BAY43-9006 (Sorafenib) Versus Interferon Alpha-2a in Patients With Unresectable and/or Metastatic Renal Cell Carcinoma

Sponsor

Bayer (Industry)

Overall Status

Completed

CT.gov ID

NCT00117637

Collaborator

(none)

189

Enrollment

Locations

Arms

Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of the study is to:

Find out if patients receiving BAY43-9006 will live longer without tumor progression than those receiving standard therapy with interferon alpha-2a
Find out if a higher dose of BAY43-9006 can inhibit tumor progression in patients who progressed during standard dose treatment with BAY43-9006, and for how long these patients live without progression
Find out how long patients live without progression who receive BAY43-9006 after failing to respond to standard therapy with interferon alpha-2a
Find out in how many percent of patients BAY43-9006 prevents the growth of or shrinks kidney tumors and/or their metastases depending on treatment and dosage
Find out if BAY43-9006 has any effect on the quality of life of patients with kidney cancer
Find out the level of BAY43-9006 in the blood once per month and any changes in this level
Find out whether BAY43-9006 effects are associated with specific biomarkers

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Renal Cell	Drug: Sorafenib (Nexavar, BAY43-9006) Drug: Interferon	Phase 2

Detailed Description

Analyses on Biomarkers were exploratory and assessed as tertiary objective of the trial.

Study Design

Study Type:

Interventional

Actual Enrollment :

189 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomised, Open-label, Multi-centre Phase II Study of BAY43-9006 (Sorafenib) Versus Standard Treatment With Interferon Alpha-2a in Patients With Unresectable and/or Metastatic Renal Cell Carcinoma.

Study Start Date :

Jun 1, 2005

Actual Primary Completion Date :

Sep 1, 2006

Actual Study Completion Date :

Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: First Sorafenib (Nexavar, BAY43-9006) 400 mg then 600 mg Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Drug: Sorafenib (Nexavar, BAY43-9006) Multi kinase inhibitor
Active Comparator: First Interferon then Sorafenib (Nexavar, BAY43-9006) 400 mg Interferon (IFN) α-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period.After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).	Drug: Interferon Interferon

Arm

Intervention/Treatment

Experimental: First Sorafenib (Nexavar, BAY43-9006) 400 mg then 600 mg

Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.

Drug: Sorafenib (Nexavar, BAY43-9006)

Multi kinase inhibitor

Active Comparator: First Interferon then Sorafenib (Nexavar, BAY43-9006) 400 mg

Interferon (IFN) α-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period.After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).

Drug: Interferon

Interferon

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) Based on Independent Radiological Review for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation

Secondary Outcome Measures

Progression-free Survival (PFS) Based on Investigator Assessment for the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation
Disease Control (DC) According to Independent Central Review for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Disease Control (DC) According to the Investigator Assessment for the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Disease Control (DC) According to the Investigator Assessment for the Second Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Analysis of the Quality of Life by Use of the Respiratory Domain of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) After Intervention for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns. The respiratory domain of the FKSI comprises 2 questions:" I have been short in breath" and "I have been coughing"; its score ranges from 0 to 8.
Analysis of the Quality of Life by Use of the Respiratory Domain of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns. The respiratory domain of the FKSI comprises 2 questions:" I have been short in breath" and "I have been coughing"; its score ranges from 0 to 8.
Analysis of the Quality of Life by Use of Total Score of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns.
Analysis of the Quality of Life by Use of Total Score of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns.
Analysis of the Quality of Life (QoL) by Use of Functional Assessment of Cancer Therapy-Biologic-response Modifiers (FACT-BRM) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FACT-BRM comprises 40 questions within 6 domains (physical well being, social/family well being, emotional well being, additional concern: physical, and additional concern: emotional). Each question was answered on a five point scale from 0 (not at all) to 4 (very much). The total score range is from 0 to 160 with higher scores indicating better QoL.
Analysis of the Quality of Life (QoL) by Use of Functional Assessment of Cancer Therapy-Biologic-response Modifiers (FACT-BRM) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The FACT-BRM comprises 40 questions within 6 domains (physical well being, social/family well being, emotional well being, additional concern: physical, and additional concern: emotional). Each question was answered on a five point scale from 0 (not at all) to 4 (very much). The total score range is from 0 to 160 with higher scores indicating better QoL.
Analysis of the Treatment Tolerability (Effectiveness) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Side Effects) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Convenience) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Global Satisfaction) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Effectiveness) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Side Effects) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Convenience) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Analysis of the Treatment Tolerability (Global Satisfaction) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Tumor Response According to the Independent Radiological Review for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Tumor Response According to the Investigator Assessment for the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes
Tumor Response According to the Investigator Assessment for the Second Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes
Progression Free Survival According to the Investigator Assessment (Second Intervention Period) [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation
Overall Survival (OS) [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Overall Survival was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact
Slope - Change in Trough Concentration/Cycle [From start of treatment of the first subject until 15 months later assessed every 4 weeks.]
Plasma samples were collected prior to dosing every 4 weeks after the patient reached steady-state (at least 10 days at 400 mg BID (bis in die, twice daily)) to assess any potential trends in trough concentration over time.
Average of All Trough Plasma Concentrations [From start of treatment of the first subject until 15 months later assessed every 4 weeks.]
Plasma samples were collected prior to dosing every 4 weeks after the patient reached steady-state (at least 10 days at 400 mg BID).
Duration of Response According to the Independent Radiological Review for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Duration of Response According to the Investigator Assessment for the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Duration of Response According to the Investigator Assessment for the Second Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks]
Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Time to Response According to the Independent Radiological Review for the First Intervention Period [From randomization of the first subject until 15 months later, assessed every 8 weeks]
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation was defined as the time from date of randomization to the earliest date that the response was first documented
Time to Response According to the Investigator Assessment for the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks]
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation was defined as the time from date of randomization to the earliest date that the response was first documented
Time to Response According to the Investigator Assessment for the Second Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks]
Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation) was defined as the time from date of randomization to the earliest date that the response was first documented
Analysis of the Eastern Co-operative Oncology Group (ECOG) Status at the End of the First Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks]
Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst).
Analysis of the Eastern Co-operative Oncology Group (ECOG) Status at the End of the Second Intervention Period [From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks]
Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice
Male or female patients >= 18 years of age
Patients who have a life expectancy of at least 12 weeks
Patients, who suffer from unresectable and/or metastatic, measurable predominantly clear cell RCC (Renal Cell Carcinoma) histologically or cytologically documented
Patients must have undergone prior (at the time of primary diagnosis) complete surgical excision of primary RCC tumor
Patients must have had no prior systemic therapy for advanced RCC. Prior systemic therapy is defined as any treatment with a chemotherapy agent (or regimen), an immunotherapy agent (or regimen) or an investigational treatment agent (or regimen) against the renal cell carcinoma. Megestrol acetate or medroxyprogesterone will constitute as a prior systemic therapy
Patients who have at least one uni-dimensional measurable lesion by CT (Computed tomography)-scan or MRI (Magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST)
Patients who have an Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1
Adequate bone marrow, liver , and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening
Hemoglobin >9.0 g/l
Absolute neutrophil count ( ANC)>1,500/mm3
Platelets> or = 100,000/ul
Total bilirubin < 1.5 x the upper limit of normal
ALT (Alanine aminotransferase) and AST (Aspartate aminotransferase) < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer)
Amylase and lipase < 1.5 x the upper limit of normal
Serum creatinine < 2.0 x the upper limit of normal
PT (Prothrombin Time) or INR (International Normalized Ratio) and PTT (Partial Thromboplastin Time) < 1.5 x upper limit of normal (patients who receive anti-coagulation treatment with an agent such as warfarin or heparin will be allowed to participate. For patients on warfarin, close monitoring of at least weekly evaluations will be performed until INR is stable based on a measurement at pre dose, as defined by the local standard of care)

