Trial Outcomes & Findings for Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma (NCT NCT00425555)

NCT ID: NCT00425555

Last Updated: 2021-08-20

Results Overview

Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL (Olsen et al 2007). Responses in the skin based on SWAT are defined as: * Complete Response (CR): no evidence of skin disease * Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline * Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score * Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 139 participants
• Primary outcome timeframe: Baseline up to 6 Months of Follow up
• Results posted on: 2021-08-20

Participant Flow

The study was conducted at 41 centers in 12 countries.

A total 139 Participants were enrolled in the Study. No Patients completed treatment. All patients discontinued the treatment on this study and 136 patients discontinued the study (97.8%). The remaining three patients discontinued the study treatment were immediately transferred to another program.

Participant milestones

Measure	Bexarotene Exposed Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Overall Study STARTED	79	60
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	79	60

Reasons for withdrawal

Measure	Bexarotene Exposed Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 milligrams per day (mg/day) capsule orally, once a day (OD) on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Overall Study Withdrawal by Subject	11	8
Overall Study Lost to Follow-up	0	1
Overall Study Administrative problems	3	0
Overall Study Death	1	2
Overall Study New cancer therapy	2	1
Overall Study Disease progression	36	33
Overall Study Adverse Event	25	15
Overall Study Protocol Violation	1	0

Baseline Characteristics

Study of Oral LBH589 in Adult Patients With Refractory Cutaneous T-Cell Lymphoma

Baseline characteristics by cohort

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Total n=139 Participants Total of all reporting groups
Age, Continuous	57.9 years STANDARD_DEVIATION 14.70 • n=5 Participants	62.1 years STANDARD_DEVIATION 11.51 • n=7 Participants	59.7 years STANDARD_DEVIATION 13.53 • n=5 Participants
Sex: Female, Male Female	32 Participants n=5 Participants	19 Participants n=7 Participants	51 Participants n=5 Participants
Sex: Female, Male Male	47 Participants n=5 Participants	41 Participants n=7 Participants	88 Participants n=5 Participants
Race/Ethnicity, Customized Caucasian	68 Participants n=5 Participants	54 Participants n=7 Participants	122 Participants n=5 Participants
Race/Ethnicity, Customized Black	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized Asian	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Other	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to 6 Months of Follow up

Population: The analysis was performed in Full Analysis Set (FAS) population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Skin response was primarily classified based on an assessment using mSWAT, provided there was documented evidence of stable disease or better in lymph node/viscera.The mSWAT is a tool specifically developed to evaluate the extent of skin disease in CTCL (Olsen et al 2007).

Responses in the skin based on SWAT are defined as:

• Complete Response (CR): no evidence of skin disease
• Partial Response (PR): ≥ 50% decrease of the modified SWAT score compared with baseline
• Stable Disease (SD): Neither CR, PR, or PD as compared with baseline, i.e. change from baseline is less than a 50% decrease but also less than a 25 % increase in the modified SWAT score
• Progressive Disease (PD): ≥ 25% increase in the modified SWAT score compared with baseline.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Overall Response Rate of Participants Using the Modified Severity-Weighted Assessment Tool (mSWAT)	16.7 percentage Interval 8.1 to 25.0	20.3 percentage Interval 10.8 to 32.3	18.5 percentage Interval 11.4 to 24.6

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Estimate of the response rate of participants with resistant cutaneous T-cell lymphoma (CTCL) treated with Panobinostat using the mSWAT skin scores and 95% CI will be analyzed.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
The Overall Response Rate Using mSWAT Skin Score mSWAT skin response (CR/PR)flare considered as disease progression ( f.i.p ) - Number of responders	12 Participants	14 Participants	26 Participants
The Overall Response Rate Using mSWAT Skin Score Physician's Global Assessment- Responder (CR/PR)	15 Participants	18 Participants	33 Participants

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Time to response were summarized. A Kaplan-Meier analysis of time to progression was performed, including estimation and 95% confidence interval of the median time to progression and progression-free survival.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Time to Response for Responders	69.5 Days Interval 29.0 to 141.0	85.5 Days Interval 29.0 to 115.0	82.0 Days Interval 30.0 to 113.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Duration of response and time to response were summarized. A Kaplan-Meier analysis of time to progression was performed, including estimation and 95% confidence interval of the median time to progression and progression-free survival.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Duration of Response (DOS)	170.0 Days Interval 86.0 to 294.0	NA Days Interval 84.0 to There were an insufficient number of participants with events and therefore the Median and Upper limit of the 95% CI for the duration of response could not be calculated.	280.0 Days Interval 115.0 to 311.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

