Trial Outcomes & Findings for A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma (NCT NCT01107418)

NCT ID: NCT01107418

Last Updated: 2015-08-26

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

52 participants

Primary outcome timeframe

Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Results posted on

2015-08-26

Participant Flow

Participant milestones

Participant milestones
Measure	Vemurafenib - All Cohorts Participants received vemurafenib (RO5185426) film-coated tablets, orally, twice daily at doses of 240, 480, 720, or 960 milligrams (mg) on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Overall Study STARTED	52
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	52

Reasons for withdrawal

Reasons for withdrawal
Measure	Vemurafenib - All Cohorts Participants received vemurafenib (RO5185426) film-coated tablets, orally, twice daily at doses of 240, 480, 720, or 960 milligrams (mg) on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Overall Study Disease Progression	45
Overall Study Adverse Event	3
Overall Study Withdrawal by Subject	1
Overall Study Study Closing	1
Overall Study Started Other Therapy	1
Overall Study Entered Extension Study	1

Baseline Characteristics

A Pharmacokinetic/Pharmacodynamic Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 - Vemurafenib 240 mg n=12 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Total n=52 Participants Total of all reporting groups
Age, Continuous	52.0 years STANDARD_DEVIATION 15.06 • n=5 Participants	46.3 years STANDARD_DEVIATION 10.58 • n=7 Participants	54.3 years STANDARD_DEVIATION 10.70 • n=5 Participants	50.5 years STANDARD_DEVIATION 11.91 • n=4 Participants	50.8 years STANDARD_DEVIATION 12.14 • n=21 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	8 Participants n=4 Participants	26 Participants n=21 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants	8 Participants n=4 Participants	26 Participants n=21 Participants

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Population: Pharmacokinetic (PK) population included all participants who provided essential PK data up to and including the pre-dose PK sample taken on Cycle 1, Day 22, without major protocol violation.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=12 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 1	8.3 microgramshour/milliliter (mcgh/mL) Standard Deviation 6.13	13.8 microgramshour/milliliter (mcgh/mL) Standard Deviation 7.72	21.9 microgramshour/milliliter (mcgh/mL) Standard Deviation 12.97	27.0 microgramshour/milliliter (mcgh/mL) Standard Deviation 18.87

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 1

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=11 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 1	40.9 mcg*h/mL Standard Deviation 23.43	62.4 mcg*h/mL Standard Deviation 35.71	111.6 mcg*h/mL Standard Deviation 34.22	130.6 mcg*h/mL Standard Deviation 71.78

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Population: PK population.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=12 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 1	1.9 micrograms/milliliter (mcg/mL) Standard Deviation 1.66	2.6 micrograms/milliliter (mcg/mL) Standard Deviation 1.56	4.4 micrograms/milliliter (mcg/mL) Standard Deviation 1.98	4.8 micrograms/milliliter (mcg/mL) Standard Deviation 3.34

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1

Population: PK population.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=12 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 1	4.0 hours Interval 1.92 to 8.0	4.0 hours Interval 1.95 to 5.0	5.0 hours Interval 2.0 to 8.08	5.0 hours Interval 2.0 to 8.0

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=11 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 9	102.1 mcg*h/mL Standard Deviation 41.37	180.0 mcg*h/mL Standard Deviation 84.23	301.2 mcg*h/mL Standard Deviation 108.67	329.0 mcg*h/mL Standard Deviation 108.85

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=11 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 9	15.4 mcg/mL Standard Deviation 5.84	28.9 mcg/mL Standard Deviation 16.95	45.9 mcg/mL Standard Deviation 14.44	53.2 mcg/mL Standard Deviation 19.08

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 9

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=11 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=12 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 9	2.0 hours Interval 0.0 to 8.0	2.0 hours Interval 0.0 to 5.08	0.0 hours Interval 0.0 to 8.0	1.8 hours Interval 0.0 to 8.0

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 8 Hours (AUC[0-8h]) of Vemurafenib on Day 15	117.8 mcg*h/mL Standard Deviation 50.52	233.8 mcg*h/mL Standard Deviation 106.93	343.3 mcg*h/mL Standard Deviation 151.23	392.2 mcg*h/mL Standard Deviation 126.37

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=10 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24h]) of Vemurafenib on Day 15	317.7 mcg*h/mL Standard Deviation 133.34	598.8 mcg*h/mL Standard Deviation 297.44	1003.7 mcg*h/mL Standard Deviation 441.36	1126.0 mcg*h/mL Standard Deviation 423.01

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=8 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Area Under the Plasma Concentration-Time Curve From Time Zero to 168 Hours (AUC[0-168h]) of Vemurafenib on Day 15	920.3 mcg*h/mL Standard Deviation 538.35	2243.5 mcg*h/mL Standard Deviation 1336.15	3127.1 mcg*h/mL Standard Deviation 1789.97	3530.3 mcg*h/mL Standard Deviation 1811.43

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15	17.2 mcg/mL Standard Deviation 7.43	35.4 mcg/mL Standard Deviation 17.44	52.7 mcg/mL Standard Deviation 22.40	61.4 mcg/mL Standard Deviation 22.76

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Time to Reach Maximum Plasma Concentration (Tmax) of Vemurafenib on Day 15	4.0 hours Interval 0.0 to 8.0	2.3 hours Interval 0.0 to 5.0	2.0 hours Interval 0.0 to 24.17	2.0 hours Interval 0.0 to 24.0

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=8 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Apparent Clearance (CL/F) of Vemurafenib on Day 15	0.3 liters/hour (L/h) Standard Deviation 0.13	0.8 liters/hour (L/h) Standard Deviation 1.45	0.4 liters/hour (L/h) Standard Deviation 0.28	0.3 liters/hour (L/h) Standard Deviation 0.19

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8, 24, 28, 72, 76, 168 hours post-dose on Day 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Time measured for vemurafenib plasma concentrations to decrease by one-half (t1/2) was calculated as 0.693 divided by apparent first-order terminal elimination rate constant (0.693/kel).

