Trial Outcomes & Findings for Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease (NCT NCT02697734)

NCT ID: NCT02697734

Last Updated: 2021-11-01

Results Overview

A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 73 participants
• Primary outcome timeframe: at Week 12
• Results posted on: 2021-11-01

Participant Flow

Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). There are 73 participants in the FAS who were randomized and received treatment.

Participant milestones

Measure	Osilodrostat Group Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).
Core Phase - up to Week 48 STARTED	48	25
Core Phase - up to Week 48 COMPLETED	42	23
Core Phase - up to Week 48 NOT COMPLETED	6	2
Optional Extension Phase STARTED	38	22
Optional Extension Phase COMPLETED	33	20
Optional Extension Phase NOT COMPLETED	5	2

Reasons for withdrawal

Measure	Osilodrostat Group Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).
Core Phase - up to Week 48 Withdrawal by Subject	4	0
Core Phase - up to Week 48 Adverse Event	1	2
Core Phase - up to Week 48 Physician Decision	1	0
Optional Extension Phase Adverse Event	5	1
Optional Extension Phase Physician Decision	0	1

Baseline Characteristics

Participants

Baseline characteristics by cohort

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	Total n=73 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	46 Participants n=5 Participants	25 Participants n=7 Participants	71 Participants n=5 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Age, Continuous	42.3 Years STANDARD_DEVIATION 13.82 • n=5 Participants • Participants	38.9 Years STANDARD_DEVIATION 12.33 • n=7 Participants • Participants	41.2 Years STANDARD_DEVIATION 13.35 • n=5 Participants • Participants
Sex: Female, Male Female	43 Participants n=5 Participants	18 Participants n=7 Participants	61 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	34 Participants n=5 Participants	15 Participants n=7 Participants	49 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: at Week 12

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)

A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12.

Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Percentage of Randomized Participants With a Complete Response	37 Participants	2 Participants	—

SECONDARY outcome

Timeframe: At Week 36

Population: Full Analysis Set participants: comprises all randomized participants who received at least one dose of osilodrostat. Only a single arm is reported since the endpoint is 'To assess the complete response rate in both arms combined at Week 36 in patients receiving osilodrostat treatment.'

The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol <= upper limit of normal (mUFC <= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.

Outcome measures

Measure	Osilodrostat Group n=73 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Percentage of Participants With mUFC ≤ ULN at Week 36	80.8 Percentage of participants Interval 69.9 to 89.1	—	—

SECONDARY outcome

Timeframe: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in mUFC actual - baseline	421.4 nmol/24hr Standard Deviation 291.25	451.5 nmol/24hr Standard Deviation 535.09	—
Change From Baseline in mUFC change from baseline at week 2 (n=47,24)	-139.3 nmol/24hr Standard Deviation 404.45	164.9 nmol/24hr Standard Deviation 543.82	—
Change From Baseline in mUFC change from baseline at week 5 (n=46,25)	-252.8 nmol/24hr Standard Deviation 338.48	-37.3 nmol/24hr Standard Deviation 280.84	—
Change From Baseline in mUFC change from baseline at week 8 (n=44,25)	-330.2 nmol/24hr Standard Deviation 303.35	-35.0 nmol/24hr Standard Deviation 325.30	—
Change From Baseline in mUFC change from baseline at week 12 (n=44,24)	-332.7 nmol/24hr Standard Deviation 315.50	-49.1 nmol/24hr Standard Deviation 332.29	—
Change From Baseline in mUFC change from baseline at week 14 (n=45,25)	-191.7 nmol/24hr Standard Deviation 446.77	-209.5 nmol/24hr Standard Deviation 407.62	—
Change From Baseline in mUFC change from baseline at week 17 (n=45,25)	-238.8 nmol/24hr Standard Deviation 362.46	-284.5 nmol/24hr Standard Deviation 557.47	—
Change From Baseline in mUFC change from baseline at week 20 (n=44,24)	-294.5 nmol/24hr Standard Deviation 316.65	-355.1 nmol/24hr Standard Deviation 538.96	—
Change From Baseline in mUFC change from baseline at week 23 (n=44,25)	-314.1 nmol/24hr Standard Deviation 307.60	-387.8 nmol/24hr Standard Deviation 466.15	—
Change From Baseline in mUFC change from baseline at week 26 (n=43,25)	-345.2 nmol/24hr Standard Deviation 306.35	-365.4 nmol/24hr Standard Deviation 458.28	—
Change From Baseline in mUFC change from baseline at week 29 (n=43,25)	-331.4 nmol/24hr Standard Deviation 299.63	-391.4 nmol/24hr Standard Deviation 534.57	—
Change From Baseline in mUFC change from baseline at week 32 (n=44,25)	-341.3 nmol/24hr Standard Deviation 298.96	-298.0 nmol/24hr Standard Deviation 655.52	—
Change From Baseline in mUFC change from baseline at week 36 (n=43,25)	-349.6 nmol/24hr Standard Deviation 310.46	-372.9 nmol/24hr Standard Deviation 519.17	—
Change From Baseline in mUFC change from baseline at week 40 (n=43,23)	-333.4 nmol/24hr Standard Deviation 307.63	-364.7 nmol/24hr Standard Deviation 542.28	—
Change From Baseline in mUFC change from baseline at week 48 (n=42,22)	-325.1 nmol/24hr Standard Deviation 314.30	-367.5 nmol/24hr Standard Deviation 554.16	—
Change From Baseline in mUFC change from baseline at week 60 (n=33,19)	-364.4 nmol/24hr Standard Deviation 339.57	-335.2 nmol/24hr Standard Deviation 571.06	—
Change From Baseline in mUFC change from baseline at week 72 (n=31,17)	-381.2 nmol/24hr Standard Deviation 338.68	-372.4 nmol/24hr Standard Deviation 624.69	—
Change From Baseline in mUFC change from baseline at week 84 (n=23,17)	-398.6 nmol/24hr Standard Deviation 377.81	-196.0 nmol/24hr Standard Deviation 916.83	—
Change From Baseline in mUFC change from baseline at week 96 (n=6,7)	-414.5 nmol/24hr Standard Deviation 347.83	-616.4 nmol/24hr Standard Deviation 881.92	—

