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A Phase III Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma (SHARP)

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ClinicalTrials.gov Identifier: NCT00105443
Recruitment Status : Completed
First Posted : March 15, 2005
Results First Posted : September 27, 2010
Last Update Posted : October 31, 2014
Sponsor:
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Carcinoma, Hepatocellular
Interventions Drug: Sorafenib (Nexavar, BAY43-9006)
Drug: Placebo
Enrollment 602
Recruitment Details Subjects with advanced hepatocellular carcinoma (HCC) were enrolled from Mar 10, 2005 to Apr 11, 2006 at 121 study centers in 21 countries around the Globe.
Pre-assignment Details After a 28 day screening period (902 subjects), 602 were randomized to Sorafenib (400 mg) twice daily (bid), or matching placebo. Majority of screen failures did not meet inclusion criteria. Efficacy population (intent-to-treat, ITT) was all randomized subjects (602), safety population was all subjects receiving at least 1 dose of study drug (599).
Arm/Group Title A1) Sorafenib (Nexavar, BAY43-9006) - no Open Label Phase A2) Sorafenib (Nexavar, BAY43-9006) - With Open Label Phase B1) Placebo - no Open Label Phase B2) Placebo First - Then Open Label Sorafenib Treatment Phase
Hide Arm/Group Description Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Note: Safety Data of participants in the arm presented here are reported in Reporting Groups (RG) RG1 and RG3 in the Safety section. Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study Note: Safety Data of participants in the arm presented here are reported in Reporting Groups (RG) RG1 and RG3 in the Safety section.

Sorafenib-matching placebo tablets were orally administered twice daily (bid).

Note: Safety Data of participants in the arm presented here are reported in Reporting Groups (RG) RG2 and RG4 in the Safety section.

Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.

Note: Safety Data of participants in the arm presented here are reported in Reporting Groups (RG) RG2, RG4, and RG5 in the Safety section.

Period Title: Double-Blind Treatment
Started 242 57 256 47
Received Treatment 240 [1] 57 [2] 255 [3] 47 [4]
Completed 228 [5] 57 [6] 245 [7] 47 [8]
Not Completed 14 0 11 0
Reason Not Completed
Adverse Event             1             0             0             0
Lost to Follow-up             0             0             1             0
Withdrawal by Subject             8             0             7             0
Physician Decision             1             0             2             0
Radiological and symptomatic progression             4             0             1             0
[1]
Subjects at Risk/Safety Population - partly in RG1 and RG3 (RG = Reporting Group for Safety Data)
[2]
Subjects at Risk/Safety Population - partly in RG1 and RG3
[3]
Subjects at Risk/Safety Population - partly in RG2 and RG4
[4]
Subjects at Risk/Safety Population - partly in RG2 and RG4 as well as RG5
[5]
228 participants directly switched to the Follow-up (FU) phase only
[6]
47 participants continued with Sorafenib Open Label (OL); 10 first to FU prior to also switch to OL
[7]
245 participants directly switched to the Follow-up (FU) phase
[8]
36 participants switched to Sorafenib Open Label (OL); 11 first to FU prior to also switch to OL
Period Title: Follow-up and/or Open Label Nexavar
Started 228 [1] 57 [2] 245 [3] 47 [4]
Follow-up Only (no Open Label Treatment) 228 [5] 0 245 [5] 0
Open Label Treatment Only (no Follow-up) 0 47 [6] 0 36 [6]
Follow-up First, Then Open Label 0 10 0 11
Completed 0 0 [7] 0 0 [8]
Not Completed 228 57 245 47
Reason Not Completed
Death             180             7             219             4
Lost to Follow-up             14             0             10             0
Withdrawal by Subject             24             3             13             4
Adverse Event             0             14             0             16
Physician Decision             1             0             1             0
Protocol Violation             0             2             0             0
Progression by clinical judgment             0             2             0             5
Progression, measurement proven             0             3             0             3
Disease progression, recurrence, relapse             6             0             1             0
Endpoint record not completed             2             2             1             2
Planned switch to OL; record incomplete             1             0             0             0
Non-compliant with study medication             0             0             0             1
Reached ECOG 4             0             1             0             1
Switch to commercial drug             0             23             0             11
[1]
At start of period, 228 participants directly switched to Follow-up (FU)
[2]
At start of period, 47 participants directly switched to Open Label (OL) Sorafenib treatment
[3]
At start of period, 245 participants directly switched to Follow-up (FU)
[4]
At start of period, 36 participants directly switched to Open Label (OL) Sorafenib treatment
[5]
In parallel to "Open Label treatment only" phase
[6]
In parallel to "Follow-up only" phase; participants received Sorafenib 400 mg bid
[7]
57 participants in total (47 + 10) received Open Label Sorafenib treatment (Subjects at Risk)
[8]
47 participants in total (36 + 11) received Open Label Sorafenib treatment (Subjects at Risk)
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo Total
Hide Arm/Group Description Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study. Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study. Total of all reporting groups
Overall Number of Baseline Participants 299 303 602
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 299 participants 303 participants 602 participants
64.9  (11.2) 66.3  (10.2) 65.6  (10.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 299 participants 303 participants 602 participants
Female
39
  13.0%
39
  12.9%
78
  13.0%
Male
260
  87.0%
264
  87.1%
524
  87.0%
Baseline Eastern Cooperative Oncology Group (ECOG)   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 299 participants 303 participants 602 participants
0 = fully active 161 164 325
1 = restricted in physical activity but ambulatory 114 117 231
2 = capable of selfcare 24 22 46
[1]
Measure Description: Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is a scale that measures how cancer affects a patient. The scale ranges from 0 (fully active) to 5 (dead). Subjects entering this study were to have an ECOG score of 0, 1 or 2.