Exclusion Criteria:

Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta [Noninvasive papillary carcinoma], Tis [Carcinoma in situ: "flat tumor"]&T1 [Tumor invades subepithelial connective tissue]) or any cancer curatively treated > 5 years prior to study entry
Complete renal shut-down requiring hemo- or peritoneal dialysis
History of cardiac disease : congestive heart failure > NYHA (New York Heart Association) class 2: active cardiovascular disease( MI (Distant metastasis) more than 6 months prior to study entry is allowed); cardiac arrhythmia requiring anti-arrythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
Active clinically serious bacterial or fungal infections (>= grade 2 NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events), Version 3)
Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to this brain tumour site at the time of study entry. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies (head CT or MRI at screening always required)
Patients with seizure disorder requiring medication (such as steroid anti-epileptics)
History of organ allograft
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Known or suspected allergy to the investigational agent or any agent given in association with this trial
Any condition that is unstable or which could jeopardise the safety of the patient and his/her compliance in the study
Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Sacramento	California	United States	95817
2	Aurora	Colorado	United States	80010
3	Chicago	Illinois	United States	60637
4	Frederick	Maryland	United States	21701
5	Las Vegas	Nevada	United States	89135
6	Cleveland	Ohio	United States	44195-0002
7	Portland	Oregon	United States	97239
8	Dallas	Texas	United States	75246
9	Seattle	Washington	United States	98101
10	Bordeaux		France	33000
11	Lille Cedex		France	59020
12	Lyon Cedex		France	69008
13	Marseille		France	13273
14	Nantes		France	44805
15	Paris Cedex 15		France	75908
16	Toulouse		France	31052
17	Villejuif		France	94805
18	Ulm	Baden-Württemberg	Germany	89075
19	München	Bayern	Germany	81377
20	Frankfurt	Hessen	Germany	60488
21	Düsseldorf	Nordrhein-Westfalen	Germany	40225
22	Mainz	Rheinland-Pfalz	Germany	55131
23	Berlin		Germany	12203
24	Hamburg		Germany	20246
25	Gdansk		Poland	80-210
26	Krakow		Poland	31-115
27	Poznan		Poland	61-878
28	Szczecin		Poland	70-111
29	Warszawa		Poland	02-781
30	Warszawa		Poland	04-141
31	Wroclaw		Poland	50-043
32	Kazan		Russian Federation	420029
33	Kirov		Russian Federation	610021
34	Moscow		Russian Federation	115478
35	Moscow		Russian Federation	125284
36	St. Petersburg		Russian Federation	197758
37	Donetsk		Ukraine	83092
38	Kharkiv		Ukraine	61024
39	Kiev		Ukraine	115
40	Lviv		Ukraine	79031
41	Sutton	Surrey	United Kingdom	SM2 5PT
42	London		United Kingdom	SW3 6JJ

Sponsors and Collaborators

Bayer

Investigators

Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Publications

None provided.