SECONDARY outcome

Timeframe: up to 12 weeks

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)

To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.

Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN	45 Participants	8 Participants	—

SECONDARY outcome

Timeframe: up to 12 weeks

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).

To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.

Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.

The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response	35 Days Interval 34.0 to 52.0	NA Days Interval 87.0 to Not estimable. Due to the low number of participants achieving control in the placebo arm, median time-to-first control was not reached and the median with corresponding upper 95% confidence interval could not be estimated.	—

SECONDARY outcome

Timeframe: up to 12 weeks

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).

To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.

Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.

% Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Time-to-first Control of mUFC - % Event Probability Estimates 2 Weeks	25.0 Percent (event probability estimates) Interval 15.0 to 39.8	16.0 Percent (event probability estimates) Interval 6.3 to 37.2	—
Time-to-first Control of mUFC - % Event Probability Estimates 5 Weeks	60.4 Percent (event probability estimates) Interval 47.0 to 74.1	20.0 Percent (event probability estimates) Interval 8.9 to 41.6	—
Time-to-first Control of mUFC - % Event Probability Estimates 8 Weeks	79.4 Percent (event probability estimates) Interval 67.0 to 89.4	28.0 Percent (event probability estimates) Interval 14.5 to 49.9	—
Time-to-first Control of mUFC - % Event Probability Estimates 12 Weeks	NA Percent (event probability estimates) Not estimable as not reached	28.0 Percent (event probability estimates) Interval 14.5 to 49.9	—

SECONDARY outcome

Timeframe: up to 48 weeks

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug.

To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants n=73 Participants All Participants
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: from week 26 to week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).

To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.

The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants n=73 Participants All Participants
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC	NA days Not estimable as not reached due to the low number of events.	NA days Interval 116.0 to Not estimable as not reached due to the low number of events.	NA days Not estimable as not reached due to the low number of events.

SECONDARY outcome

Timeframe: week 26 and week 36

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).

Escape is defined as the first loss of control of urinary free cortisol (UFC) that meets all of the following criteria: 1. prior normalization of UFC has occurred (median urinary free cortisol (mUFC)≤ upper limit of normal (ULN)); 2. patient reached the highest tolerated dose of osilodrostat; 3. 2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN; 4. the loss of control of UFC is not related to a dose interruption or dose reduction due to safety reasons; 5. happened beyond Week 26 when the patients have a chance to be treated with doses as high as 30 mg bid.

• Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point.
• Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants n=73 Participants All Participants
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates % Event probability estimates (95% CI) at 26 Weeks	0 Percent (event probability estimates) Not estimable as not reached due to the low number of events	21.3 Percent (event probability estimates) Interval 5.7 to 61.9	15.6 Percent (event probability estimates) Interval 4.1 to 49.6
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates % Event probability estimates (95% CI) at 36 Weeks	0 Percent (event probability estimates) Not estimable as not reached due to the low number of events	NA Percent (event probability estimates) Not estimable as not reached due to the low number of events	15.6 Percent (event probability estimates) Interval 4.1 to 49.6