Tumor burden   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 299 participants 303 participants 602 participants
Absent 90 91 181
Present 209 212 421
[1]
Measure Description: Tumor burden refers to the number of cancer cells, the size of a tumor, or the amount of cancer in the body and is also called the tumor load. Randomization was stratified by "tumor burden" assessment, ie, the presence of either macroscopic vascular invasion as determined by radiological assessment and/or extra-hepatic spread versus none.
1.Primary Outcome
Title Overall Survival (OS)
Hide Description Overall Survival was defined as the time from date of starting treatment 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 to death due to any cause until an average 7.2 months later up to the data cut-off date approximately 19 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
In this study the overall survival was measured for the ITT population from the date of randomization until the date of death due to any cause. For patients alive or lost to follow-up at the time of analysis, time to death was to be censored at their last date of follow-up, or at the data cut-off of 17 Oct 2006.
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: days
324
(286 to 405)
241
(206 to 276)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib (Nexavar, BAY43-9006), Placebo
Comments The 2 arms were compared using a 1-sided log-rank test with an overall alpha of 0.02 stratified by region, ECOG PS and “tumor burden”. In addition to the final analysis at the end of the study, 2 formal interim analyses of overall survival were planned. An alpha spending function was used to ensure that the false positive rate is less than or equal to 0.02 (1-sided). The study was stopped at the second interim analysis, the results of which are reported here.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00583
Comments According to the pre-specified O’Brien-Fleming alpha spending function, the alpha value for this second interim analysis was 0.0073 (corresponding to a nominal value of 0.0077 after taking into account the first interim analysis).
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.6931
Confidence Interval 95%
0.5549 to 0.8658
Estimation Comments This is the sorafenib to placebo hazard ratio.
2.Primary Outcome
Title Time to Symptomatic Progression (TTSP)
Hide Description TTSP was defined as the time from randomization to the first documented symptomatic progression.
Time Frame from randomization to the first documented symptomatic progression until an average 4.8 months later up to the data cut-off date approximately 19 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis was for the ITT population. For subjects who had not progressed symptomatically at the time of interim analysis, TTSP was censored at the date of their last Functional Assessment of Cancer Therapy (FACT) Hepatobiliary Symptom Index (FHSI-8) questionnaire assessment.
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: days
126
(105 to 126)
148
(129 to 192)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib (Nexavar, BAY43-9006), Placebo
Comments The 2 arms were compared using a 1-sided log-rank test with an overall alpha of 0.005 stratified by region, ECOG PS and “tumor burden”. This was a co-primary endpoint with overall survival. No alpha-spending adjustments were necessary as it was only to be analyzed at the end of study.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7676
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.0764
Confidence Interval 95%
0.8837 to 1.3110
Estimation Comments This is the sorafenib to placebo hazard ratio.
3.Secondary Outcome
Title Time to Progression (TTP)
Hide Description TTP was defined as the time from randomization to disease progression (radiological only). Subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation.
Time Frame from randomization to disease progression based on radiological assessment until an average 2.8 months later up to the data cut-off date approximately 19 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
The primary analysis of TTP for the ITT population was based on the independent radiological review for the interim analysis. The cut-off date chosen for the analysis of radiological progression events was 12 May 2006
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: days
168
(126 to 210)
86
(82 to 120)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib (Nexavar, BAY43-9006), Placebo
Comments In the analysis of TTP, based on independent radiological review performed to review data up to 12 May 2006, the 2 treatment groups were compared using a 1-sided log rank test with an alpha of 0.025, stratified by region, ECOG PS, and “tumor burden”.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.000007
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.5764
Confidence Interval 95%
0.4484 to 0.7410
Estimation Comments This is the sorafenib to placebo hazard ratio.
4.Secondary Outcome
Title Disease Control (DC)
Hide Description The DC is defined as the number of subjects with a best response rating of complete response (CR), partial response (PR), or stable disease (SD) that is maintained at least 28 days from the first manifestation of that rating. Definitions: CR = disappearance of all clinical and radiological tumor lesions; PR = at least 30% decrease in sum of the longest diameters of tumor lesions; SD = neither sufficient shrinkage to qualify for PR nor sufficient increase for progressive disease.
Time Frame time from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
In this study, the DC for the ITT population was determined by independent radiological review and also by investigator assessment (both by using response evaluation criteria in solid tumors [RECIST])
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Measure Type: Number
Unit of Measure: Participants
130 96
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sorafenib (Nexavar, BAY43-9006), Placebo
Comments Disease control rates were compared between treatment groups using the Cochran Mantel Haenszel (CMH) test with a 1-sided alpha of 0.025, adjusting for region, ECOG PS, and “tumor burden”.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001641
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -11.95
Confidence Interval 95%
-19.56 to -4.35
Estimation Comments Sorafenib minus placebo difference
5.Secondary Outcome
Title Patients Reported Outcome (PRO) by Use of the FACT-Hep Questionnaire
Hide Description PRO is a disease-specific measure, developed as symptom-focused approach in HCC and measured by the response rates for the PWB and FWB subscales of the 45-item Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. The FACT-Hep response rate was based on the number of subjects who achieved the 8-point minimally important difference (MID) for this subscale. FACT-Hep total score ranges from 0 to 180, where the highest score represents a maximum achievable quality of life (QoL) value.