Responsible Party:

Bayer

ClinicalTrials.gov Identifier:

NCT00117637

Other Study ID Numbers:

11848
2005-000544-86

First Posted:

Jul 8, 2005

Last Update Posted:

Oct 31, 2014

Last Verified:

Oct 1, 2014

Keywords provided by Bayer

Renal Cell Cancer

RCC

Cancer

Additional relevant MeSH terms:

Carcinoma

Carcinoma, Renal Cell

Interferons

Sorafenib

Study Results

Participant Flow

Recruitment Details	The start of enrollment was 14 June 2005 and the last day of enrollment was 12 September 2005.
Pre-assignment Detail	All 189 (97 Sorafenib/92 Interferon) randomized subjects were included in the intent to treat (ITT) population, and 187 (97 Sorafenib/90 Interferon) were included in the safety population according to the protocol, which defined eligibility for safety analyses by the prerequisite that a patient had received at least one dose of study medication.

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Period Title: First Intervention (Period 1)
STARTED	97	92
Subjects Received Treatment	97	90
COMPLETED	79	67
NOT COMPLETED	18	25
Period Title: First Intervention (Period 1)
STARTED	49	61
Subjects Received Treatment	49	61
COMPLETED	39	39
NOT COMPLETED	10	22

Baseline Characteristics

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg	Total
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).	Total of all reporting groups
Overall Participants	97	92	189
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	62.5	62
Sex: Female, Male (Count of Participants)
Female	32 33%	40 43.5%	72 38.1%
Male	65 67%	52 56.5%	117 61.9%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0	56 57.7%	49 53.3%	105 55.6%
1	41 42.3%	43 46.7%	84 44.4%
Motzer risk factors (participants) [Number]
low	52 53.6%	47 51.1%	99 52.4%
intermediate	44 45.4%	44 47.8%	88 46.6%
high	1 1%	0 0%	1 0.5%
missing	0 0%	1 1.1%	1 0.5%
Race (participants) [Number]
White	68 70.1%	75 81.5%	143 75.7%
Asian	0 0%	1 1.1%	1 0.5%
Missing	29 29.9%	16 17.4%	45 23.8%
Renal Cell Carcinoma (RCC) subtype (participants) [Number]
clear cell	85 87.6%	81 88%	166 87.8%
other variant	12 12.4%	11 12%	23 12.2%
Time since first progression (years) [Median (Full Range) ]
Median (Full Range) [years]	0.2	0.2	0.2
Time since initial diagnosis (years) [Median (Full Range) ]
Median (Full Range) [years]	0.9	1	1

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Based on Independent Radiological Review for the First Intervention Period
Description	Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
Median (95% Confidence Interval) [months]	5.7	5.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The study was planned to show a 80% improvement in PFS for the group treated with Sorafenib compared to the group treated with Interferon, with a 80% power and a 2-sided type I error of 5%
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.50
	Comments	The log rank test is stratified by region (western Europe, Eastern Europe, USA) and by Motzer risk category (low, intermediate).
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.61 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-free Survival (PFS) Based on Investigator Assessment for the First Intervention Period
Description	Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
Median (95% Confidence Interval) [months]	5.6	7.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The study was planned to show a 80% improvement in PFS for the group treated with Sorafenib compared to the group treated with Interferon, with a 80% power and a 2-sided type I error of 5%
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.469
	Comments	The log rank test is stratified by region (western Europe, Eastern Europe, USA) and by Motzer risk category (low, intermediate).
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.882
	Confidence Interval	(2-Sided) 95% 0.628 to 1.239
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Disease Control (DC) According to Independent Central Review for the First Intervention Period
Description	Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
disease control (CR or PR or SD)	77 79.4%	59 64.1%
no disease control	10 10.3%	24 26.1%
Unknown	10 10.3%	9 9.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.006
	Comments	The Cochran-Mantel-Haenszel statistics was stratified by region and Motzer risk category.
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Disease Control (DC) According to the Investigator Assessment for the First Intervention Period
Description	Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
disease control (CR or PR or SD)	83 85.6%	62 67.4%
no disease control	7 7.2%	24 26.1%
Unknown	7 7.2%	6 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0004
	Comments	the Cochran-Mantel-Haenszel statistics was stratified by region and Motzer risk category.
	Method	Cochran-Mantel-Haenszel
	Comments

5. Secondary Outcome

Title	Disease Control (DC) According to the Investigator Assessment for the Second Intervention Period
Description	Disease Control (DC) was defined as the total number of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD); CR, PR, or SD had to be maintained for at least 28 days from the first demonstration of that rating). CR: disappearance of tumor lesions (TL); PR: a decrease of at least 30% in the sum of TL sizes; SD: steady state of disease; PD: an increase of at least 20% in the sum of TL sizes.
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	49	61
disease control (CR or PR or SD)	25 25.8%	49 53.3%
no disease control	16 16.5%	6 6.5%
Unknown	8 8.2%	6 6.5%

6. Secondary Outcome

Title	Analysis of the Quality of Life by Use of the Respiratory Domain of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) After Intervention for the First Intervention Period
Description	The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns. The respiratory domain of the FKSI comprises 2 questions:" I have been short in breath" and "I have been coughing"; its score ranges from 0 to 8.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	91	87
Least Squares Mean (95% Confidence Interval) [scores on a scale]	6.4	5.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline) and using the baseline respiratory score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Analysis of the Quality of Life by Use of the Respiratory Domain of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the Second Intervention Period
Description	The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns. The respiratory domain of the FKSI comprises 2 questions:" I have been short in breath" and "I have been coughing"; its score ranges from 0 to 8.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	37	42
Least Squares Mean (95% Confidence Interval) [scores on a scale]	5.7	6.4

8. Secondary Outcome

Title	Analysis of the Quality of Life by Use of Total Score of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the First Intervention Period
Description	The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	90	86
Least Squares Mean (95% Confidence Interval) [scores on a scale]	40.5	34.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline) and using the baseline respiratory score as covariate.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.015
	Comments
	Method	Mixed Models Analysis
	Comments

