic,  France,  Germany,  Greece,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Norway,  Poland,  Saudi Arabia,  Slovakia,  Spain,  Sweden,  Switzerland,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS) Per Independent Central Radiology Review	Assessed according to RECIST 1.1. PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. If a patient had not progressed or died, on the date of the analysis cut-off or when he/she received any further anti-neoplastic therapy, PFS was censored on the date of last tumor assessment before the cutoff date or the anti-neoplastic therapy date. The distribution of PFS was estimated using the Kaplan-Meier method. The median PFS along with 95% confidence intervals was presented by treatment group.	Until disease progression or discontinuation of treatment due to unacceptable toxicity up to 30-Jun-2014 (discontinuation)	No
Secondary	Overall Survival (OS)	Overall survival (OS) was the key secondary endpoint and was defined as the time from date of randomization to the date of death due to any cause. If a patient was not known to have died, survival was censored on the date of last contact.	until at least 386 deaths are documented in the clinical database.	No
Secondary	Progression Free Survival (PFS) Per Investigator's Radiology Review	PFS was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. The primary analysis for PFS (based on central review) was also to be repeated on FAS considering the Investigator assessments and using the same analytical conventions as the primary analysis.	Until disease progression or discontinuation of treatment due to unacceptable toxicity	No
Secondary	Percentage of Participants With Overall Response Rate (ORR) by Central Radiology Review	Overall response rate (ORR) was defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR). Best overall esponse (BOR) for each patient was determined from the sequence of overall (lesion) responses according to the following rules: CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. CR = at least two determinations of CR at least 4 weeks apart before progression where confirmation required or one determination of CR prior to progression where confirmation not required. SD = at least one SD assessment (or better) > 6 weeks after randomization (and not qualifying for CR or PR). PD = progression = 17 weeks after randomization (and not qualifying for CR, PR or SD).	Until disease progression or discontinuation of treatment due to unacceptable toxicity	No
Secondary	Time to Definitive Worsening of Karnofsky Performance Status (KPS)	Time to definitive worsening of Karnofsky performance status (KPS) was defined as the time from date of randomization to the date of definitive worsening of KPS or to the date of death whichever occurred earlier. Definitive worsening was defined as a definitive decrease in performance status by at least one Karnofsky category (i.e. at least 10 points less) compared to Baseline. Worsening was considered definitive if no later increase above the defined threshold was observed within the course of the study. A single measure reporting a decrease in Karnofsky performance status was sufficient to consider it as definitive only if it was the last one available for this patient. Time to definitive worsening of KPS was analyzed at the time of the final analysis for PFS.	from date of randomization to the date of definitive worsening of KPS or to the date of death whichever occurred earlier	No
Secondary	Patient-reported Outcomes (PROs): Time to Deterioration of Functional Assessment of Cancer Therapy-Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) by at Least 2 Scores	The Kidney Cancer Symptom Index - Disease Related Symptoms (FKSI-DRS) is a validated symptom scale used in studies of patients with kidney cancer. It includes 9-items that assess pain, bone pain, fatigue, lack of energy, shortness of breath, fevers, weight loss, coughing, and blood in urine and responses to each question are answered on a 5-point Likert-type scale ranging from 0 to 4 (e.g., 0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). FKSI-DRS scores range from 0 to 36, where higher scores correspond to better outcomes (eg, fewer symptoms).	from date of randomization, at least 2 score units	No
Secondary	Patient-reported Outcomes (PROs): Time to Definitive Deterioration of the Physical Functioning (PF) Scale of EORTC QLQ-C30 by at Least 10%	The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). Each of the multiitem scales includes a different set of items - no item occurs in more than one scale. Each item in the EORTC QLQ-C30 has 4 response categories (1=Not at all, 2= A little, 3= Quite a bit, 4= Very much) with the higher number representing a worse outcome.	from date of randomization	No
Secondary	Patient-reported Outcomes (PROs): Time to Definitive Deterioration of the Quality of Life (QoL) Scale Scores of EORTC QLQ-C30 by at Least 10%	The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-item measures. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales (fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). Each of the multiitem scales includes a different set of items - no item occurs in more than one scale. Each item in the EORTC QLQ-C30 has 4 response categories (1=Not at all, 2= A little, 3= Quite a bit, 4= Very much) with the higher number representing a worse outcome.	from date of randomization	No
Secondary	Pre-dose Concentration in Plasma in Dovitinib	Predose concentrations of dovitinib were summarized by visit using PAS. All concentration data was listed by patient and time point using FAS. Mean pre-dose concentrations along with standard deviation (SD) was plotted over time if appropriate.	Week 2 Day 5, Week 4 Day 5, Week 6 Day 5	No