Time Frame from randomization to end of treatment up to the data cutoff date approximately 19 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
In this study, the PRO was a tertiary efficacy variable assessed for the ITT population at Cycle 3 day 1 or, for those discontinuing prior to that visit, at end of study. It was summarized as number of patients with change from baseline <8 or ≥8 points for each treatment group up to the cutoff date of 17 Oct 2006
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 174 178
Measure Type: Number
Unit of Measure: Participants
Cycle 3 day 1 change <8 points 151 139
Cycle 3 day 1 change ≥8 points 23 39
6.Post-Hoc Outcome
Title Overall Survival
Hide Description Overall Survival was defined as the time from date of starting treatment 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 to death due to any cause until an average 8.5 months later up to the data cut-off date approximately 23 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
The OS data (ITT population) are descriptive only (no p-values) from the date of randomization to the date of death due to any cause. For patients alive at the time of analysis, time to death was censored at the date of last follow-up or at the data cutoff date of 09 Feb 2007 when subjects were given the option to crossover to sorafenib treatment
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: Days
327
(287 to 400)
243
(206 to 289)
7.Post-Hoc Outcome
Title Time to Symptomatic Progression (TTSP)
Hide Description TTSP was defined as the time from randomization to the first documented symptomatic progression
Time Frame from randomization to the first documented symptomatic progression until an average 5.7 months later up to the data cut-off date approximately 23 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
For subjects (in the ITT population) who had not progressed symptomatically at the time of interim analysis, TTSP was censored at the date of last FACT FHSI-8 questionnaire assessment (upon an interim review by the Data Monitoring Committee on 09 Feb 2007), when the study was considered positive for its primary endpoint, OS, and was stopped early.
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: Days
127
(106 to 152)
148
(132 to 195)
8.Post-Hoc Outcome
Title Time to Progression (TTP)
Hide Description TTP was defined as the time from randomization to disease progression (radiological only). Subjects without tumor progression at the time of analysis were censored at their last date of tumor evaluation.
Time Frame from randomization to disease progression based on radiological assessment until an average 2.8 months later up to the data cut-off date approximately 23 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
The independent radiological review as initially scheduled for the interim analysis did not continue after 12 May 2006. The primary analysis of TTP for the ITT population after 12 May 2006 up to the cutoff date of 09 Feb 2007 was based on the Investigator radiological assessments
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Median (95% Confidence Interval)
Unit of Measure: Days
168
(126 to 210)
86
(82 to 120)
9.Post-Hoc Outcome
Title Disease Control (DC)
Hide Description The DC is defined as the number of subjects with a best response rating of CR, PR, or SD that is maintained at least 28 days from the first manifestation of that rating.
Time Frame from randomization to end of treatment up to the data cutoff date approximately 23 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
The disease control rate for the ITT population was determined by independent radiological review and also by investigator assessment (both by using response evaluation criteria in solid tumors (RECIST) up to the cutoff date of 09 Feb 2007
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 299 303
Measure Type: Number
Unit of Measure: Participants
130 96
10.Post-Hoc Outcome
Title Patients Reported Outcome (PRO) by Use of the FACT-Hep Questionnaire
Hide Description PRO is a disease-specific measure, developed as symptom-focused approach in HCC and measured by the response rates for the PWB and FWB subscales of the 45-item Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaire. The FACT-Hep response rate was based on the number of subjects who achieved the 8-point minimally important difference (MID) for this subscale. FACT-Hep total score ranges from 0 to 180, where the highest score represents a maximum achievable quality of life (QoL) value. At the cut-off date for this analysis, one more patient data has been gained.
Time Frame from randomization to end of treatment up to the data cutoff date approximately 23 months after start of enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
In this study, the PRO was a tertiary efficacy variable assessed for the ITT population at Cycle 3 Day 1 or, for those discontinuing prior to that visit, at the end of study. It was summarized as number of patients with change from baseline <8 to ≥8 points for each treatment group up to the cutoff date of 09 Feb 2007.
Arm/Group Title Sorafenib (Nexavar, BAY43-9006) Placebo
Hide Arm/Group Description:
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Follow-up / Open Label phase: Subjects on sorafenib who continued the study, continued on the same dose of sorafenib as during the double-blind study.
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
Overall Number of Participants Analyzed 174 179
Measure Type: Number
Unit of Measure: Participants
Cycle 3 day 1 change <8 points 151 139
Cycle 3 day 1 change ≥8 points 23 40
Time Frame Reporting Group (RG) 1 + 2: Data for Interim Analysis, cut-off Oct 17, 2006; RG 3: Data during and after unblinding (until Nov 21, 2008); RG 4: Data prior to date of unblinding (Feb 9, 2007); RG 5: Data after unblinding (Open Label; until Nov 21, 2008)
Adverse Event Reporting Description RG 1 + 3 description: All subjects randomized to Sorafenib treatment; RG 2 + 4 description: All subjects randomized to Placebo before unblinding (when they were on Placebo, before they had the opportunity to switch to Sorafenib treatment); RG 5 description: All placebo subjects who switched to Sorafenib treatment after unblinding occurred.