SECONDARY outcome

Timeframe: Baseline, week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=43 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)	0.8 g/cm2 Standard Deviation 0.16	0.8 g/cm2 Standard Deviation 0.14	—
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected FEMORAL NECK QC CORRECTED - week 48 - Actual change from baseline (n=28,19)	0.0 g/cm2 Standard Deviation 0.04	0.0 g/cm2 Standard Deviation 0.03	—
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected HIP QC CORRECTED - baseline - Actual (n=43,24)	0.9 g/cm2 Standard Deviation 0.14	0.9 g/cm2 Standard Deviation 0.11	—
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected HIP QC CORRECTED - week 48 - Actual change from baseline (n=28,19)	0.0 g/cm2 Standard Deviation 0.03	0.0 g/cm2 Standard Deviation 0.02	—
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)	1.0 g/cm2 Standard Deviation 0.15	1.0 g/cm2 Standard Deviation 0.18	—
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected SPINAL CORD QC CORRECTED - week 48 - Actual change from baseline (n=28,18)	0.0 g/cm2 Standard Deviation 0.04	0.0 g/cm2 Standard Deviation 0.04	—

SECONDARY outcome

Timeframe: Baseline, week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of -1.0 or higher"

Outcome measures

Measure	Osilodrostat Group n=43 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)	-1.2 scores on a scale Standard Deviation 1.06	-1.3 scores on a scale Standard Deviation 0.89	—
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected FEMORAL NECK QC CORRECTED - Actual change from baseline at week 48 (n=28,19)	0.1 scores on a scale Standard Deviation 0.30	0.1 scores on a scale Standard Deviation 0.21	—
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected HIP QC CORRECTED - baseline - Actual (n=43,24)	-0.7 scores on a scale Standard Deviation 1.08	-0.8 scores on a scale Standard Deviation 0.84	—
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected HIP QC CORRECTED - Actual change from baseline at week 48 (n=28,19)	0.0 scores on a scale Standard Deviation 0.27	0.0 scores on a scale Standard Deviation 0.16	—
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)	-1.2 scores on a scale Standard Deviation 1.10	-1.1 scores on a scale Standard Deviation 1.40	—
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected SPINAL CORD QC CORRECTED - Actual change from baseline at week 48 (n=28,18)	0.1 scores on a scale Standard Deviation 0.32	0.1 scores on a scale Standard Deviation 0.33	—

SECONDARY outcome

Timeframe: baseline, week 12, 36 and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).

Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and >ULN) at week 12, 36, 48 by treatment arms for all patients.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 12 Complete responders	37 Participants	2 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 12 Partial responders	2 Participants	2 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 12 Overall responders (complete or partial responders)	39 Participants	4 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 12 Non-responders	9 Participants	21 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 36 Complete responders	38 Participants	21 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 36 Partial responders	2 Participants	3 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 36 Overall responders (complete or partial responders)	40 Participants	24 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 36 Non-responders	8 Participants	1 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 48 Complete responders	34 Participants	16 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 48 Partial responders	5 Participants	3 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 48 Overall responders (complete or partial responders)	39 Participants	19 Participants	—
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 week 48 Non-responders	9 Participants	6 Participants	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=47 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Fasting Plasma Glucose Fasting glucose (mg/dL) - baseline - actual (n=47,24)	97.3 mg/dL Standard Deviation 18.14	91.4 mg/dL Standard Deviation 15.15	—
Change in Fasting Plasma Glucose Fasting glucose (mg/dL) - change from baseline at week 12 (n=44,23)	-4.3 mg/dL Standard Deviation 14.84	-1.7 mg/dL Standard Deviation 10.59	—
Change in Fasting Plasma Glucose Fasting glucose (mg/dL) - change from baseline at week 36 (n=43,24)	-6.7 mg/dL Standard Deviation 12.48	-1.1 mg/dL Standard Deviation 12.93	—
Change in Fasting Plasma Glucose Fasting glucose (mg/dL) - change from baseline at week 48 (n=41,21)	-5.6 mg/dL Standard Deviation 14.13	1.8 mg/dL Standard Deviation 13.92	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Hemoglobin A1C Hemoglobin A1C (%) - Actual - baseline	6.0 percentage of Hemoglobin A1C Standard Deviation 0.92	5.7 percentage of Hemoglobin A1C Standard Deviation 0.56	—
Change in Hemoglobin A1C Hemoglobin A1C (%) - Actual change from baseline at week 12 (n=46,24)	-0.2 percentage of Hemoglobin A1C Standard Deviation 0.44	0.0 percentage of Hemoglobin A1C Standard Deviation 0.27	—
Change in Hemoglobin A1C Hemoglobin A1C (%) Actual change from baseline at week 36 (n=44,25)	-0.2 percentage of Hemoglobin A1C Standard Deviation 0.54	-0.1 percentage of Hemoglobin A1C Standard Deviation 0.46	—
Change in Hemoglobin A1C Hemoglobin A1C (%) Actual change from baseline at week 48 (n=41,21)	-0.2 percentage of Hemoglobin A1C Standard Deviation 0.58	0.1 percentage of Hemoglobin A1C Standard Deviation 0.37	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=45 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Cholesterol Cholesterol (mmol/L) - actual - baseline (n=45,25)	5.7 mmol/L Standard Deviation 1.30	5.3 mmol/L Standard Deviation 1.15	—
Change in Cholesterol Cholesterol (mmol/L) - change from baseline at week 12 (n=44,24)	-0.8 mmol/L Standard Deviation 0.95	0.0 mmol/L Standard Deviation 0.65	—
Change in Cholesterol Cholesterol (mmol/L) - change from baseline at week 36 (n=44,25)	-1.0 mmol/L Standard Deviation 1.28	-0.4 mmol/L Standard Deviation 0.89	—
Change in Cholesterol Cholesterol (mmol/L) - change from baseline at week 48 (n=42,22)	-0.6 mmol/L Standard Deviation 1.36	-0.4 mmol/L Standard Deviation 1.18	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=45 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in LDL Cholesterol LDL Cholesterol (mmol/L) - Actual - baseline (n=45,24)	3.4 mmol/L Standard Deviation 1.12	3.0 mmol/L Standard Deviation 1.07	—
Change in LDL Cholesterol LDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,23)	-0.5 mmol/L Standard Deviation 0.80	0.1 mmol/L Standard Deviation 0.47	—
Change in LDL Cholesterol LDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,24)	-0.6 mmol/L Standard Deviation 1.08	-0.2 mmol/L Standard Deviation 0.70	—
Change in LDL Cholesterol LDL Cholesterol (mmol/L) - Actual change from baseline at week 48 (n=41,21)	-0.5 mmol/L Standard Deviation 0.99	-0.2 mmol/L Standard Deviation 0.92	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=45 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in HDL Cholesterol HDL Cholesterol (mmol/L) - Actual - baseline (n=45,25)	1.6 mmol/L Standard Deviation 0.35	1.5 mmol/L Standard Deviation 0.38	—
Change in HDL Cholesterol HDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,24)	-0.3 mmol/L Standard Deviation 0.29	0.0 mmol/L Standard Deviation 0.28	—
Change in HDL Cholesterol HDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,25)	-0.3 mmol/L Standard Deviation 0.27	-0.2 mmol/L Standard Deviation 0.25	—
Change in HDL Cholesterol HDL Cholesterol (mmol/L) - Actual - change from baseline at week 48 (n=42,22)	-0.2 mmol/L Standard Deviation 0.27	-0.1 mmol/L Standard Deviation 0.29	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=45 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Triglyceride Triglyceride (mmol/L) - Actual - baseline (n=45,25)	1.5 mmol/L Standard Deviation 0.79	1.7 mmol/L Standard Deviation 0.85	—
Change in Triglyceride Triglyceride (mmol/L) - Actual change from baseline at week 12(n=44,24)	0.0 mmol/L Standard Deviation 0.53	-0.2 mmol/L Standard Deviation 0.54	—
Change in Triglyceride Triglyceride (mmol/L) - Actual change from baseline at week 36 (n=44,25)	-0.1 mmol/L Standard Deviation 0.55	-0.1 mmol/L Standard Deviation 0.71	—
Change in Triglyceride Triglyceride (mmol/L) - Actual change from baseline at week 48 (n=42,22)	0.1 mmol/L Standard Deviation 0.92	-0.2 mmol/L Standard Deviation 0.62	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=46 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Standing Systolic Blood Pressure Standing Systolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)	132.4 mmHg Standard Deviation 19.16	130.0 mmHg Standard Deviation 17.72	—
Change in Standing Systolic Blood Pressure Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)	-7.1 mmHg Standard Deviation 18.08	-0.9 mmHg Standard Deviation 11.77	—
Change in Standing Systolic Blood Pressure Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	-9.3 mmHg Standard Deviation 19.09	-7.0 mmHg Standard Deviation 21.04	—
Change in Standing Systolic Blood Pressure Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	-9.1 mmHg Standard Deviation 19.45	-11.0 mmHg Standard Deviation 22.30	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Supine Systolic Blood Pressure Supine Systolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)	131.7 mmHg Standard Deviation 18.33	127.8 mmHg Standard Deviation 18.69	—
Change in Supine Systolic Blood Pressure Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)	-8.0 mmHg Standard Deviation 17.54	2.3 mmHg Standard Deviation 15.91	—
Change in Supine Systolic Blood Pressure Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	-9.7 mmHg Standard Deviation 19.88	-4.4 mmHg Standard Deviation 17.43	—
Change in Supine Systolic Blood Pressure Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=42,22)	-7.4 mmHg Standard Deviation 19.38	-7.5 mmHg Standard Deviation 18.91	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=46 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Standing Diastolic Blood Pressure Standing Diastolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)	87.2 mmHg Standard Deviation 12.74	88.2 mmHg Standard Deviation 10.83	—
Change in Standing Diastolic Blood Pressure Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)	-4.8 mmHg Standard Deviation 11.14	-1.4 mmHg Standard Deviation 9.84	—
Change in Standing Diastolic Blood Pressure Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	-6.0 mmHg Standard Deviation 12.09	-4.4 mmHg Standard Deviation 13.98	—
Change in Standing Diastolic Blood Pressure Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	-4.4 mmHg Standard Deviation 11.64	-3.9 mmHg Standard Deviation 13.36	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Supine Diastolic Blood Pressure Supine Diastolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)	83.9 mmHg Standard Deviation 11.71	81.4 mmHg Standard Deviation 11.21	—
Change in Supine Diastolic Blood Pressure Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)	-6.3 mmHg Standard Deviation 11.05	-0.1 mmHg Standard Deviation 8.31	—
Change in Supine Diastolic Blood Pressure Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=44,25)	-7.7 mmHg Standard Deviation 11.92	-3.4 mmHg Standard Deviation 11.37	—
Change in Supine Diastolic Blood Pressure Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	-5.8 mmHg Standard Deviation 11.60	-3.7 mmHg Standard Deviation 10.92	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Weight Weight (kg) - Actual - baseline (n=48,25)	78.8 kg Standard Deviation 17.46	77.3 kg Standard Deviation 16.90	—
Change in Weight Weight (kg) - Actual change from baseline at week 12(n=46,24)	-0.8 kg Standard Deviation 3.09	-0.1 kg Standard Deviation 2.12	—
Change in Weight Weight (kg) - Actual change from baseline at week 36 (n=44,25)	-3.0 kg Standard Deviation 5.53	-4.8 kg Standard Deviation 5.63	—
Change in Weight Weight (kg) - Actual change from baseline at week 48 (n=42,22)	-3.6 kg Standard Deviation 6.53	-5.5 kg Standard Deviation 6.38	—