PFS is defined as time from first dose of study treatment to progression or death due to any cause, based on modified European Society for Bone and Marrow Transplantation (EBMT) criteria per Investigator's assessment

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Progression-free Survival (PFS)	127.0 months Interval 87.0 to 197.0	113.0 months Interval 85.0 to 142.0	114.0 months Interval 87.0 to 143.0

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Skin index measurement (Skindex-29) was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the "Dermatology Survey" page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess emotions scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 4	40.8 score on a scale Standard Deviation 23.87	34.7 score on a scale Standard Deviation 21.59	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 5	35.8 score on a scale Standard Deviation 22.19	34.4 score on a scale Standard Deviation 20.53	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 6	34.5 score on a scale Standard Deviation 22.72	35.4 score on a scale Standard Deviation 20.74	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 7	39.3 score on a scale Standard Deviation 24.98	36.8 score on a scale Standard Deviation 22.61	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 8	39.4 score on a scale Standard Deviation 20.03	35.8 score on a scale Standard Deviation 22.39	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Baseline	52.2 score on a scale Standard Deviation 22.66	50.6 score on a scale Standard Deviation 22.26	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 2	48.6 score on a scale Standard Deviation 23.79	46.6 score on a scale Standard Deviation 24.18	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 3	45.9 score on a scale Standard Deviation 21.53	44.1 score on a scale Standard Deviation 24.37	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 10	43.6 score on a scale Standard Deviation 20.48	43.5 score on a scale Standard Deviation 24.10	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 12	42.0 score on a scale Standard Deviation 16.80	43.1 score on a scale Standard Deviation 21.29	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 9	44.6 score on a scale Standard Deviation 23.09	32.8 score on a scale Standard Deviation 18.36	—
Skindex-29 Measurements of Average Sub-scores for Emotions From Baseline up to Cycle 12 Cycle 11	48.3 score on a scale Standard Deviation 20.92	43.5 score on a scale Standard Deviation 22.86	—

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population will include all participants enrolled into the study.

Skindex-29 was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the "Dermatology Survey" page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess functioning scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Baseline	46.7 score on a scale Standard Deviation 24.44	44.7 score on a scale Standard Deviation 25.33	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 5	32.8 score on a scale Standard Deviation 23.35	31.4 score on a scale Standard Deviation 21.38	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 6	33.0 score on a scale Standard Deviation 27.79	29.5 score on a scale Standard Deviation 21.25	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 7	33.1 score on a scale Standard Deviation 26.04	28.3 score on a scale Standard Deviation 22.98	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 8	34.4 score on a scale Standard Deviation 22.73	30.5 score on a scale Standard Deviation 25.16	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 9	37.2 score on a scale Standard Deviation 25.28	28.7 score on a scale Standard Deviation 19.54	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 10	35.2 score on a scale Standard Deviation 25.21	41.5 score on a scale Standard Deviation 27.22	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 11	40.0 score on a scale Standard Deviation 24.47	38.1 score on a scale Standard Deviation 25.46	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 12	26.3 score on a scale Standard Deviation 12.79	36.2 score on a scale Standard Deviation 20.95	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 2	43.5 score on a scale Standard Deviation 26.27	43.3 score on a scale Standard Deviation 24.53	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 3	42.6 score on a scale Standard Deviation 25.58	39.2 score on a scale Standard Deviation 26.38	—
Skindex-29 Measurements of Average Sub-scores for Functioning From Baseline up to Cycle 12 Cycle 4	38.8 score on a scale Standard Deviation 25.91	30.7 score on a scale Standard Deviation 22.91	—

SECONDARY outcome

Timeframe: Baseline up to Cycle 12, an average of 12 months

Population: The analysis was performed in FAS population was defined according to the intention-to-treat principle. This population included all participants enrolled into the study.