 
Arm/Group Title Sorafenib (Nexavar) Arm Double-Blind Phase (Interim Data Only) Placebo Arm Double-Blind Phase (Interim Data Only) Sorafenib (Nexavar) Arm Complete (Incl. Open Label Phase) Placebo Arm, Complete Double-Blind Phase Subjects Switching From Placebo to Sorafenib (Open Label Only)
Hide Arm/Group Description Reporting Group 1 (RG 1): All participants in Double-Blind phase randomized to Sorafenib treatment (data before Oct 17, 2006); Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Note: Safety Data presented here include participants listed in Arms A1 and A2 of the Participant Flow section.

Reporting Group 2 (RG 2): All participants in Double-Blind phase randomized to Sorafenib-matching placebo (data before Oct 17, 2006); Sorafenib-matching placebo tablets were orally administered twice daily (bid).

Note: Safety Data presented here include participants listed in Arms B1 and B2 of the Participant Flow section.

Reporting Group 3 (RG 3): All participants that initially were randomized to Sorafenib treatment (data before unblinding (= Double-Blind phase) and after unblinding (= Open Label phase)), until Nov 21, 2008); Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid); 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment. Note: Safety Data presented here include participants listed in Arms A1 and A2 of the Participant Flow section.

Reporting Group 4 (RG 4): All participants that initially were randomized to Placebo (data from Placebo patients before unblinding at Feb 09, 2007); Sorafenib-matching placebo tablets were orally administered twice daily (bid).

Note: Safety Data presented here include participants listed in Arms B1 and B2 of the Participant Flow section.

Reporting Group 5 (RG 5): Participants initially randomized to Placebo who switched to Sorafenib in Open Label phase (data after unblinding only, from Feb 09, 2007 until Nov 21, 2008); Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily (bid). Note: Safety Data presented here include participants listed in Arm B2 of the Participant Flow section.
All-Cause Mortality
Sorafenib (Nexavar) Arm Double-Blind Phase (Interim Data Only) Placebo Arm Double-Blind Phase (Interim Data Only) Sorafenib (Nexavar) Arm Complete (Incl. Open Label Phase) Placebo Arm, Complete Double-Blind Phase Subjects Switching From Placebo to Sorafenib (Open Label Only)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Sorafenib (Nexavar) Arm Double-Blind Phase (Interim Data Only) Placebo Arm Double-Blind Phase (Interim Data Only) Sorafenib (Nexavar) Arm Complete (Incl. Open Label Phase) Placebo Arm, Complete Double-Blind Phase Subjects Switching From Placebo to Sorafenib (Open Label Only)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   153/297 (51.52%)   164/302 (54.30%)   191/297 (64.31%)   185/302 (61.26%)   26/47 (55.32%) 
Blood and lymphatic system disorders           
neutrophils * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
hemoglobin * 1  8/297 (2.69%)  6/302 (1.99%)  11/297 (3.70%)  7/302 (2.32%)  0/47 (0.00%) 
leukocytes * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
inr * 1  1/297 (0.34%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
edema: limb * 1  2/297 (0.67%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
lymphatics - other * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
lymphedema-related fibrosis * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
edema: head and neck * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Cardiac disorders           
supraventricular arrhythmia, atrial fibrillation * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  3/302 (0.99%)  0/47 (0.00%) 
conduction abnormality, av block - first degree * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
supraventricular arrhythmia, sinus tachycardia * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
ventricular arrhythmia, ventricular fibrillation * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
ventricular arrhythmia, ventricular tachycardia * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
left ventricular diastolic dysfunction * 1  2/297 (0.67%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
hypertension * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
cardiac ischemia/infarction * 1  8/297 (2.69%)  4/302 (1.32%)  9/297 (3.03%)  5/302 (1.66%)  1/47 (2.13%) 
hypotension * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
cardiac general - other * 1  0/297 (0.00%)  3/302 (0.99%)  0/297 (0.00%)  3/302 (0.99%)  0/47 (0.00%) 
right ventricular dysfunction * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
left ventricular systolic dysfunction * 1  1/297 (0.34%)  2/302 (0.66%)  2/297 (0.67%)  2/302 (0.66%)  0/47 (0.00%) 
conduction abnormality, asystole * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
conduction abnormality, av block-3rd degree (complete av block * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