9. Secondary Outcome

Title	Analysis of the Quality of Life by Use of Total Score of the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI) for the Second Intervention Period
Description	The FKSI questionnaire comprises 15 questions dispatched within 4 domains (respiratory, pain, general symptoms and overall Quality of Life (QoL)) plus 2 individual items. Each question was answered on a five point scale from 0 (not at all) to 4 (very much) indicating the severity of symptoms. The total score range was from 0 to 60 with higher scores indicating subjects reported fewer kidney cancer related symptoms and concerns.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	37	42
Least Squares Mean (95% Confidence Interval) [scores on a scale]	34.6	42.3

10. Secondary Outcome

Title	Analysis of the Quality of Life (QoL) by Use of Functional Assessment of Cancer Therapy-Biologic-response Modifiers (FACT-BRM) for the First Intervention Period
Description	The FACT-BRM comprises 40 questions within 6 domains (physical well being, social/family well being, emotional well being, additional concern: physical, and additional concern: emotional). Each question was answered on a five point scale from 0 (not at all) to 4 (very much). The total score range is from 0 to 160 with higher scores indicating better QoL.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	89	86
Least Squares Mean (95% Confidence Interval) [scores on a scale]	104	93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.073
	Comments
	Method	Mixed Models Analysis
	Comments

11. Secondary Outcome

Title	Analysis of the Quality of Life (QoL) by Use of Functional Assessment of Cancer Therapy-Biologic-response Modifiers (FACT-BRM) for the Second Intervention Period
Description	The FACT-BRM comprises 40 questions within 6 domains (physical well being, social/family well being, emotional well being, additional concern: physical, and additional concern: emotional). Each question was answered on a five point scale from 0 (not at all) to 4 (very much). The total score range is from 0 to 160 with higher scores indicating better QoL.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	37	40
Least Squares Mean (95% Confidence Interval) [scores on a scale]	89.7	108.4

12. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Effectiveness) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	29	34
Least Squares Mean (95% Confidence Interval) [scores on a scale]	52	42

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Mixed Models Analysis
	Comments

13. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Side Effects) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	27	30
Least Squares Mean (95% Confidence Interval) [scores on a scale]	63	46

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.005
	Comments
	Method	Mixed Models Analysis
	Comments

14. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Convenience) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	30	33
Least Squares Mean (95% Confidence Interval) [scores on a scale]	82	66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments

15. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Global Satisfaction) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the First Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	30	33
Least Squares Mean (95% Confidence Interval) [scores on a scale]	60	46

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments	The least square (LS) means have been adjusted according to the stratification factors (geographical region, Motzer score at baseline).
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.019
	Comments
	Method	Mixed Models Analysis
	Comments

16. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Effectiveness) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	10	9
Least Squares Mean (95% Confidence Interval) [scores on a scale]	56.9	40.3

17. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Side Effects) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	10	8
Least Squares Mean (95% Confidence Interval) [scores on a scale]	61.3	57.6

18. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Convenience) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	11	9
Least Squares Mean (95% Confidence Interval) [scores on a scale]	86.5	82.5

19. Secondary Outcome

Title	Analysis of the Treatment Tolerability (Global Satisfaction) by Use of Treatment Satisfaction Questionnaire for Medication (TSQM) for the Second Intervention Period
Description	The TSQM comprises 14 questions dispatched within 4 domains (effectiveness, side effects, convenience, and global satisfaction). Each question was answered on either a 5-point or 7-point scale. Each domain score can vary from 0 to 100 with higher scores indicating subject reported higher effectiveness of treatment, less bothered by side-effects, more convenient use of medication and overall greater satisfaction with the treatment. No total score is calculated.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
The number of analyzed patients regarding quality of life parameters varied considerably due to missing questionnaires which had not been filled in by patients or invalidity of these questionnaires according to the protocol.

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	11	8
Least Squares Mean (95% Confidence Interval) [scores on a scale]	39.9	35.4

20. Secondary Outcome

Title	Tumor Response According to the Independent Radiological Review for the First Intervention Period
Description	Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes.
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
Complete Response (CR)	0 0%	1 1.1%
Partial Response (PR)	5 5.2%	7 7.6%
Stable Disease (SD)	72 74.2%	51 55.4%
Progressive Disease (PD)	10 10.3%	24 26.1%
Not Evaluated	10 10.3%	9 9.8%

21. Secondary Outcome

Title	Tumor Response According to the Investigator Assessment for the First Intervention Period
Description	Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
Complete Response (CR)	0 0%	1 1.1%
Partial Response (PR)	21 21.6%	13 14.1%
Stable Disease (SD)	62 63.9%	48 52.2%
Progressive Disease (PD)	7 7.2%	24 26.1%
Not Evaluated	7 7.2%	6 6.5%

22. Secondary Outcome

Title	Tumor Response According to the Investigator Assessment for the Second Intervention Period
Description	Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	49	61
Complete Response (CR)	0 0%	1 1.1%
Partial Response (PR)	0 0%	11 12%
Stable Disease (SD)	25 25.8%	37 40.2%
Progressive Disease (PD)	16 16.5%	6 6.5%
Not Evaluated	8 8.2%	6 6.5%

23. Secondary Outcome

Title	Progression Free Survival According to the Investigator Assessment (Second Intervention Period)
Description	Progression-free Survival (PFS) was defined as the time from date of randomization to disease progression (radiological or clinical or death due to any cause, whichever occurs first). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	49	61
Median (95% Confidence Interval) [months]	4.5	5.5

24. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival was defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	97	92
Median (95% Confidence Interval) [months]	14.8	26.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg, First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.014
	Comments
	Method	Log Rank
	Comments

25. Secondary Outcome

Title	Slope - Change in Trough Concentration/Cycle
Description	Plasma samples were collected prior to dosing every 4 weeks after the patient reached steady-state (at least 10 days at 400 mg BID (bis in die, twice daily)) to assess any potential trends in trough concentration over time.
Time Frame	From start of treatment of the first subject until 15 months later assessed every 4 weeks.

