Trial Outcomes & Findings for A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma (NCT NCT01327053)

Last Updated: 2019-08-28

Results Overview

ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 6 months after starting LDE225 treatment.Treatment with sonidegib was considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

230 participants

Primary outcome timeframe

6 months

Results posted on

2019-08-28

Participant Flow

Randomization was stratified across the two treatment arms according to the stage of disease (laBCC or mBCC), histological subtype (non-aggressive or aggressive for laBCC patients) and the regions (Australia, Europe, and North America).

All eligible, enrolled patients were randomized in 1:2 ratio to sonidegib treatment with either 200 mg or 800 mg once-daily dose. In total, 230 patients were evaluated as FAS population: 79 and 151 patients randomized to 200mg and 800 mg sonidegib respectively. However, 1 patient randomized to 800 mg sonidegib did not receive study treatment.

Participant milestones

Participant milestones
Measure	LDE225 (Sonidegib) 200 mg The study is double blinded and will enroll at least 50 evaluable patients in the 200 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 (Sonidegib) 800 mg The study is double blinded and will enroll at least 100 evaluable patients in the 800 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Overall Study STARTED	79	151
Overall Study Untreated	0	1
Overall Study Patients Cont. to Next Phase of Trial	52	89
Overall Study Survival Follow-up	33	49
Overall Study Post-treatment Follow-up	19	40
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	79	151

Reasons for withdrawal

Reasons for withdrawal
Measure	LDE225 (Sonidegib) 200 mg The study is double blinded and will enroll at least 50 evaluable patients in the 200 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 (Sonidegib) 800 mg The study is double blinded and will enroll at least 100 evaluable patients in the 800 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Overall Study Adverse Event	23	57
Overall Study Patient/guardian decision	11	35
Overall Study Physician Decision	10	14
Overall Study Death	1	5
Overall Study Lost to Follow-up	2	4
Overall Study Non-compliance with study treatment	0	5
Overall Study Study terminated by Sponsor	1	3
Overall Study Progressive disease	31	26
Overall Study Protocol Violation	0	1
Overall Study Untreated	0	1

Baseline Characteristics

A Phase II Study of Efficacy and Safety in Patients With Locally Advanced or Metastatic Basal Cell Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LDE225 (Sonidegib) 200 mg n=79 Participants The study is double blinded and will enroll at least 50 evaluable patients in the 200 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 (Sonidegib) 800 mg n=151 Participants The study is double blinded and will enroll at least 100 evaluable patients in the 800 mg LDE225 arm. The efficacy and safety of LDE225 will be analyzed separately in each group. Patients who meet all the inclusion and none of the exclusion criteria will be treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	Total n=230 Participants Total of all reporting groups
Age, Continuous	65.6 Years STANDARD_DEVIATION 15.67 • n=5 Participants	63.6 Years STANDARD_DEVIATION 14.59 • n=7 Participants	64.3 Years STANDARD_DEVIATION 14.96 • n=5 Participants
Sex: Female, Male Female	31 Participants n=5 Participants	55 Participants n=7 Participants	86 Participants n=5 Participants
Sex: Female, Male Male	48 Participants n=5 Participants	96 Participants n=7 Participants	144 Participants n=5 Participants
Race/Ethnicity, Customized Black	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	71 Participants n=5 Participants	145 Participants n=7 Participants	216 Participants n=5 Participants
Race/Ethnicity, Customized Other	8 Participants n=5 Participants	5 Participants n=7 Participants	13 Participants n=5 Participants

PRIMARY outcome

Timeframe: 6 months

Population: The primary efficacy analysis set (pEAS) was a subset of the full analysis set (FAS) including patients with laBCC with tumors that were adequately assessed by MRI or photography or both, \& including all patients with mBCC included in the FAS which comprised all patients who were assigned study treatment irrespective of receiving it.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS)	42.9 Percentage of participants Interval 27.7 to 59.0	37.6 Percentage of participants Interval 27.8 to 48.3	15.4 Percentage of participants Interval 1.9 to 45.4	17.4 Percentage of participants Interval 5.0 to 38.8

PRIMARY outcome

Timeframe: 6 months

Population: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients).

ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 6 months after starting LDE225 treatment.Treatment with sonidegib was to be considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Objective Response Rate (ORR) Based on Central Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (Metastatic Basal Cell Carcinoma (mBCC)) Per Full Analysis Set (FAS)	47.0 Percentage of participants Interval 34.6 to 59.7	35.2 Percentage of participants Interval 26.9 to 44.1	15.4 Percentage of participants Interval 1.9 to 45.4	17.4 Percentage of participants Interval 5.0 to 38.8

SECONDARY outcome

Timeframe: 42 months

Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason. Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm. Progressive disease (PD): At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm2.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	12.9 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	23.7 Months Interval 10.8 to 29.6	24.0 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	NA Months N/A = Median DoR was non-estimable for patients with mBCC receiving treatment with sonidegib 800 mg as limited numbers of PD or death were observed.

SECONDARY outcome

Timeframe: 42 months

Population: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients). Patients were classified according to the treatment they were assigned in accordance with the intention-to-treat (ITT) principle.

Duration of response is the time from the first observed confirmed response (CR or PR) to disease progression or death due to any reason. Median DoR for patients with laBCC was non-estimable for both treatment arms. Duration of response was for participants with ORR. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Duration of Response (DoR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	26.1 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	23.3 Months Interval 12.2 to 29.6	24.0 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	NA Months NA = Median DoR was non-estimable for patients with mBCC receiving treatment with sonidegib 800 mg as limited numbers of PD or death were observed.

SECONDARY outcome

Timeframe: 42 months

Rate of complete response is the percentage of patients with best overall response of complete response (CR) after starting LDE225 treatment. The rate of CR was determined according to mRECIST for laBCC and RECIST 1.1 for mBCC. Patients with best overall response of 'Unknown" were treated as non responders. Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Complete Response Rate (CRR) Per Central Review (pEAS)	4.8 Percentage of participants Interval 0.6 to 16.2	2.2 Percentage of participants Interval 0.3 to 7.6	0.0 Percentage of participants Interval 0.0 to 24.7	0.0 Percentage of participants Interval 0.0 to 14.8

SECONDARY outcome

Timeframe: 6 months

Rate of complete response is the proportion of patients with best overall response of complete response (CR) after starting LDE225 treatment. The rate of CR will be determined according to mRECIST for laBCC and RECIST 1.1 for mBCC. Patients with best overall response of 'Unknown" will be treated as non responders

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Complete Response Rate (CRR) Per Central Review (FAS)	3.0 Percentage of participants Interval 0.4 to 10.5	0.0 Percentage of participants Interval 0.0 to 2.8	0.0 Percentage of participants Interval 0.0 to 24.7	0.0 Percentage of participants Interval 0.0 to 14.8

SECONDARY outcome

Timeframe: 42 months

Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	19.0 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	19.4 Months Interval 13.8 to 30.5	13.1 Months Interval 5.6 to 33.1	11.1 Months Interval 7.3 to 16.6

SECONDARY outcome

Timeframe: 42 months

Population: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients).

Progression-free survival (PFS) is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, PFS is censored at the date of last adequate tumor assessment.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Progression-free Survival (PFS) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	22.1 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	24.9 Months Interval 19.2 to 33.4	13.1 Months Interval 5.6 to 33.1	11.1 Months Interval 7.3 to 16.6

SECONDARY outcome

Timeframe: 42 months

Time to tumor response (TTR) is defined as the time from date of enrollment to the date of first documented tumor response (CR or PR). PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	4.0 Months Interval 3.7 to 5.6	3.7 Months Interval 2.0 to 5.5	9.2 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	1.0 Months Interval 1.0 to 2.1

SECONDARY outcome

Timeframe: 42 months

Population: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients).

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Time to Tumor Response (TTR) Per Central Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	4.0 Months Interval 3.7 to 5.6	3.7 Months Interval 2.0 to 5.5	9.2 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.	1.0 Months Interval 1.0 to 2.1

SECONDARY outcome

Timeframe: 42 months

ORR is the percentage of patient's objective response (ORR) by 42 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 42 months after starting LDE225 treatment. Treatment with sonidegib was considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Objective Response Rate (ORR) Based on Site Investigator Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (for Metastatic Basal Cell Carcinoma (mBCC)) Per Primary Efficacy Analysis Set (pEAS)	71.4 Percentage of participants Interval 55.4 to 84.3	61.3 Percentage of participants Interval 50.6 to 71.2	23.1 Percentage of participants Interval 5.0 to 53.8	34.8 Percentage of participants Interval 16.4 to 57.3

SECONDARY outcome

Timeframe: 42 months

Population: The full analysis set (FAS) comprised all patients who were assigned study treatment irrespective of receiving it (all randomized patients).