cardiac arrhythmia - other * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
cardiopulmonary arrest * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Endocrine disorders           
hyperthyroidism * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
adrenal insufficiency * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
Eye disorders           
retinal detachment * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
Gastrointestinal disorders           
anorexia * 1  3/297 (1.01%)  1/302 (0.33%)  3/297 (1.01%)  1/302 (0.33%)  0/47 (0.00%) 
ascites * 1  14/297 (4.71%)  13/302 (4.30%)  16/297 (5.39%)  20/302 (6.62%)  4/47 (8.51%) 
colitis * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  0/302 (0.00%)  0/47 (0.00%) 
constipation * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
dehydration * 1  9/297 (3.03%)  1/302 (0.33%)  10/297 (3.37%)  1/302 (0.33%)  0/47 (0.00%) 
diarrhea * 1  14/297 (4.71%)  5/302 (1.66%)  16/297 (5.39%)  5/302 (1.66%)  1/47 (2.13%) 
dysphagia * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
enteritis * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
gastritis * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
nausea * 1  0/297 (0.00%)  4/302 (1.32%)  0/297 (0.00%)  3/302 (0.99%)  0/47 (0.00%) 
gi - other * 1  4/297 (1.35%)  0/302 (0.00%)  6/297 (2.02%)  0/302 (0.00%)  1/47 (2.13%) 
perforation, gi, colon * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
stricture, gi, biliary tree * 1  0/297 (0.00%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
ulcer, gi, duodenum * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  1/47 (2.13%) 
ulcer, gi, stomach * 1  1/297 (0.34%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
vomiting * 1  5/297 (1.68%)  4/302 (1.32%)  5/297 (1.68%)  4/302 (1.32%)  0/47 (0.00%) 
cholecystitis * 1  1/297 (0.34%)  0/302 (0.00%)  3/297 (1.01%)  0/302 (0.00%)  0/47 (0.00%) 
liver dysfunction * 1  21/297 (7.07%)  14/302 (4.64%)  21/297 (7.07%)  18/302 (5.96%)  1/47 (2.13%) 
hepatobiliary - other * 1  11/297 (3.70%)  16/302 (5.30%)  16/297 (5.39%)  22/302 (7.28%)  5/47 (10.64%) 
pancreatitis * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
distension * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
obstruction, gi, small bowel nos * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
perforation, gi, appendix * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
General disorders           
death not associated with ctcae term, death nos * 1  1/297 (0.34%)  4/302 (1.32%)  1/297 (0.34%)  5/302 (1.66%)  1/47 (2.13%) 
death not associated with ctcae term, disease progression nos * 1  56/297 (18.86%)  61/302 (20.20%)  68/297 (22.90%)  66/302 (21.85%)  10/47 (21.28%) 
death not associated with ctcae term, multi-organ failure * 1  1/297 (0.34%)  0/302 (0.00%)  4/297 (1.35%)  0/302 (0.00%)  0/47 (0.00%) 
death not associated with ctcae term, sudden death * 1  0/297 (0.00%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  1/47 (2.13%) 
fever * 1  3/297 (1.01%)  4/302 (1.32%)  4/297 (1.35%)  4/302 (1.32%)  1/47 (2.13%) 
insomnia * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  0/302 (0.00%)  0/47 (0.00%) 
fatigue * 1  5/297 (1.68%)  9/302 (2.98%)  7/297 (2.36%)  6/302 (1.99%)  1/47 (2.13%) 
weight loss * 1  0/297 (0.00%)  3/302 (0.99%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
constitutional symptoms - other * 1  3/297 (1.01%)  6/302 (1.99%)  6/297 (2.02%)  8/302 (2.65%)  2/47 (4.26%) 
pain, back * 1  3/297 (1.01%)  3/302 (0.99%)  3/297 (1.01%)  4/302 (1.32%)  0/47 (0.00%) 
pain, extremity-limb * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
pain, tumor pain * 1  1/297 (0.34%)  1/302 (0.33%)  2/297 (0.67%)  1/302 (0.33%)  0/47 (0.00%) 
pain, abdomen nos * 1  7/297 (2.36%)  8/302 (2.65%)  10/297 (3.37%)  9/302 (2.98%)  0/47 (0.00%) 
pain, joint * 1  3/297 (1.01%)  0/302 (0.00%)  3/297 (1.01%)  1/302 (0.33%)  0/47 (0.00%) 
pain, bone * 1  3/297 (1.01%)  1/302 (0.33%)  3/297 (1.01%)  1/302 (0.33%)  0/47 (0.00%) 
pain, other * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
pain, liver * 1  0/297 (0.00%)  2/302 (0.66%)  0/297 (0.00%)  3/302 (0.99%)  0/47 (0.00%) 
pain, neuralgia/peripheral nerve * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
pain, stomach * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  0/302 (0.00%)  0/47 (0.00%) 
syndromes - other * 1  2/297 (0.67%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
not coded yet * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  0/302 (0.00%)  0/47 (0.00%) 
pain, chest/thorax nos * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
tumor flare * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Infections and infestations           
infection (documented clinically), abdomen nos * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection (documented clinically), anal/perianal * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection (documented clinically), biliary tree * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection (documented clinically), lung (pneumonia) * 1  3/297 (1.01%)  3/302 (0.99%)  6/297 (2.02%)  4/302 (1.32%)  2/47 (4.26%) 