Outcome Measure Data

Analysis Population Description
Patients who started on Sorafenib, not Interferon, and had been at the same dose (400 mg) for at least 10 days were considered valid for the analysis. Concentrations collected between 10-14 hours from the last dose were included in the analysis.

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.
Measure Participants	24
Mean (95% Confidence Interval) [100*(mg/L/cycle)]	-8.3

26. Secondary Outcome

Title	Average of All Trough Plasma Concentrations
Description	Plasma samples were collected prior to dosing every 4 weeks after the patient reached steady-state (at least 10 days at 400 mg BID).
Time Frame	From start of treatment of the first subject until 15 months later assessed every 4 weeks.

Outcome Measure Data

Analysis Population Description
Patients who started on Sorafenib, not Interferon, and had been at the same dose (400 mg or 600 mg BID) for at least 10 days were considered valid for the analysis. Concentrations collected between 10-14 hours from the last dose were included in the analysis.

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.
Measure Participants	24
Geometric Mean (95% Confidence Interval) [100*mg/L]	93.9

27. Secondary Outcome

Title	Duration of Response According to the Independent Radiological Review for the First Intervention Period
Description	Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	5	8
Median (Full Range) [months]	7.5	7.7

28. Secondary Outcome

Title	Duration of Response According to the Investigator Assessment for the First Intervention Period
Description	Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	21	14
Median (Full Range) [months]	4.4	9.2

29. Secondary Outcome

Title	Duration of Response According to the Investigator Assessment for the Second Intervention Period
Description	Duration of Response was defined as the time from date of first response (Complete Response (CR) or Partial Response (PR)) to the date when Progressive Disease (PD) is first documented or to the date of death, whichever occurs first. Subjects still having CR or PR at the time of analysis were censored at their last date of last contact
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	0	12
Median (Full Range) [months]	5.5

30. Secondary Outcome

Title	Time to Response According to the Independent Radiological Review for the First Intervention Period
Description	Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation was defined as the time from date of randomization to the earliest date that the response was first documented
Time Frame	From randomization of the first subject until 15 months later, assessed every 8 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	5	8
Median (Full Range) [months]	1.8	5.4

31. Secondary Outcome

Title	Time to Response According to the Investigator Assessment for the First Intervention Period
Description	Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation was defined as the time from date of randomization to the earliest date that the response was first documented
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	21	14
Median (Full Range) [months]	3.5	5.4

32. Secondary Outcome

Title	Time to Response According to the Investigator Assessment for the Second Intervention Period
Description	Time to Response (TTR) for subjects who achieved a response (Complete Response (CR) or Partial Response (PR) with confirmation) was defined as the time from date of randomization to the earliest date that the response was first documented
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	First Sorafenib (Nexavar, BAY43-9006) 400 mg Then 600 mg	First Interferon Then Sorafenib (Nexavar, BAY43-9006) 400 mg
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	0	12
Median (Full Range) [months]	1.7

33. Secondary Outcome

Title	Analysis of the Eastern Co-operative Oncology Group (ECOG) Status at the End of the First Intervention Period
Description	Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst).
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks

Outcome Measure Data

Analysis Population Description
At the time of the analysis, only 95 subjects in Sorafenib 400 mg bid group and 89 in Interferon group were documented by study investigators due to various reasons (drop-out of patients by AEs, death etc.)

Arm/Group Title	Sorafenib 400 mg in Period 1	Interferon Therapy in Period 1
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	95	89
0= Fully active without restriction	20 20.6%	19 20.7%
1= Restricted in physically strenuous activity	48 49.5%	42 45.7%
2= Ambulatory, capable of all selfcare	20 20.6%	21 22.8%
3= Capable of limited selfcare	5 5.2%	5 5.4%
4= Completely disabled	1 1%	2 2.2%
5= Dead	1 1%	0 0%

34. Secondary Outcome

Title	Analysis of the Eastern Co-operative Oncology Group (ECOG) Status at the End of the Second Intervention Period
Description	Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale that measures how cancer affects the daily life of a patient on an ordinal scale from grade 0 (best) to grade 5 (worst).
Time Frame	From randomization of the first subject until 3 years and 9 months later, assessed every 4 weeks

Outcome Measure Data

Analysis Population Description
At the time of the analysis, only 45 subjects in Sorafenib 400/600 mg bid group and 58 in Interferon/Sorafenib 400 mg bid group were documented by study investigators due to various reasons (drop-out of patients by AEs, death etc.)