ORR is the percentage of patient's objective response (ORR) by 6 months after starting LDE225 treatment. A responder was defined as a subject with confirmed partial response (PR) or confirmed complete response (CR) 42 months after starting LDE225 treatment.Treatment with sonidegib was to be considered sufficiently efficacious if the observed ORR on any treatment arm at the end of the study was 30% or higher. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Objective Response Rate (ORR) Based on Site Investigator Review According to mRECIST (for Locally Advanced Basal Cell Carcinoma (laBCC)) and RECIST 1.1 (Metastatic Basal Cell Carcinoma (mBCC)) Per Full Analysis Set (FAS)	71.2 Percentage of participants Interval 58.7 to 81.7	58.6 Percentage of participants Interval 49.6 to 67.2	23.1 Percentage of participants Interval 5.0 to 53.8	34.8 Percentage of participants Interval 16.4 to 57.3

SECONDARY outcome

Timeframe: 42 months

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Duration of Response (DoR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	18.2 Months Interval 12.9 to 23.0	26.0 Months Interval 15.7 to 47.3	18.1 Months Interval 17.7 to 18.4	10.2 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.

SECONDARY outcome

Timeframe: 42 months

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Duration of Response (DoR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (FAS)	15.7 Months Interval 12.0 to 20.2	26.0 Months Interval 18.3 to 47.3	18.1 Months Interval 17.7 to 18.4	10.2 Months N/A = Both lower and upper confidence intervals were not estimable as limited numbers of PD or death were observed.

SECONDARY outcome

Timeframe: 42 months

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Progression-free Survival (PFS) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	20.1 Months Interval 14.8 to 23.8	28.0 Months Interval 19.4 to 49.8	13.1 Months Interval 9.2 to 19.4	14.3 Months Interval 11.1 to 17.0

SECONDARY outcome

Timeframe: 42 months

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=42 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=93 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Time to Tumor Response (TTR) Per Site Investigator Review Using mRECIST for laBCC and RECIST 1.1 for mBCC (pEAS)	1.9 Months Interval 1.8 to 3.9	1.8 Months Interval 1.1 to 2.0	1.0 Months Interval 0.9 to 3.7	2.7 Months Interval 1.0 to 5.6

SECONDARY outcome

Timeframe: Weeks 1, 3, 5, 9, 13, 17, 21, 33, 45, 57, 69

Population: The PK analysis set (PAS) consisted of all patients with at least one evaluable plasma concentration.

Blood PK samples were collected either by direct venipuncture or an indwelling cannula inserted in a forearm vein for the determination of trough (Cmin) plasma concentrations of sonidegib and its main circulating metabolite, LGE899, from all patients who enrolled in the study. Blood was collected in Weeks 1, 3, 5, 9 (pre-dose), and subsequently pre-dose every 4 weeks up to Week 21, and every 12 weeks thereafter up to week 69.

Outcome measures

SECONDARY outcome

Timeframe: 42 months

OS is defined as the time from date of randomization to date of death due to any cause or the last date that a patient was known to be alive (censored observation) as of the data cut-off.

Outcome measures

Outcome measures
Measure	LDE225 200mg laBCC n=66 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=128 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC n=13 Participants The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC n=23 Participants The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Overall Survival (OS)	NA Months N/A = Median OS was non-estimable for patients with laBCC receiving treatment with sonidegib 200 mg as limited number of deaths were observed.	NA Months N/A = Median OS was non-estimable for patients with laBCC receiving treatment with sonidegib 800 mg as limited number of deaths were observed.	47.6 Months N/A = Both lower and upper confidence intervals were not estimable as limited number of deaths were observed.	33.8 Months N/A = Both lower and upper confidence intervals were not estimable as limited number of deaths were observed.