infection (documented clinically), skin (cellulitis) * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
infection (documented clinically), soft tissue nos * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection (documented clinically), upper airway nos * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection (documented clinically), urinary tract nos * 1  3/297 (1.01%)  0/302 (0.00%)  3/297 (1.01%)  0/302 (0.00%)  0/47 (0.00%) 
infection with normal anc, bronchus * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection with normal anc, gallbladder (cholecystitis) * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with normal anc, oral cavity-gums (gingivitis) * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection with normal anc, peritoneal cavity * 1  0/297 (0.00%)  2/302 (0.66%)  0/297 (0.00%)  2/302 (0.66%)  0/47 (0.00%) 
infection with normal anc, skin (cellulitis) * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection with normal anc, urinary tract nos * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection - other * 1  0/297 (0.00%)  3/302 (0.99%)  2/297 (0.67%)  4/302 (1.32%)  0/47 (0.00%) 
infection with unknown anc, biliary tree * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with unknown anc, lung (pneumonia) * 1  0/297 (0.00%)  3/302 (0.99%)  0/297 (0.00%)  4/302 (1.32%)  0/47 (0.00%) 
infection with unknown anc, peritoneal cavity * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  2/302 (0.66%)  0/47 (0.00%) 
infection with unknown anc, urinary tract nos * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
infection with unknown anc, wound * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection (documented clinically), blood * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with normal anc, anal/perianal * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with normal anc, appendix * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with normal anc, pancreas * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with unknown anc, appendix * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
infection with unknown anc, blood * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
infection with unknown anc, bronchus * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Injury, poisoning and procedural complications           
intraop injury, biliary tree - common bile duct * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Metabolism and nutrition disorders           
ALT * 1  0/297 (0.00%)  2/302 (0.66%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
AST * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
cpk * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
creatinine * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  2/302 (0.66%)  1/47 (2.13%) 
ggt * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
bilirubin (hyperbilirubinemia) * 1  6/297 (2.02%)  4/302 (1.32%)  6/297 (2.02%)  5/302 (1.66%)  1/47 (2.13%) 
hypercalcemia * 1  2/297 (0.67%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
hyperglycemia * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  2/302 (0.66%)  0/47 (0.00%) 
hyperkalemia * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
hypoalbuminemia * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
hypoglycemia * 1  5/297 (1.68%)  3/302 (0.99%)  5/297 (1.68%)  3/302 (0.99%)  1/47 (2.13%) 
hypomagnesemia * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  1/47 (2.13%) 
hyponatremia * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hypocalcemia * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
hypokalemia * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
Musculoskeletal and connective tissue disorders           
fracture * 1  4/297 (1.35%)  3/302 (0.99%)  5/297 (1.68%)  4/302 (1.32%)  1/47 (2.13%) 
musculoskeletal - other * 1  2/297 (0.67%)  3/302 (0.99%)  3/297 (1.01%)  3/302 (0.99%)  0/47 (0.00%) 
device/prosthesis * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
muscle weakness, whole body/generalized * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
Nervous system disorders           
cns ischemia * 1  0/297 (0.00%)  4/302 (1.32%)  1/297 (0.34%)  4/302 (1.32%)  2/47 (4.26%) 
confusion * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
dizziness * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
encephalopathy * 1  2/297 (0.67%)  2/302 (0.66%)  4/297 (1.35%)  3/302 (0.99%)  1/47 (2.13%) 
mood alteration, depression * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
neuropathy: motor * 1  1/297 (0.34%)  3/302 (0.99%)  1/297 (0.34%)  3/302 (0.99%)  0/47 (0.00%) 
neurology - other * 1  0/297 (0.00%)  3/302 (0.99%)  0/297 (0.00%)  3/302 (0.99%)  0/47 (0.00%) 
neuropathy: sensory * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
seizure * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  2/302 (0.66%)  0/47 (0.00%) 