SECONDARY outcome

Timeframe: Baseline, weeks 12, 36, and 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change in Waist Circumference Waist Circumference (cm)) - Actual - baseline (n=48,25)	102.5 cm Standard Deviation 17.01	103.4 cm Standard Deviation 15.52	—
Change in Waist Circumference Waist Circumference (cm) - Actual change from baseline at week 12 (n=46,24)	-1.0 cm Standard Deviation 4.43	-0.5 cm Standard Deviation 3.35	—
Change in Waist Circumference Waist Circumference (cm)) - Actual change from baseline at week 36 (n=44,25)	-3.9 cm Standard Deviation 6.36	-2.1 cm Standard Deviation 8.60	—
Change in Waist Circumference Waist Circumference (cm) - Actual change from baseline at week 48 (n=42,22)	-4.1 cm Standard Deviation 6.10	-5.3 cm Standard Deviation 5.68	—

SECONDARY outcome

Timeframe: baseline, Week 12, Week 36 and Week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Values for improvement or no change are reported. Hirsutism applies only to females, and thus the number analyzed is lower than for other clinical signs.

Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing's disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported

Outcome measures

Measure	Osilodrostat Group n=42 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Proximal Muscle Atrophy - week 48 (n=39,22)	35 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Facial Rubor - week 12 (n=42,20)	36 Participants	19 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Hirsutism - week 12 (n=36,16)	34 Participants	15 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Striae - week 12 (n=41,20)	38 Participants	19 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Supraclavicular Fat Pad - week 12 (n=42,21)	41 Participants	19 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Dorsal Fat Pad - week 12 (n=41,21)	35 Participants	17 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Proximal Muscle Atrophy - week 12 (n=42,21)	38 Participants	20 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Central Obesity - week 12 (n=42,21)	37 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Ecchymoses - week 12 (n=42,20)	39 Participants	19 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Facial Rubor - week 36 (n=41,23)	39 Participants	22 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Hirsutism - week 36 (n=34,17)	28 Participants	16 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Striae - week 36 (n=40,23)	38 Participants	23 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Supraclavicular Fat Pad - week 36 (n=41,24)	40 Participants	24 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Dorsal Fat Pad - week 36 (n=40,24)	36 Participants	22 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Proximal Muscle Atrophy - week 36 (n=41,23)	37 Participants	22 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Central Obesity - week 36 (n=41,24)	37 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Ecchymoses - week 36 (n=41,23)	39 Participants	22 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Facial Rubor - week 48 (n=39,21)	37 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Hirsutism - week 48 (n=33,15)	29 Participants	15 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Striae - week 48 (n=38,21)	38 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Supraclavicular Fat Pad - week 48 (n=39,22)	38 Participants	22 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Dorsal Fat Pad - week 48 (n=38,22)	36 Participants	20 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Central Obesity - week 48 (n=39,22)	35 Participants	21 Participants	—
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease Ecchymoses - week 48 (n=39,21)	38 Participants	20 Participants	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').