Skindex-29 was a self-administered 29-item dermatology patient-reported outcome measure that explores the domains of Functioning, Emotions and Symptoms. Data from the Skindex-29 came from the "Dermatology Survey" page. Scoring of the Skindex-29 was performed as per the developers' scoring algorithms. The score for each dimension was found by adding responses of 1 to 5 for each question, with higher scores indicating worse quality of life. The Skindex-29 yields three scale scores that assess physical symptoms scores range from 29 to 116, with higher scores indicating worse health-related quality of life. Average sub-scores for emotions, physical symptoms, and functioning was displayed.

Outcome measures

Measure	Bexarotene Exposed n=79 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Baseline	60.1 score on a scale Standard Deviation 19.03	55.3 score on a scale Standard Deviation 20.35	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 2	51.4 score on a scale Standard Deviation 23.10	47.7 score on a scale Standard Deviation 20.28	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 3	51.1 score on a scale Standard Deviation 21.92	42.9 score on a scale Standard Deviation 21.72	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 4	47.3 score on a scale Standard Deviation 22.16	35.2 score on a scale Standard Deviation 16.66	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 5	43.2 score on a scale Standard Deviation 23.96	35.6 score on a scale Standard Deviation 18.81	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 6	43.5 score on a scale Standard Deviation 24.72	36.2 score on a scale Standard Deviation 19.02	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 7	45.5 score on a scale Standard Deviation 23.67	37.7 score on a scale Standard Deviation 18.66	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 8	42.7 score on a scale Standard Deviation 21.45	36.5 score on a scale Standard Deviation 19.29	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 9	47.1 score on a scale Standard Deviation 23.42	35.9 score on a scale Standard Deviation 15.79	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 10	46.8 score on a scale Standard Deviation 23.11	47.0 score on a scale Standard Deviation 21.17	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 11	46.7 score on a scale Standard Deviation 22.04	48.3 score on a scale Standard Deviation 19.44	—
Skindex-29 Measurements of Average Sub-scores for Physical Symptoms From Baseline up to Cycle 12 Cycle 12	37.7 score on a scale Standard Deviation 15.52	45.1 score on a scale Standard Deviation 21.93	—

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Population: The analysis was performed in PK population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Cmax is defined as the maximum observed drug concentration observed in plasma over all PK sample concentrations. It will be obtained from the Cmax parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Cmax will be missing for that subject. Cmax will be reported in units of ng/mL.

Outcome measures

Measure	Bexarotene Exposed n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Maximum Plasma Concentration (Cmax) of Panobinostat Day 8	13.490 ng/mL Standard Deviation 6.4529	—	—
Maximum Plasma Concentration (Cmax) of Panobinostat Day 1	11.379 ng/mL Standard Deviation 6.6608	—	—

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Tmax is defined as the time at which the Cmax occurs. It will be obtained from the Tmax parameter calculated by WinNonlin®. If there is no measurable Cmax in the subject's PK profile, then Tmax will be missing for that subject. Tmax will be reported in units of h.

Outcome measures

Measure	Bexarotene Exposed n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Time to Peak Concentration (Tmax) of Panobinostat Day 1	1.5 h (hours) Interval 0.0 to 4.0	—	—
Time to Peak Concentration (Tmax) of Panobinostat Day 8	1.5 h (hours) Interval 0.25 to 3.5	—	—

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

AUC is defined as the area under concentration-time curve as a measure of drug exposure. The area under the plasma concentration-time curve from time zero to 24 hours. The area under the plasma concentration-time curve from time zero to 48 hours. AUC (0-inf) is defined as the area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time.

Outcome measures

Measure	Bexarotene Exposed n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 1 - AUC0-24	110.138 ng*hr/ml Standard Deviation 58.0235	—	—
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 8 - AUC0-24	134.033 ng*hr/ml Standard Deviation 61.5203	—	—
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 1 - AUC0-48	132.019 ng*hr/ml Standard Deviation 69.3453	—	—
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 8 - AUC0-48	159.750 ng*hr/ml Standard Deviation 64.2278	—	—
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 1- AUC (0-inf)	134.828 ng*hr/ml Standard Deviation 64.9389	—	—
Area Under the Plasma Concentration AUC0-24, AUC0-48 and AUC 0-infinity of Panobinostat Day 8 - AUC (0-inf)	162.673 ng*hr/ml Standard Deviation 65.0664	—	—

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Time of Clast (Tlast) will be obtained from the Tlast parameter calculated by WinNonlin®. If there is no measurable concentration in the subject's PK profile, then Tlast will be missing for that participants. Tlast will be reported in units of h.

