BAY43-9006/12414

Bayer AG

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

No

No

No

Final

27 Feb 2014

Yes

29 Nov 2013

Yes

28 Nov 2014

No

To evaluate the efficacy and safety of sorafenib versus placebo in the adjuvant treatment of hepatocellular carcinoma (HCC) after potentially curative treatment with surgical resection or local ablation.

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. A core information and informed consent form was provided. Prior to the beginning of the study, the investigator was required to have the Ethics committee's written approval / favorable opinion of the written informed consent form and any other written information to be provided to subjects. Before entering the study, the informed consent form was read by and explained to all subjects or their legally authorized representative. Each subject had ample opportunity to ask questions and was assured of the right to withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. For the collection of images in post-study follow up, the investigator was required to obtain written informed consent from the subject prior to performing any computed tomography / magnetic resonance imaging scan or chest X-ray imaging procedures according to the protocol image acquisition guidelines.

15 Aug 2008

Yes

Yes

Portugal: 1

Romania: 14

Spain: 25

Sweden: 7

United Kingdom: 9

Austria: 17

Belgium: 13

Bulgaria: 1

France: 59

Germany: 25

Greece: 1

Italy: 146

Argentina: 3

Brazil: 7

Canada: 13

Chile: 1

Mexico: 5

United States: 91

Australia: 8

China: 256

Hong Kong: 31

Japan: 149

Korea, Democratic People's Republic of: 126

New Zealand: 9

Singapore: 13

Taiwan: 68

Switzerland: 5

Russian Federation: 11

1114

318

0

0

0

0

0

0

744

369

1

Overall Study (overall period)

Randomised - controlled

Yes

Sorafenib

BAY43-9006

Nexavar

Tablet

Oral use

Subjects received an oral dose of sorafenib 400 mg tablets (each containing 200 mg) twice daily, on a continuous basis until a criterion for withdrawal was reached. Doses could be interrupted or reduced due to clinically significant toxicities that were considered related to protocol therapy.

Placebo

Tablet

Oral use

Subjects received an oral dose of placebo matching to sorafenib 400 mg tablets (each containing 200 mg) twice daily, on a continuous basis until a criterion for withdrawal was reached. Doses could be interrupted or reduced due to clinically significant toxicities that were considered related to protocol therapy.

Sorafenib (Nexavar, BAY43-9006)

Placebo

Sorafenib (Nexavar, BAY43-9006)

Placebo

Disease recurrence of HCC (intra or extra hepatic) was defined as the appearance of a new intrahepatic lesions fulfilling the American Association for the Study of Liver Diseases (AASLD) criteria of diagnosis of HCC or a new extra-hepatic lesions according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.0. In addition to investigator assessment, all images were reviewed by an independent panel of radiologists. The calculation of the RFS was based on the independent evaluation of the scans. RFS was defined as the time from randomization to the first documented disease recurrence by independent radiological assessment or death due to any cause whichever occurred first. For subjects who had not recurred or died at the time of analysis, RFS was censored at their last date of evaluable scan before drop-out for any other reason than recurrence or death.

Primary

From randomization up to 4 years or until disease recurrence whichever came first

Placebo v Sorafenib (Nexavar, BAY43-9006)

1114

Pre-specified

0.94

2-sided

TTR was defined as the time from randomization to the first documented disease recurrence by independent radiological assessment. For subjects who had not recurred at the time of analysis, TTR was censored at their last date of evaluable scan before withdrawal for any other reason than recurrence. '99999' in the reported data indicates value could not be estimated due to censored data.

Secondary

From randomization up to 4 years or until disease recurrence whichever came first

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

0.891

2-sided

OS was defined as the time from randomization to date of death due to any cause. OS for subjects alive at the time of analysis was censored at their last date of contact. '99999' in the reported data indicates value could not be estimated due to censored data.

Secondary

From randomization of the first subject until 4 years later.