The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual - Baseline (n=48,25)	49.1 Scores on a scale Standard Deviation 19.60	56.9 Scores on a scale Standard Deviation 18.99	—
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 12 (n=46,24)	6.2 Scores on a scale Standard Deviation 14.85	8.6 Scores on a scale Standard Deviation 12.06	—
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 48 (n=42,22)	11.7 Scores on a scale Standard Deviation 16.30	12.8 Scores on a scale Standard Deviation 14.24	—
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 12 at Week 36 (n=44,23)	4.7 Scores on a scale Standard Deviation 9.01	-0.5 Scores on a scale Standard Deviation 9.99	—
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 36 at Week 48 (n=42,22)	0.1 Scores on a scale Standard Deviation 8.43	2.5 Scores on a scale Standard Deviation 7.52	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').

The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual - baseline (n=48,25)	49.9 Scores on a scale Standard Deviation 20.34	56.7 Scores on a scale Standard Deviation 21.11	—
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 12 (n=46,24)	6.1 Scores on a scale Standard Deviation 17.21	9.6 Scores on a scale Standard Deviation 13.61	—
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 48 (n=42,22)	11.1 Scores on a scale Standard Deviation 17.84	13.0 Scores on a scale Standard Deviation 16.30	—
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 12 at Week 36 (n=44,23)	4.1 Scores on a scale Standard Deviation 9.94	-1.3 Scores on a scale Standard Deviation 12.36	—
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 36 at Week 48 (n=42,22)	0.1 Scores on a scale Standard Deviation 9.60	2.4 Scores on a scale Standard Deviation 8.96	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').

The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual - baseline (n=48,25)	46.9 Scores on a scale Standard Deviation 22.32	57.7 Scores on a scale Standard Deviation 21.91	—
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 12 (n=46,24)	6.3 Scores on a scale Standard Deviation 13.29	5.6 Scores on a scale Standard Deviation 13.38	—
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Baseline at Week 48 (n=42,22)	13.3 Scores on a scale Standard Deviation 19.83	12.1 Scores on a scale Standard Deviation 15.59	—
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 12 at Week 36 (n=44,23)	6.6 Scores on a scale Standard Deviation 12.40	2.2 Scores on a scale Standard Deviation 12.11	—
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment Actual Change from Week 36 at Week 48 (n=42,22)	23.59 Scores on a scale Standard Deviation 11.27	2.7 Scores on a scale Standard Deviation 12.17	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

EQ-5D-5L Utility Index:

The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an "unconscious" health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in EQ-5D-5L Utility Index Actual Change from Week 12 at Week 36 (n=44,23)	0.025 Scores on a scale Standard Deviation 0.1283	0.010 Scores on a scale Standard Deviation 0.0487	—
Change From Baseline in EQ-5D-5L Utility Index Actual Change from Week 36 at Week 48 (n=42,22)	0.023 Scores on a scale Standard Deviation 0.0762	-0.008 Scores on a scale Standard Deviation 0.0367	—
Change From Baseline in EQ-5D-5L Utility Index Actual - baseline (n=48,24)	0.825 Scores on a scale Standard Deviation 0.1486	0.903 Scores on a scale Standard Deviation 0.1125	—
Change From Baseline in EQ-5D-5L Utility Index Actual Change from Baseline at Week 12 (n=46,24)	-0.000 Scores on a scale Standard Deviation 0.1402	0.021 Scores on a scale Standard Deviation 0.0771	—
Change From Baseline in EQ-5D-5L Utility Index Actual Change from Baseline at Week 48 (n=42,22)	0.044 Scores on a scale Standard Deviation 0.1393	0.033 Scores on a scale Standard Deviation 0.0826	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100='the best health you can imagine' and 0='the worst health you can imagine'. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=24 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in EQ-5D VAS Actual Change from Baseline at week 12 (n=46,24)	0.5 Scores on a scale Standard Deviation 13.57	-0.3 Scores on a scale Standard Deviation 10.52	—
Change From Baseline in EQ-5D VAS Actual - baseline (n=48,23)	70.3 Scores on a scale Standard Deviation 17.26	76.7 Scores on a scale Standard Deviation 17.88	—
Change From Baseline in EQ-5D VAS Actual Change from Baseline at week 48 (n=42,22)	9.4 Scores on a scale Standard Deviation 13.13	5.8 Scores on a scale Standard Deviation 9.45	—
Change From Baseline in EQ-5D VAS Actual Change from Week 12 at Week 36 (n=44,23)	6.0 Scores on a scale Standard Deviation 11.08	3.7 Scores on a scale Standard Deviation 9.29	—
Change From Baseline in EQ-5D VAS Actual Change from Week 36 at Week 48 (n=42,22)	3.2 Scores on a scale Standard Deviation 8.40	-0.8 Scores on a scale Standard Deviation 4.44	—