somnolence * 1  2/297 (0.67%)  2/302 (0.66%)  2/297 (0.67%)  2/302 (0.66%)  0/47 (0.00%) 
syncope (fainting) * 1  2/297 (0.67%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
cognitive disturbance * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
Renal and urinary disorders           
renal failure * 1  1/297 (0.34%)  8/302 (2.65%)  2/297 (0.67%)  8/302 (2.65%)  1/47 (2.13%) 
obstruction, gu, ureter * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
urinary retention * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
pleural effusion * 1  1/297 (0.34%)  1/302 (0.33%)  2/297 (0.67%)  1/302 (0.33%)  1/47 (2.13%) 
hiccoughs * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hypoxia * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
pulmonary - other * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
pneumothorax * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
dyspnea (shortness of breath) * 1  3/297 (1.01%)  2/302 (0.66%)  3/297 (1.01%)  2/302 (0.66%)  0/47 (0.00%) 
Skin and subcutaneous tissue disorders           
hand-foot skin reaction * 1  2/297 (0.67%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
dermatology - other * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  1/47 (2.13%) 
pruritus * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
decubitus * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
wound complication, non-infectious * 1  0/297 (0.00%)  0/302 (0.00%)  2/297 (0.67%)  0/302 (0.00%)  0/47 (0.00%) 
rash/desquamation * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
ulceration * 1  0/297 (0.00%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  1/47 (2.13%) 
Vascular disorders           
cns hemorrhage * 1  2/297 (0.67%)  1/302 (0.33%)  2/297 (0.67%)  1/302 (0.33%)  0/47 (0.00%) 
hematoma * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage, gi, abdomen nos * 1  2/297 (0.67%)  3/302 (0.99%)  2/297 (0.67%)  3/302 (0.99%)  0/47 (0.00%) 
hemorrhage, gi, colon * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
hemorrhage, gi, duodenum * 1  1/297 (0.34%)  2/302 (0.66%)  1/297 (0.34%)  3/302 (0.99%)  0/47 (0.00%) 
hemorrhage, gi, esophagus * 1  2/297 (0.67%)  3/302 (0.99%)  4/297 (1.35%)  4/302 (1.32%)  1/47 (2.13%) 
hemorrhage, gi, varices (esophageal) * 1  7/297 (2.36%)  11/302 (3.64%)  8/297 (2.69%)  13/302 (4.30%)  1/47 (2.13%) 
hemorrhage, gi, stomach * 1  4/297 (1.35%)  2/302 (0.66%)  5/297 (1.68%)  2/302 (0.66%)  0/47 (0.00%) 
hemorrhage, gi, liver * 1  4/297 (1.35%)  1/302 (0.33%)  6/297 (2.02%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage, gi, lower gi nos * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage, gi, oral cavity * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage, gi, peritoneal cavity * 1  0/297 (0.00%)  6/302 (1.99%)  2/297 (0.67%)  8/302 (2.65%)  0/47 (0.00%) 
hemorrhage, gi, varices (rectal) * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
hemorrhage, gi, upper gi nos * 1  3/297 (1.01%)  6/302 (1.99%)  5/297 (1.68%)  6/302 (1.99%)  0/47 (0.00%) 
hemorrhage with surgery * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage - other * 1  1/297 (0.34%)  1/302 (0.33%)  2/297 (0.67%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage pulmonary, lung * 1  1/297 (0.34%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  0/47 (0.00%) 
hemorrhage pulmonary, pleura * 1  0/297 (0.00%)  1/302 (0.33%)  0/297 (0.00%)  1/302 (0.33%)  0/47 (0.00%) 
peripheral arterial ischemia * 1  1/297 (0.34%)  0/302 (0.00%)  0/297 (0.00%)  0/302 (0.00%)  0/47 (0.00%) 
thrombosis/thrombus/embolism * 1  3/297 (1.01%)  3/302 (0.99%)  7/297 (2.36%)  5/302 (1.66%)  1/47 (2.13%) 
visceral arterial ischemia * 1  1/297 (0.34%)  1/302 (0.33%)  1/297 (0.34%)  1/302 (0.33%)  0/47 (0.00%) 
hemorrhage, gi, rectum * 1  0/297 (0.00%)  0/302 (0.00%)  1/297 (0.34%)  0/302 (0.00%)  1/47 (2.13%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI-CTCAE v. 3.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sorafenib (Nexavar) Arm Double-Blind Phase (Interim Data Only) Placebo Arm Double-Blind Phase (Interim Data Only) Sorafenib (Nexavar) Arm Complete (Incl. Open Label Phase) Placebo Arm, Complete Double-Blind Phase Subjects Switching From Placebo to Sorafenib (Open Label Only)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   275/297 (92.59%)   259/302 (85.76%)   281/297 (94.61%)   271/302 (89.74%)   43/47 (91.49%) 
Blood and lymphatic system disorders           
hemoglobin * 1  25/297 (8.42%)  22/302 (7.28%)  36/297 (12.12%)  25/302 (8.28%)  5/47 (10.64%) 
edema: limb * 1  45/297 (15.15%)  53/302 (17.55%)  59/297 (19.87%)  57/302 (18.87%)  9/47 (19.15%) 
platelets * 1  9/297 (3.03%)  7/302 (2.32%)  15/297 (5.05%)  8/302 (2.65%)  0/47 (0.00%) 
Cardiac disorders           
hypertension * 1  27/297 (9.09%)  12/302 (3.97%)  32/297 (10.77%)  13/302 (4.30%)  6/47 (12.77%) 
Gastrointestinal disorders           