Arm/Group Title	Sorafenib 600 mg (as Dose Escalation After 400 mg)	Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.	Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
Measure Participants	45	58
0= Fully active without restriction	5	16
1= Restricted in physically strenuous activity	25	26
2= Ambulatory, capable of all selfcare	10	10
3= Capable of limited selfcare	4	5
4= Completely disabled	1	1
5= Dead	0	0

Adverse Events

	Sorafenib 400 mg in Period 1		Interferon Therapy in Period 1		Sorafenib 600 mg (as Dose Escalation After 400 mg)		Sorafenib 400 mg (After Interferon Therapy)
Time Frame
Adverse Event Reporting Description	Acronyms and abbreviations used: Common Terminology Criteria for Adverse Events (CTCAE); Not Otherwise Specified (NOS); Gastrointestinal (GI); Absolute Neutrophil Count (ANC); Alanine aminotransferase (ALT); Aspartate aminotransferase (AST); Central nervous system (CNS); Acute respiratory distress syndrome (ARDS)

Arm/Group Title	Sorafenib 400 mg in Period 1		Interferon Therapy in Period 1		Sorafenib 600 mg (as Dose Escalation After 400 mg)		Sorafenib 400 mg (After Interferon Therapy)
Arm/Group Description	Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.		Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).		Subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (bid) (ie 12-hourly) orally until progression in (= first intervention period, 5.7 months [median] ) and 3 tablets of Sorafenib twice daily (ie 12-hourly) orally until the following progression (= second intervention period, 3.6 months [median]) on a continuous basis.		Interferon (IFN) a-2a was administered at a dose of 9 million international units(MIU) subcutaneously three times a week until progression (= first intervention period, 5.6 months [median]). Subjects initially started with a single dose of 3 MIU IFN and increased the dose as rapidly as possible to 9 MIU IFN three times a week within 1 or 2 weeks in first intervention period. After first progression, subjects received 2 tablets of Sorafenib (200 mg tablets) twice daily (BID) (ie 12-hourly) until the next progression (=second intervention period, 5.3 months [median]).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sorafenib 400 mg in Period 1		Interferon Therapy in Period 1		Sorafenib 600 mg (as Dose Escalation After 400 mg)		Sorafenib 400 mg (After Interferon Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/97 (48.5%)		36/90 (40%)		14/49 (28.6%)		30/61 (49.2%)
Blood and lymphatic system disorders
hemoglobin	2/97 (2.1%)		6/90 (6.7%)		2/49 (4.1%)		4/61 (6.6%)
platelets	0/97 (0%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
edema: limb	0/97 (0%)		0/90 (0%)		1/49 (2%)		1/61 (1.6%)
Cardiac disorders
conduction abnormality, asystole	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
supraventricular arrhythmia, supraventricular arrhythmi	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
supraventricular arrhythmia, atrial fibrillation	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
cardiopulmonary arrest	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
cardiac ischemia / infarction	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		1/61 (1.6%)
cardiac general - other	1/97 (1%)		2/90 (2.2%)		1/49 (2%)		4/61 (6.6%)
Ear and labyrinth disorders
auditory / ear - other	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
Gastrointestinal disorders
ascites	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		1/61 (1.6%)
constipation	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
dehydration	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		1/61 (1.6%)
diarrhea	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		2/61 (3.3%)
nausea	0/97 (0%)		2/90 (2.2%)		0/49 (0%)		1/61 (1.6%)
obstruction, GI, stomach	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
perforation, GI, colon	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
vomiting	2/97 (2.1%)		1/90 (1.1%)		1/49 (2%)		1/61 (1.6%)
ileus	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
GI - other	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
General disorders
death not associated with CTCAE term, death NOS	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
death not associated with CTCAE term, disease progress	10/97 (10.3%)		1/90 (1.1%)		2/49 (4.1%)		7/61 (11.5%)
fever	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
fatigue	1/97 (1%)		3/90 (3.3%)		0/49 (0%)		2/61 (3.3%)
constitutional symptoms - other	6/97 (6.2%)		4/90 (4.4%)		0/49 (0%)		5/61 (8.2%)
pain, back	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
pain, chest / thorax NOS	1/97 (1%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
pain, extremity - limb	0/97 (0%)		1/90 (1.1%)		1/49 (2%)		1/61 (1.6%)
pain, tumor pain	1/97 (1%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
pain, abdomen NOS	3/97 (3.1%)		1/90 (1.1%)		0/49 (0%)		1/61 (1.6%)
pain, head / headache	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
pain, bone	2/97 (2.1%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
pain, other	1/97 (1%)		0/90 (0%)		1/49 (2%)		1/61 (1.6%)
pain, joint	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
Hepatobiliary disorders
hepatobiliary - other	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