SECONDARY outcome

Timeframe: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. A reduction from baseline in BDI-II is indicative of an improvement.

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Beck Depression Inventory-II - Total Score Derived Actual - baseline (n=48,25)	12.2 Scores on a scale Standard Deviation 10.22	8.4 Scores on a scale Standard Deviation 7.82	—
Change From Baseline in Beck Depression Inventory-II - Total Score Derived Actual Change from Baseline at Week 12 (n=46,24)	-1.4 Scores on a scale Standard Deviation 7.99	-3.9 Scores on a scale Standard Deviation 5.42	—
Change From Baseline in Beck Depression Inventory-II - Total Score Derived Actual Change from Baseline at Week 48 (n=42,22)	-4.3 Scores on a scale Standard Deviation 7.52	-4.0 Scores on a scale Standard Deviation 7.70	—
Change From Baseline in Beck Depression Inventory-II - Total Score Derived Actual Change from Week 12 at Week 36 (n=44,23)	-2.0 Scores on a scale Standard Deviation 4.70	0.6 Scores on a scale Standard Deviation 6.29	—
Change From Baseline in Beck Depression Inventory-II - Total Score Derived Actual Change from Week 36 at Week 48 (n=42,22)	-1.1 Scores on a scale Standard Deviation 4.83	-0.4 Scores on a scale Standard Deviation 3.39	—

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 36, Week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in serum cortisol

Outcome measures

Measure	Osilodrostat Group n=47 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Serum Cortisol Baseline - actual (n=47,25)	565.8 nmol/L Standard Deviation 169.01	486.1 nmol/L Standard Deviation 198.12	—
Change From Baseline in Serum Cortisol Actual Change from Baseline at Week 12 (n=44,24)	-276.0 nmol/L Standard Deviation 178.43	73.0 nmol/L Standard Deviation 185.29	—
Change From Baseline in Serum Cortisol Actual Change from Baseline at Week 36 (n=42,25)	-267.0 nmol/L Standard Deviation 174.18	-157.8 nmol/L Standard Deviation 225.56	—
Change From Baseline in Serum Cortisol Actual Change from Baseline at Week 48 (n=41,22)	-210.7 nmol/L Standard Deviation 161.07	-131.0 nmol/L Standard Deviation 236.88	—

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 36, Week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in late night saliva cortisol (nmol/L)

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Late Night Saliva Cortisol Baseline - actual (n=48,25)	11.7 nmol/L Standard Deviation 28.68	9.0 nmol/L Standard Deviation 6.74	—
Change From Baseline in Late Night Saliva Cortisol Actual Change from Baseline at Week 12 (n=46,24)	-8.5 nmol/L Standard Deviation 29.60	1.3 nmol/L Standard Deviation 8.87	—
Change From Baseline in Late Night Saliva Cortisol Actual Change from Baseline at Week 36 (n=42,25)	-9.6 nmol/L Standard Deviation 30.82	-5.8 nmol/L Standard Deviation 6.84	—
Change From Baseline in Late Night Saliva Cortisol Actual Change from Baseline at Week 48 (n=41,22)	-9.3 nmol/L Standard Deviation 29.05	-5.0 nmol/L Standard Deviation 5.75	—

SECONDARY outcome

Timeframe: Baseline, Week 12, Week 36, Week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in morning saliva cortisol (nmol/L)

Outcome measures

Measure	Osilodrostat Group n=48 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=25 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Morning Saliva Cortisol Baseline - actual (n=48,25)	17.2 nmol/L Standard Deviation 30.00	14.1 nmol/L Standard Deviation 12.29	—
Change From Baseline in Morning Saliva Cortisol Actual Change from Baseline at Week 12 (n=46,24)	-11.6 nmol/L Standard Deviation 30.05	-0.3 nmol/L Standard Deviation 11.21	—
Change From Baseline in Morning Saliva Cortisol Actual Change from Baseline at Week 36 (n=40,25)	-11.8 nmol/L Standard Deviation 30.74	-9.3 nmol/L Standard Deviation 11.82	—
Change From Baseline in Morning Saliva Cortisol Actual Change from Baseline at Week 48 (n=41,22)	-11.8 nmol/L Standard Deviation 31.74	-6.0 nmol/L Standard Deviation 10.97	—

SECONDARY outcome

Timeframe: Baseline, Week 26, Week 48

Population: Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.