Outcome measures

Measure	Bexarotene Exposed n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Time of Clast (Tlast) of Panobinostat Day 1	47.9 Hours Interval 23.4 to 49.5	—	—
Time of Clast (Tlast) of Panobinostat Day 8	NA Hours Interval 16.8 to 47.0 below the level of detection	—	—

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 1-2, and 3-4 hours post dose on Day 1 and Day 8

Population: The analysis was performed in PAS population, defined as all participants who provide at least one post-dose PK plasma sample. Here, number of participants analyzed refer to the number of participants evaluable for this outcome at specified time point.

Clast is defined as the Last observed (quantifiable) plasma concentration (Clast), in units of ng/mL. Blood samples were collected to assess Clast.

Outcome measures

Measure	Bexarotene Exposed n=139 Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.	All Participants Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). The treatment duration was not fixed. Participants continued treatment until disease progression or unacceptable toxicity occurred.
Last Observed Plasma Concentration (Clast) of Panobinostat Day 1	0.632 ng/mL Standard Deviation 0.9737	—	—
Last Observed Plasma Concentration (Clast) of Panobinostat Day 8	1.524 ng/mL Standard Deviation 0.9076	—	—

Adverse Events

Bexarotene Exposed

Serious events: 33 serious events

Other events: 77 other events

Deaths: 3 deaths

Bexarotene Naive

Serious events: 23 serious events

Other events: 59 other events

Deaths: 3 deaths

Serious adverse events

Measure	Bexarotene Exposed n=79 participants at risk Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 participants at risk Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). Participants continued treatment until disease progression or unacceptable toxicity occurred.
Blood and lymphatic system disorders Anaemia	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Lymphadenopathy	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Neutropenia	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Thrombocytopenia	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Angina pectoris	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Atrial fibrillation	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Atrioventricular block second degree	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Cardiac arrest	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Cardiac failure congestive	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Cardiomyopathy	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Coronary artery insufficiency	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Cardiac disorders Tachycardia	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Ear and labyrinth disorders Ear pain	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Abdominal pain	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Diarrhoea	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Duodenal ulcer	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Gastric ulcer perforation	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Vomiting	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Adverse drug reaction	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Asthenia	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Chest pain	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Death	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Fatigue	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders General physical health deterioration	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Hypothermia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Pyrexia	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Sudden cardiac death	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Hepatobiliary disorders Cholecystitis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Hepatobiliary disorders Cholelithiasis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Appendicitis	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Bacteraemia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Bronchitis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Cellulitis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Device related sepsis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Erysipelas	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Herpes zoster	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Infected skin ulcer	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Infection	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Peritoneal abscess	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Pneumocystis jiroveci pneumonia	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Pneumonia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Rotavirus infection	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Sepsis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Septic shock	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Skin bacterial infection	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Staphylococcal bacteraemia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Staphylococcal infection	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Superinfection	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Wound infection	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Injury, poisoning and procedural complications Accidental overdose	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Injury, poisoning and procedural complications Fall	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Injury, poisoning and procedural complications Post procedural complication	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Injury, poisoning and procedural complications Post procedural haemorrhage	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Injury, poisoning and procedural complications Subdural haematoma	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram QT prolonged	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram ST segment depression	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram ST-T segment abnormal	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram abnormal	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram repolarisation abnormality	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Platelet count decreased	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Decreased appetite	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Failure to thrive	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypoalbuminaemia	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Muscular weakness	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma pancreas	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bowen's disease	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Carotid artery occlusion	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Carotid artery stenosis	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Cerebral infarction	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Dizziness	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Headache	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Presyncope	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Somnolence	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Calculus urinary	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Haematuria	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Renal colic	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Renal failure	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Renal failure acute	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Renal and urinary disorders Renal impairment	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Dermatitis exfoliative	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Skin lesion	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Skin ulcer	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Deep vein thrombosis	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Hypotension	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Jugular vein thrombosis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Orthostatic hypotension	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Peripheral artery stenosis	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Peripheral embolism	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.