liver dysfunction	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
Immune system disorders
allergic reaction	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
Infections and infestations
infection (documented clinically), appendix	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
infection with normal ANC, abdomen NOS	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
infection with normal ANC, lung (pneumonia)	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
infection with unknown ANC, bronchus	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
infection with unknown ANC, upper airway NOS	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
infection (documented clinically), lung (pneumonia)	0/97 (0%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
infection - other	0/97 (0%)		0/90 (0%)		0/49 (0%)		3/61 (4.9%)
Metabolism and nutrition disorders
ALT	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
AST	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
bilirubin (hyperbilirubinemia)	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
hyperkalemia	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
hypocalcemia	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
hypoglycemia	1/97 (1%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
metabolic / lab - other	1/97 (1%)		2/90 (2.2%)		0/49 (0%)		0/61 (0%)
Musculoskeletal and connective tissue disorders
fracture	0/97 (0%)		4/90 (4.4%)		0/49 (0%)		0/61 (0%)
osteoporosis	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
secondary malignancy (possibly related to cancer treat)	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
Nervous system disorders
CNS ischemia	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
confusion	0/97 (0%)		3/90 (3.3%)		0/49 (0%)		0/61 (0%)
dizziness	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
hydrocephalus	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
mood alteration, depression	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
neurology - other	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		3/61 (4.9%)
seizure	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
somnolence	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
speech impairment	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
Renal and urinary disorders
renal failure	3/97 (3.1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
urinary retention	1/97 (1%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
Respiratory, thoracic and mediastinal disorders
cough	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
pleural effusion	3/97 (3.1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
pneumonitis	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
pneumothorax	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
dyspnea (shortness of breath)	2/97 (2.1%)		1/90 (1.1%)		1/49 (2%)		1/61 (1.6%)
ARDS	0/97 (0%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
airway obstruction, bronchus	0/97 (0%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
pulmonary - other	0/97 (0%)		0/90 (0%)		1/49 (2%)		3/61 (4.9%)
Skin and subcutaneous tissue disorders
hand-foot skin reaction	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		2/61 (3.3%)
ulceration	1/97 (1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
Vascular disorders
hematoma	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
hemorrhage, GI, colon	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
hemorrhage, GI, stomach	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
hemorrhage, GI, lower GI NOS	0/97 (0%)		1/90 (1.1%)		0/49 (0%)		1/61 (1.6%)
hemorrhage, GI, upper GI NOS	0/97 (0%)		2/90 (2.2%)		0/49 (0%)		0/61 (0%)
hemorrhage - other	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
hemorrhage pulmonary, bronchopulmonary NOS	1/97 (1%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
hemorrhage, GI, anus	0/97 (0%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
hemorrhage, GI, varices (rectal)	0/97 (0%)		0/90 (0%)		1/49 (2%)		0/61 (0%)
thrombosis / thrombus / embolism	2/97 (2.1%)		0/90 (0%)		0/49 (0%)		1/61 (1.6%)
Other (Not Including Serious) Adverse Events
	Sorafenib 400 mg in Period 1		Interferon Therapy in Period 1		Sorafenib 600 mg (as Dose Escalation After 400 mg)		Sorafenib 400 mg (After Interferon Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/97 (95.9%)		84/90 (93.3%)		40/49 (81.6%)		55/61 (90.2%)
Blood and lymphatic system disorders
neutrophils	2/97 (2.1%)		13/90 (14.4%)		0/49 (0%)		0/61 (0%)
hemoglobin	14/97 (14.4%)		23/90 (25.6%)		10/49 (20.4%)		8/61 (13.1%)
platelets	1/97 (1%)		11/90 (12.2%)		2/49 (4.1%)		4/61 (6.6%)
leukocytes	2/97 (2.1%)		11/90 (12.2%)		0/49 (0%)		0/61 (0%)
lymphopenia	0/97 (0%)		0/90 (0%)		4/49 (8.2%)		3/61 (4.9%)
edema: limb	4/97 (4.1%)		5/90 (5.6%)		5/49 (10.2%)		2/61 (3.3%)
Cardiac disorders
hypertension	24/97 (24.7%)		7/90 (7.8%)		1/49 (2%)		13/61 (21.3%)
Gastrointestinal disorders
anorexia	34/97 (35.1%)		28/90 (31.1%)		11/49 (22.4%)		8/61 (13.1%)
constipation	12/97 (12.4%)		2/90 (2.2%)		3/49 (6.1%)		9/61 (14.8%)
diarrhea	54/97 (55.7%)		14/90 (15.6%)		12/49 (24.5%)		31/61 (50.8%)
dry mouth	5/97 (5.2%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