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

0.995

2-sided

The EQ-5D is a generic quality of life preference based on a validated instrument used in cancer and in general population, with 2 parts: Index and Visual Analogue Scale. The EQ-5D Index is a descriptive system of the following health dimensions: mobility, selfcare, usual activities, pain/discomfort, and anxiety/depression. Subjects were asked to choose any one of the 3 response levels for each dimension: no problems, some problems, and severe problems. The 5 health dimensions were summarized into a single score, the EQ-5D Index score which ranged from -0.59 to 1 with higher scores representing better health states (0=death, 1= perfect health, and -0.59=a health state worse than death). A change of at least 0.10 to 0.12 points was considered a minimally important difference using Eastern Cooperative Oncology Group Performance Status as the anchor. The results on the Analysis of covariance of time-adjusted Area under curve for the EQ-5D index score were reported.

Other pre-specified

Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)

An analysis of covariance (ANCOVA) model was used to estimate the mean difference in the time-adjusted Area Under Curve (AUC) between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the EQ-5D index score. Statistical tests were performed with a 2 sided type I error of 5%.

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

0.039

2-sided

The EQ-5D is a generic quality of life preference based on a validated instrument used in cancer and in general population, with 2 parts: Index and Visual Analogue Scale. The EQ-5D VAS is a measure that represents health status as a single value. It is a 20-centimetre vertical graduated visual analogue scale with scores that ranged from 0 (worst imaginable health state) to 100 (best imaginable health state). The respondent rated his/her current health state by drawing a line from the box marked ‘your own health state today’ to the appropriate point on the EQ-5D VAS. A 3-digit number (including leading zeros) was read off the scale from the point where the respondent’s line crossed the scale, which was the EQ-5D VAS score. A change of at least 7 points on the VAS was considered as minimally important. The results on the ANCOVA analysis of time-adjusted AUC for the EQ-5D VAS score were reported.

Other pre-specified

Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)

An analysis of covariance (ANCOVA) model was used to estimate the mean difference in the time-adjusted Area Under Curve (AUC) between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the EQ-5D VAS score. Statistical tests were performed with a 2 sided type I error of 5%.

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

2.978

2-sided

The FACT-HEP is a 45 item, self-administered, multi-dimensional, psychometrically sound questionnaire used extensively in oncology clinical trials. FACT-HEP consisted of five subscales: Physical Well-Being (PWB), Social Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being (FWB), and Hepatobiliary Cancer Subscale (HCS). The PWB, FWB, SWB and EWB were summed to form the FACT-General (FACT-G) total score. The FACT-G and HCS scores were summed to form the FACT-HEP total score. FACT-HEP scores ranged from 0 to 180 and the higher scores represented a better quality of life. Subjects responded to each item on a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). The minimally important difference (MID) for the FACT-Hep total score was in the range of 8 to 9. The results on the ANCOVA analysis of time-adjusted AUC for the FACT-HEP score were reported.

Other pre-specified

Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)

An ANCOVA model was used to estimate the mean difference in the time-adjusted AUC between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the FACT-HEP score. Statistical tests were performed with a 2 sided type I error of 5%.

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

5.1

2-sided

The PWB, FWB, SWB and EWB were summed to form the FACT-G total score. Subjects responded to each item on a 5-point Likert-type scale ranging from 0 (not at all) to 4 (very much). FACT-G scores ranged from 0 to 108 and the higher scores represented a better quality of life. The MID for the FACT-G total score was in the range of 6 to 7. The results on the ANCOVA analysis of time-adjusted AUC for the FACT-G score were reported.

Other pre-specified

Cycle (C) Day (D)1, C2D1, C3D1 and subsequent cycles up to C18, end of intervention visit (1 to 2 weeks after last dose)

An ANCOVA model was used to estimate the mean difference in the time-adjusted AUC between the two treatment groups, with covariates for baseline scores and stratification factors. To test the treatment effect, a mixed linear model (random coefficient model) was used for the FACT-G score. Statistical tests were performed with a 2 sided type I error of 5%.

Sorafenib (Nexavar, BAY43-9006) v Placebo

1114

Pre-specified

2.5

2-sided

After the subject has signed the informed consent, up to 30 days post treatment discontinuation

17.1

Placebo

Sorafenib (Nexavar, BAY43-9006)