Adverse Events

LDE225 200 mg qd

Serious events: 16 serious events

Other events: 76 other events

Deaths: 1 deaths

LDE225 800 mg qd

Serious events: 58 serious events

Other events: 145 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
Publication restrictions are in place

Restriction type: OTHER

Measure	LDE225 200mg laBCC n=73 Participants The efficacy and safety of LDE225 200mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg laBCC n=139 Participants The efficacy and safety of LDE225 800mg laBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 200mg mBCC The efficacy and safety of LDE225 200mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800mg mBCC The efficacy and safety of LDE225 800mg mBCC cohort were analyzed separately in each group. Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Plasma Concentration of Sonidegib (LDE225) Week 3 (0 h (pre-dose))	207.76 ng/mL Geometric Coefficient of Variation 78.29	586.76 ng/mL Geometric Coefficient of Variation 97.13	—	—
Plasma Concentration of Sonidegib (LDE225) Week 17 (2 h (post-dose))	939.56 ng/mL Geometric Coefficient of Variation 50.79	1922.38 ng/mL Geometric Coefficient of Variation 34.90	—	—
Plasma Concentration of Sonidegib (LDE225) Week 17 (4 h (post-dose))	842.31 ng/mL Geometric Coefficient of Variation 62.22	1750.70 ng/mL Geometric Coefficient of Variation 53.32	—	—
Plasma Concentration of Sonidegib (LDE225) Week 9 (0 h (pre-dose))	559.29 ng/mL Geometric Coefficient of Variation 67.30	1353.06 ng/mL Geometric Coefficient of Variation 63.43	—	—
Plasma Concentration of Sonidegib (LDE225) Week 13 (0 h (pre-dose))	714.01 ng/mL Geometric Coefficient of Variation 60.79	1443.84 ng/mL Geometric Coefficient of Variation 61.57	—	—
Plasma Concentration of Sonidegib (LDE225) Week 1 (0 h (pre-dose))	NA ng/mL Geometric Coefficient of Variation NA N/A = Week1 pre-dose concentrations were below limit of quantitation	NA ng/mL Geometric Coefficient of Variation NA N/A = Week1 pre-dose concentrations were below limit of quantitation	—	—
Plasma Concentration of Sonidegib (LDE225) Week 5 (0 h (pre-dose))	372.26 ng/mL Geometric Coefficient of Variation 68.89	1012.63 ng/mL Geometric Coefficient of Variation 70.42	—	—
Plasma Concentration of Sonidegib (LDE225) Week 17 (0 h (pre-dose))	688.93 ng/mL Geometric Coefficient of Variation 64.43	1574.21 ng/mL Geometric Coefficient of Variation 59.88	—	—
Plasma Concentration of Sonidegib (LDE225) Week 17 (1 h (post-dose))	841.78 ng/mL Geometric Coefficient of Variation 52.57	1803.74 ng/mL Geometric Coefficient of Variation 39.47	—	—
Plasma Concentration of Sonidegib (LDE225) Week 17 (6 h (post-dose))	759.88 ng/mL Geometric Coefficient of Variation 63.43	1673.95 ng/mL Geometric Coefficient of Variation 41.53	—	—
Plasma Concentration of Sonidegib (LDE225) Week 21 (0 h (pre-dose))	707.49 ng/mL Geometric Coefficient of Variation 63.58	1547.41 ng/mL Geometric Coefficient of Variation 63.92	—	—
Plasma Concentration of Sonidegib (LDE225) Week 33 (0 h (pre-dose))	702.67 ng/mL Geometric Coefficient of Variation 93.11	1477.60 ng/mL Geometric Coefficient of Variation 74.80	—	—
Plasma Concentration of Sonidegib (LDE225) Week 45 (0 h (pre-dose))	697.92 ng/mL Geometric Coefficient of Variation 76.02	1368.87 ng/mL Geometric Coefficient of Variation 79.60	—	—
Plasma Concentration of Sonidegib (LDE225) Week 57 (0 h (pre-dose))	559.17 ng/mL Geometric Coefficient of Variation 117.27	1257.42 ng/mL Geometric Coefficient of Variation 78.96	—	—
Plasma Concentration of Sonidegib (LDE225) Wek 69 (0 h (pre-dose))	530.91 ng/mL Geometric Coefficient of Variation 154.33	1355.91 ng/mL Geometric Coefficient of Variation 89.03	—	—