mucositis (functional / symptomatic), oral cavity	12/97 (12.4%)		2/90 (2.2%)		1/49 (2%)		8/61 (13.1%)
mucositis (clinical exam), oral cavity	5/97 (5.2%)		1/90 (1.1%)		0/49 (0%)		4/61 (6.6%)
nausea	24/97 (24.7%)		26/90 (28.9%)		5/49 (10.2%)		14/61 (23%)
taste alteration	6/97 (6.2%)		6/90 (6.7%)		0/49 (0%)		0/61 (0%)
vomiting	18/97 (18.6%)		15/90 (16.7%)		5/49 (10.2%)		9/61 (14.8%)
General disorders
fever	10/97 (10.3%)		30/90 (33.3%)		2/49 (4.1%)		4/61 (6.6%)
insomnia	2/97 (2.1%)		8/90 (8.9%)		0/49 (0%)		0/61 (0%)
fatigue	48/97 (49.5%)		41/90 (45.6%)		16/49 (32.7%)		22/61 (36.1%)
weight loss	26/97 (26.8%)		24/90 (26.7%)		12/49 (24.5%)		10/61 (16.4%)
constitutional symptoms - other	7/97 (7.2%)		11/90 (12.2%)		3/49 (6.1%)		4/61 (6.6%)
rigors / chills	1/97 (1%)		10/90 (11.1%)		0/49 (0%)		0/61 (0%)
pain, back	12/97 (12.4%)		5/90 (5.6%)		2/49 (4.1%)		4/61 (6.6%)
pain, extremity - limb	7/97 (7.2%)		7/90 (7.8%)		1/49 (2%)		7/61 (11.5%)
pain, tumor pain	4/97 (4.1%)		5/90 (5.6%)		0/49 (0%)		0/61 (0%)
pain, abdomen NOS	14/97 (14.4%)		10/90 (11.1%)		3/49 (6.1%)		7/61 (11.5%)
pain, head / headache	5/97 (5.2%)		13/90 (14.4%)		0/49 (0%)		5/61 (8.2%)
pain, joint	4/97 (4.1%)		5/90 (5.6%)		3/49 (6.1%)		3/61 (4.9%)
pain, muscle	9/97 (9.3%)		6/90 (6.7%)		0/49 (0%)		4/61 (6.6%)
pain, bone	9/97 (9.3%)		8/90 (8.9%)		4/49 (8.2%)		1/61 (1.6%)
pain, other	18/97 (18.6%)		10/90 (11.1%)		5/49 (10.2%)		9/61 (14.8%)
pain, neuralgia / peripheral nerve	5/97 (5.2%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
pain, stomach	5/97 (5.2%)		4/90 (4.4%)		0/49 (0%)		0/61 (0%)
pain, chest / thorax NOS	0/97 (0%)		0/90 (0%)		1/49 (2%)		5/61 (8.2%)
flu-like syndrome	5/97 (5.2%)		20/90 (22.2%)		0/49 (0%)		0/61 (0%)
Immune system disorders
rhinitis	6/97 (6.2%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)
Infections and infestations
infection with normal ANC, urinary tract NOS	7/97 (7.2%)		2/90 (2.2%)		3/49 (6.1%)		0/61 (0%)
infection - other	12/97 (12.4%)		2/90 (2.2%)		5/49 (10.2%)		7/61 (11.5%)
infection with unknown ANC, urinary tract NOS	5/97 (5.2%)		2/90 (2.2%)		0/49 (0%)		0/61 (0%)
infection (documented clinically), urinary tract NOS	0/97 (0%)		0/90 (0%)		0/49 (0%)		4/61 (6.6%)
infection with normal ANC, upper airway NOS	0/97 (0%)		0/90 (0%)		3/49 (6.1%)		1/61 (1.6%)
Metabolism and nutrition disorders
ALT	5/97 (5.2%)		8/90 (8.9%)		0/49 (0%)		0/61 (0%)
AST	6/97 (6.2%)		9/90 (10%)		0/49 (0%)		0/61 (0%)
creatinine	3/97 (3.1%)		6/90 (6.7%)		3/49 (6.1%)		0/61 (0%)
hyperuricemia	8/97 (8.2%)		2/90 (2.2%)		5/49 (10.2%)		5/61 (8.2%)
lipase	16/97 (16.5%)		5/90 (5.6%)		1/49 (2%)		7/61 (11.5%)
amylase	0/97 (0%)		0/90 (0%)		3/49 (6.1%)		3/61 (4.9%)
hypercalcemia	0/97 (0%)		0/90 (0%)		0/49 (0%)		4/61 (6.6%)
hypoalbuminemia	0/97 (0%)		0/90 (0%)		4/49 (8.2%)		2/61 (3.3%)
hypokalemia	0/97 (0%)		0/90 (0%)		4/49 (8.2%)		4/61 (6.6%)
hyponatremia	0/97 (0%)		0/90 (0%)		3/49 (6.1%)		1/61 (1.6%)
metabolic / lab - other	0/97 (0%)		0/90 (0%)		3/49 (6.1%)		4/61 (6.6%)
Nervous system disorders
confusion	5/97 (5.2%)		4/90 (4.4%)		0/49 (0%)		0/61 (0%)
dizziness	5/97 (5.2%)		9/90 (10%)		0/49 (0%)		0/61 (0%)
mood alteration, depression	5/97 (5.2%)		15/90 (16.7%)		4/49 (8.2%)		3/61 (4.9%)
neuropathy: sensory	6/97 (6.2%)		1/90 (1.1%)		3/49 (6.1%)		4/61 (6.6%)
Renal and urinary disorders
renal - other	6/97 (6.2%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
Respiratory, thoracic and mediastinal disorders
cough	12/97 (12.4%)		15/90 (16.7%)		3/49 (6.1%)		6/61 (9.8%)
dyspnea (shortness of breath)	13/97 (13.4%)		10/90 (11.1%)		4/49 (8.2%)		4/61 (6.6%)
voice changes	8/97 (8.2%)		0/90 (0%)		0/49 (0%)		0/61 (0%)
Skin and subcutaneous tissue disorders
alopecia	40/97 (41.2%)		6/90 (6.7%)		2/49 (4.1%)		17/61 (27.9%)
dry skin	10/97 (10.3%)		9/90 (10%)		2/49 (4.1%)		6/61 (9.8%)
hand-foot skin reaction	57/97 (58.8%)		4/90 (4.4%)		8/49 (16.3%)		28/61 (45.9%)
dermatology - other	7/97 (7.2%)		2/90 (2.2%)		4/49 (8.2%)		5/61 (8.2%)
pruritus	14/97 (14.4%)		12/90 (13.3%)		1/49 (2%)		6/61 (9.8%)
rash / desquamation	40/97 (41.2%)		8/90 (8.9%)		4/49 (8.2%)		17/61 (27.9%)
Vascular disorders
hemorrhage pulmonary, nose	5/97 (5.2%)		1/90 (1.1%)		0/49 (0%)		0/61 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Publication will be discussed with the sponsor prior to release and written consent of the sponsor will be obtained. A draft manuscript of the publication or abstract must be sent to sponsor thirty days in advance of submission.

Results Point of Contact

Name/Title	Therapeutic Area Head
Organization	BAYER
Phone
Email	clinical-trials-contact@bayerhealthcare.com

Responsible Party:

Bayer

ClinicalTrials.gov Identifier:

NCT00117637

Other Study ID Numbers:

11848
2005-000544-86

First Posted:

Jul 8, 2005

Last Update Posted:

Oct 31, 2014

Last Verified:

Oct 1, 2014

BAY43-9006 (Sorafenib) Versus Interferon Alpha-2a in Patients With Unresectable and/or Metastatic Renal Cell Carcinoma

Study Details

Study Description

Brief Summary

The purpose of the study is to:

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

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Statistical Analysis 1

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Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

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