anorexia * 1  83/297 (27.95%)  52/302 (17.22%)  89/297 (29.97%)  56/302 (18.54%)  8/47 (17.02%) 
ascites * 1  61/297 (20.54%)  67/302 (22.19%)  80/297 (26.94%)  67/302 (22.19%)  9/47 (19.15%) 
constipation * 1  41/297 (13.80%)  31/302 (10.26%)  44/297 (14.81%)  32/302 (10.60%)  3/47 (6.38%) 
diarrhea * 1  158/297 (53.20%)  74/302 (24.50%)  166/297 (55.89%)  82/302 (27.15%)  22/47 (46.81%) 
heartburn * 1  15/297 (5.05%)  10/302 (3.31%)  16/297 (5.39%)  10/302 (3.31%)  1/47 (2.13%) 
mucositis (functional/symptomatic), oral cavity * 1  15/297 (5.05%)  6/302 (1.99%)  16/297 (5.39%)  8/302 (2.65%)  0/47 (0.00%) 
mucositis (clinical exam), oral cavity * 1  16/297 (5.39%)  10/302 (3.31%)  19/297 (6.40%)  10/302 (3.31%)  1/47 (2.13%) 
nausea * 1  71/297 (23.91%)  58/302 (19.21%)  73/297 (24.58%)  63/302 (20.86%)  8/47 (17.02%) 
gi - other * 1  16/297 (5.39%)  10/302 (3.31%)  22/297 (7.41%)  13/302 (4.30%)  3/47 (6.38%) 
vomiting * 1  41/297 (13.80%)  30/302 (9.93%)  48/297 (16.16%)  34/302 (11.26%)  4/47 (8.51%) 
liver dysfunction * 1  18/297 (6.06%)  9/302 (2.98%)  21/297 (7.07%)  10/302 (3.31%)  1/47 (2.13%) 
dry mouth * 1  12/297 (4.04%)  9/302 (2.98%)  14/297 (4.71%)  9/302 (2.98%)  3/47 (6.38%) 
hemorrhoids * 1  7/297 (2.36%)  2/302 (0.66%)  8/297 (2.69%)  3/302 (0.99%)  3/47 (6.38%) 
hepatobiliary - other * 1  12/297 (4.04%)  14/302 (4.64%)  17/297 (5.72%)  17/302 (5.63%)  2/47 (4.26%) 
General disorders           
fever * 1  29/297 (9.76%)  28/302 (9.27%)  35/297 (11.78%)  30/302 (9.93%)  2/47 (4.26%) 
insomnia * 1  21/297 (7.07%)  22/302 (7.28%)  26/297 (8.75%)  23/302 (7.62%)  5/47 (10.64%) 
fatigue * 1  133/297 (44.78%)  132/302 (43.71%)  145/297 (48.82%)  144/302 (47.68%)  23/47 (48.94%) 
weight loss * 1  89/297 (29.97%)  28/302 (9.27%)  93/297 (31.31%)  31/302 (10.26%)  10/47 (21.28%) 
pain, back * 1  36/297 (12.12%)  38/302 (12.58%)  47/297 (15.82%)  42/302 (13.91%)  4/47 (8.51%) 
pain, abdomen nos * 1  91/297 (30.64%)  74/302 (24.50%)  99/297 (33.33%)  80/302 (26.49%)  11/47 (23.40%) 
pain, head/headache * 1  26/297 (8.75%)  25/302 (8.28%)  29/297 (9.76%)  25/302 (8.28%)  1/47 (2.13%) 
pain, joint * 1  20/297 (6.73%)  26/302 (8.61%)  20/297 (6.73%)  27/302 (8.94%)  1/47 (2.13%) 
pain, stomach * 1  21/297 (7.07%)  20/302 (6.62%)  23/297 (7.74%)  21/302 (6.95%)  2/47 (4.26%) 
constitutional symptoms - other * 1  7/297 (2.36%)  10/302 (3.31%)  12/297 (4.04%)  12/302 (3.97%)  4/47 (8.51%) 
pain, bone * 1  12/297 (4.04%)  13/302 (4.30%)  16/297 (5.39%)  15/302 (4.97%)  0/47 (0.00%) 
pain, liver * 1  12/297 (4.04%)  13/302 (4.30%)  13/297 (4.38%)  16/302 (5.30%)  1/47 (2.13%) 
flu-like syndrome * 1  8/297 (2.69%)  7/302 (2.32%)  9/297 (3.03%)  8/302 (2.65%)  3/47 (6.38%) 
Infections and infestations           
infection - other * 1  6/297 (2.02%)  3/302 (0.99%)  16/297 (5.39%)  6/302 (1.99%)  8/47 (17.02%) 
Metabolism and nutrition disorders           
AST * 1  8/297 (2.69%)  18/302 (5.96%)  9/297 (3.03%)  20/302 (6.62%)  1/47 (2.13%) 
bilirubin (hyperbilirubinemia) * 1  24/297 (8.08%)  23/302 (7.62%)  28/297 (9.43%)  26/302 (8.61%)  1/47 (2.13%) 
Musculoskeletal and connective tissue disorders           
musculoskeletal - other * 1  24/297 (8.08%)  15/302 (4.97%)  31/297 (10.44%)  18/302 (5.96%)  1/47 (2.13%) 
Nervous system disorders           
mood alteration, depression * 1  10/297 (3.37%)  7/302 (2.32%)  14/297 (4.71%)  9/302 (2.98%)  7/47 (14.89%) 
Respiratory, thoracic and mediastinal disorders           
cough * 1  24/297 (8.08%)  16/302 (5.30%)  26/297 (8.75%)  18/302 (5.96%)  3/47 (6.38%) 
dyspnea (shortness of breath) * 1  26/297 (8.75%)  22/302 (7.28%)  33/297 (11.11%)  24/302 (7.95%)  3/47 (6.38%) 
voice changes * 1  27/297 (9.09%)  4/302 (1.32%)  27/297 (9.09%)  5/302 (1.66%)  1/47 (2.13%) 
Skin and subcutaneous tissue disorders           
alopecia * 1  42/297 (14.14%)  5/302 (1.66%)  46/297 (15.49%)  6/302 (1.99%)  6/47 (12.77%) 
dry skin * 1  31/297 (10.44%)  18/302 (5.96%)  31/297 (10.44%)  18/302 (5.96%)  3/47 (6.38%) 
hand-foot skin reaction * 1  63/297 (21.21%)  9/302 (2.98%)  67/297 (22.56%)  9/302 (2.98%)  6/47 (12.77%) 
dermatology - other * 1  26/297 (8.75%)  12/302 (3.97%)  30/297 (10.10%)  15/302 (4.97%)  5/47 (10.64%) 
pruritus * 1  40/297 (13.47%)  33/302 (10.93%)  44/297 (14.81%)  35/302 (11.59%)  5/47 (10.64%) 
rash/desquamation * 1  55/297 (18.52%)  42/302 (13.91%)  59/297 (19.87%)  46/302 (15.23%)  6/47 (12.77%) 
erythema multiforme * 1  1/297 (0.34%)  3/302 (0.99%)  1/297 (0.34%)  4/302 (1.32%)  3/47 (6.38%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, NCI-CTCAE v. 3.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Therapeutic Area Head
Organization: BAYER
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00105443     History of Changes
Other Study ID Numbers: 100554
2004-001773-26 ( EudraCT Number )
First Submitted: March 14, 2005
First Posted: March 15, 2005
Results First Submitted: December 11, 2009
Results First Posted: September 27, 2010
Last Update Posted: October 31, 2014