Serious adverse events
Measure	LDE225 200 mg qd n=79 participants at risk Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800 mg qd n=150 participants at risk Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Blood and lymphatic system disorders Anaemia	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	3.3% 5/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Angina pectoris	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Atrial fibrillation	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Bradycardia	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Bundle branch block left	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Cardiac arrest	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Cardiac failure congestive	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Cardiovascular insufficiency	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Cardiac disorders Sinus tachycardia	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Chronic gastritis	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Constipation	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Diarrhoea	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	1.3% 2/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Duodenal stenosis	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Gastric ulcer	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Gastritis	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Gastritis erosive	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Gastrointestinal pain	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Nausea	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	2.0% 3/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Pancreatitis acute	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Peptic ulcer perforation	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	1.3% 2/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Vomiting	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	2.7% 4/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Cardiac death	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Facial pain	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders General physical health deterioration	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Non-cardiac chest pain	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Pain	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Hepatobiliary disorders Cholelithiasis	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Hepatobiliary disorders Hepatotoxicity	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Abscess	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Abscess limb	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	1.3% 2/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Bronchitis	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Cellulitis	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Endocarditis	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Escherichia urinary tract infection	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Lower respiratory tract infection	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.00% 0/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Mastoiditis	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Otitis media	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	0.67% 1/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.

Other adverse events
Measure	LDE225 200 mg qd n=79 participants at risk Patients who met all the inclusion and none of the exclusion criteria were treated with 200 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.	LDE225 800 mg qd n=150 participants at risk Patients who met all the inclusion and none of the exclusion criteria were treated with 800 mg LDE225 daily until disease progression, occurrence of intolerable toxicity, start of another anticancer treatment or withdrawal of consent.
Blood and lymphatic system disorders Anaemia	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	8.7% 13/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Ear and labyrinth disorders Vertigo	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	7.3% 11/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Abdominal pain	10.1% 8/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	6.0% 9/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Abdominal pain upper	8.9% 7/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	8.0% 12/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Constipation	7.6% 6/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	16.0% 24/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Diarrhoea	31.6% 25/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	22.7% 34/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Dry mouth	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	5.3% 8/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Nausea	39.2% 31/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	47.3% 71/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Gastrointestinal disorders Vomiting	11.4% 9/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	27.3% 41/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Asthenia	12.7% 10/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	6.0% 9/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Fatigue	32.9% 26/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	36.7% 55/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
General disorders Pyrexia	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	3.3% 5/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Influenza	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	5.3% 8/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Nasopharyngitis	10.1% 8/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	11.3% 17/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Pneumonia	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	2.0% 3/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Upper respiratory tract infection	6.3% 5/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	7.3% 11/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Infections and infestations Urinary tract infection	8.9% 7/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	4.7% 7/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Injury, poisoning and procedural complications Fall	6.3% 5/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	3.3% 5/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Investigations Blood creatine phosphokinase increased	29.1% 23/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	36.0% 54/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Investigations Lipase increased	7.6% 6/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	8.7% 13/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Investigations Weight decreased	30.4% 24/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	42.7% 64/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Metabolism and nutrition disorders Decreased appetite	22.8% 18/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	34.7% 52/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Arthralgia	16.5% 13/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	11.3% 17/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Back pain	7.6% 6/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	10.7% 16/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Muscle spasms	54.4% 43/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	69.3% 104/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Muscular weakness	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	5.3% 8/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	4.7% 7/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Myalgia	19.0% 15/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	28.0% 42/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Musculoskeletal and connective tissue disorders Pain in extremity	6.3% 5/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	5.3% 8/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	3.3% 5/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Ageusia	1.3% 1/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	10.0% 15/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Dizziness	8.9% 7/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	10.0% 15/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Dysgeusia	44.3% 35/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	59.3% 89/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Headache	15.2% 12/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	13.3% 20/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Hypogeusia	0.00% 0/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	6.0% 9/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Nervous system disorders Paraesthesia	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	4.0% 6/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Psychiatric disorders Depression	6.3% 5/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	6.0% 9/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Respiratory, thoracic and mediastinal disorders Cough	8.9% 7/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	7.3% 11/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.1% 4/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	4.0% 6/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.
Skin and subcutaneous tissue disorders Alopecia	49.4% 39/79 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.	58.0% 87/150 • Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 76.2 months. All cause mortality (deaths) was collected for as long as participants could be contacted from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV) up to a maximum of approx. 7 years.