Other adverse events

Measure	Bexarotene Exposed n=79 participants at risk Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). Participants continued treatment until disease progression or unacceptable toxicity occurred.	Bexarotene Naive n=60 participants at risk Participants received Panobinostat 20 mg/day capsule orally, OD on 3 days per week. (Monday, Wednesday and Friday or alternative Day 1, 3 and 5). Participants continued treatment until disease progression or unacceptable toxicity occurred.
Blood and lymphatic system disorders Anaemia	21.5% 17/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Leukopenia	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Neutropenia	17.7% 14/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	16.7% 10/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Blood and lymphatic system disorders Thrombocytopenia	50.6% 40/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	38.3% 23/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Ear and labyrinth disorders Vertigo	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Endocrine disorders Hypothyroidism	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Eye disorders Conjunctivitis	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Abdominal discomfort	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Abdominal pain	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Abdominal pain upper	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Constipation	10.1% 8/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	18.3% 11/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Diarrhoea	57.0% 45/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	63.3% 38/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Dry mouth	7.6% 6/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Dyspepsia	10.1% 8/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Nausea	40.5% 32/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	36.7% 22/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Gastrointestinal disorders Vomiting	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	11.7% 7/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Asthenia	27.8% 22/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	16.7% 10/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Chills	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	13.3% 8/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Fatigue	32.9% 26/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	48.3% 29/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Malaise	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Oedema peripheral	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	20.0% 12/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
General disorders Pyrexia	15.2% 12/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	13.3% 8/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Bronchitis	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Cellulitis	0.00% 0/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Influenza	1.3% 1/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Nasopharyngitis	10.1% 8/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Skin infection	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Infections and infestations Urinary tract infection	8.9% 7/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Aspartate aminotransferase increased	7.6% 6/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Blood alkaline phosphatase increased	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Blood creatinine increased	19.0% 15/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	13.3% 8/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Blood triglycerides increased	7.6% 6/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Blood urea increased	7.6% 6/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Electrocardiogram QT prolonged	6.3% 5/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	0.00% 0/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Gamma-glutamyltransferase increased	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Haemoglobin decreased	6.3% 5/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Platelet count decreased	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Investigations Weight decreased	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Decreased appetite	24.1% 19/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	28.3% 17/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Dehydration	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypercholesterolaemia	8.9% 7/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hyperglycaemia	13.9% 11/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	13.3% 8/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hyperkalaemia	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypertriglyceridaemia	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	16.7% 10/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypoalbuminaemia	15.2% 12/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypocalcaemia	13.9% 11/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypokalaemia	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypomagnesaemia	6.3% 5/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hyponatraemia	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Metabolism and nutrition disorders Hypophosphataemia	17.7% 14/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Arthralgia	13.9% 11/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Muscle spasms	10.1% 8/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Myalgia	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Musculoskeletal and connective tissue disorders Pain in extremity	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Dizziness	12.7% 10/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Dysgeusia	16.5% 13/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	20.0% 12/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Headache	20.3% 16/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	20.0% 12/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Paraesthesia	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Somnolence	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Nervous system disorders Syncope	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	3.3% 2/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Psychiatric disorders Depression	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	11.7% 7/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Psychiatric disorders Insomnia	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Cough	11.4% 9/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	10.0% 6/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	17.7% 14/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	8.9% 7/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Alopecia	6.3% 5/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	5.0% 3/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Dry skin	10.1% 8/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Erythema	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Pruritus	40.5% 32/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	26.7% 16/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Rash	5.1% 4/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Skin exfoliation	8.9% 7/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	8.3% 5/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Skin lesion	7.6% 6/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	1.7% 1/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Skin and subcutaneous tissue disorders Skin ulcer	2.5% 2/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Hypertension	13.9% 11/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.
Vascular disorders Hypotension	3.8% 3/79 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.	6.7% 4/60 • From Start of the Study up to 7 years approximately The analysis was performed on Safety analysis population (SAP) consisted of all participants who received at least one dose of study drug and had at least one valid post-baseline assessment.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: Novartis.email@novartis.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place