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=10 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Terminal Elimination Half-Life (t1/2) of Vemurafenib on Day 15	31.5 hours Standard Deviation 19.05	38.4 hours Standard Deviation 24.18	34.9 hours Standard Deviation 19.48	34.1 hours Standard Deviation 19.66

PRIMARY outcome

Timeframe: Pre-dose, 1, 2, 4, 5, 8 hours post-dose on Day 1 and 15

Population: PK population. Here, number of participants analyzed signifies participants evaluable for this outcome.

Accumulation ratio was calculated as, AUC(0-8) on Day 15 divided by AUC(0-8) on Day 1.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=10 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=9 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=11 Participants Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Accumulation Ratio of Vemurafenib on Day 15	24.9 ratio Standard Deviation 29.4	23.3 ratio Standard Deviation 16.0	18.8 ratio Standard Deviation 12.4	23.2 ratio Standard Deviation 16.5

SECONDARY outcome

Timeframe: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Population: Efficacy population: all enrolled participants who received at least one dose of vemurafenib, had measurable target lesions at baseline based on RECIST 1.1 criteria, had no major protocol violations of inclusion/exclusion criteria, and had no other violations affecting efficacy assessments.

Confirmed best overall response was defined as having best objective response as CR or PR, as assessed by investigator and confirmed at least 28 days after initial response. Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). CR was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) were required to demonstrate a reduction to normal (short axis less than \[\<\] 10 millimeters \[mm\]). PR was defined as a 30 percent (%) decrease in the sum of the diameters of the target lesions taking as a reference the baseline sum diameter. Percentage of participants with best overall response of confirmed CR or PR are reported.

Outcome measures

Outcome measures
Measure	Cohort 1 - Vemurafenib 240 mg n=49 Participants Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Percentage of Participants With a Confirmed Best Overall Response of Complete Response (CR) or Partial Response (PR)	49 percentage of participants	—	—	—

SECONDARY outcome

Timeframe: Up to approximately 3 years (assessed at Cycle 1 Day 1, Cycle 3 Day 1, Cycle 5 Day 1, thereafter every 2 cycles and then every 4 cycles after Cycle 13)

Population: Data for this outcome measure was not collected as the outcome was removed as per changes in planned analysis (protocol amendment).

OS was defined as the time, in months, from the date of the first study drug administration to the date of death, regardless of the cause of death.

Outcome measures

Outcome data not reported

Adverse Events

Cohort 1 - Vemurafenib 240 mg

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Cohort 2 - Vemurafenib 480 mg

Serious events: 3 serious events

Other events: 12 other events

Deaths: 0 deaths

Cohort 3 - Vemurafenib 720 mg

Serious events: 8 serious events

Other events: 12 other events

Deaths: 0 deaths

Cohort 4 - Vemurafenib 960 mg

Serious events: 7 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1 - Vemurafenib 240 mg n=12 participants at risk Participants received vemurafenib film-coated tablet, orally, twice daily at a dose of 240 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 2 - Vemurafenib 480 mg n=12 participants at risk Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 480 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 3 - Vemurafenib 720 mg n=12 participants at risk Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 720 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants received vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.	Cohort 4 - Vemurafenib 960 mg n=16 participants at risk Participants received vemurafenib film-coated tablets, orally, twice daily at a dose of 960 mg on Days 1 to 15 (a single morning dose was administered on Day 15). Starting at Day 22, participants resumed vemurafenib 960 mg film-coated tablets orally twice daily in 21-day cycles until the development of progressive disease, unacceptable toxicity, consent withdrawal, or any other criteria for removal.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	8.3% 1/12 • Up to approximately 3 years	16.7% 2/12 • Up to approximately 3 years	16.7% 2/12 • Up to approximately 3 years	12.5% 2/16 • Up to approximately 3 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Keratoacanthoma	8.3% 1/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	12.5% 2/16 • Up to approximately 3 years
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of the oral cavity	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
Gastrointestinal disorders Ascites	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
Gastrointestinal disorders Nausea	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
General disorders Pyrexia	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
General disorders Pain	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Musculoskeletal and connective tissue disorders Pathological fracture	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Respiratory, thoracic and mediastinal disorders Pleuritic pain	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
Vascular disorders Hypotension	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Vascular disorders Shock	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Cardiac disorders Pericarditis	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Infections and infestations Device related infection	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	6.2% 1/16 • Up to approximately 3 years
Injury, poisoning and procedural complications Femur fracture	8.3% 1/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/12 • Up to approximately 3 years	0.00% 0/12 • Up to approximately 3 years	8.3% 1/12 • Up to approximately 3 years	0.00% 0/16 • Up to approximately 3 years