Change from baseline in hair cortisol levels

Outcome measures

Measure	Osilodrostat Group n=19 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=9 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants All Participants
Change From Baseline in Hair Cortisol Levels Baseline - actual (n=19,9)	38.9 pg/mg Standard Deviation 37.48	10.5 pg/mg Standard Deviation 10.47	—
Change From Baseline in Hair Cortisol Levels Actual Change from Baseline at Week 26 (n=16,7)	-15.8 pg/mg Standard Deviation 32.83	-1.1 pg/mg Standard Deviation 12.72	—
Change From Baseline in Hair Cortisol Levels Actual Change from Baseline at Week 48 (n=14,6)	-17.8 pg/mg Standard Deviation 26.66	-9.7 pg/mg Standard Deviation 8.90	—

SECONDARY outcome

Timeframe: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26

Population: Pharmacokinetic Analysis Set (PAS): comprises all participants who received at least one dose of osilodrostat and have at least one evaluable pharmacokinetic concentration (post-first-dose) at any visit. The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Note that participants took several different doses of study medication in this dose titration study.

Plasma osilodrostat concentrations (ng/mL)

Outcome measures

Measure	Osilodrostat Group n=16 Participants Participants in this arm were randomized to receive the study drug, osilodrostat, followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration).	Osilodrostat Placebo Group n=55 Participants Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration).	All Participants n=29 Participants All Participants
Plasma Osilodrostat Concentrations (ng/mL) week 1 1-2 hrs post dose (n=1,43,0)	3.85 ng/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation is not applicable when 1 participant is analyzed	7.29 ng/mL Geometric Coefficient of Variation 101.0	—
Plasma Osilodrostat Concentrations (ng/mL) week 2 0 hrs pre dose (n=0,41,0)	—	2.19 ng/mL Geometric Coefficient of Variation 107.5	—
Plasma Osilodrostat Concentrations (ng/mL) week 2 1-2 hrs post dose (n=0,42,0)	—	9.76 ng/mL Geometric Coefficient of Variation 53.4	—
Plasma Osilodrostat Concentrations (ng/mL) week 5 pre dose (n=2,18,17)	0.576 ng/mL Geometric Coefficient of Variation 141.9	2.07 ng/mL Geometric Coefficient of Variation 82.1	5.06 ng/mL Geometric Coefficient of Variation 109.6
Plasma Osilodrostat Concentrations (ng/mL) week 5 1-2 hrs post dose (n=2,9,29)	3.64 ng/mL Geometric Coefficient of Variation 60.5	11.1 ng/mL Geometric Coefficient of Variation 31.5	25.8 ng/mL Geometric Coefficient of Variation 84.4
Plasma Osilodrostat Concentrations (ng/mL) week 8 0 hrs pre dose (n=2,4,13)	0.971 ng/mL Geometric Coefficient of Variation 76.7	2.64 ng/mL Geometric Coefficient of Variation 53.7	4.99 ng/mL Geometric Coefficient of Variation 55.6
Plasma Osilodrostat Concentrations (ng/mL) week 8 1-2 hrs post dose (n=3,6,14)	3.70 ng/mL Geometric Coefficient of Variation 47.6	8.31 ng/mL Geometric Coefficient of Variation 45.6	23.3 ng/mL Geometric Coefficient of Variation 68.1
Plasma Osilodrostat Concentrations (ng/mL) week 12 0 hrs pre dose (n=2,8,11)	1.55 ng/mL Geometric Coefficient of Variation 3.7	2.45 ng/mL Geometric Coefficient of Variation 39.2	5.03 ng/mL Geometric Coefficient of Variation 74.6
Plasma Osilodrostat Concentrations (ng/mL) week 26 0 hrs pre dose (n=12,13,10)	1.77 ng/mL Geometric Coefficient of Variation 86.4	2.12 ng/mL Geometric Coefficient of Variation 77.8	6.89 ng/mL Geometric Coefficient of Variation 85.1
Plasma Osilodrostat Concentrations (ng/mL) week 26 1-2 hrs post dose (n=16,14,10)	5.28 ng/mL Geometric Coefficient of Variation 31.5	8.04 ng/mL Geometric Coefficient of Variation 50.7	33.1 ng/mL Geometric Coefficient of Variation 31.4
Plasma Osilodrostat Concentrations (ng/mL) week 12 1-2 hrs post dose (n=4,34,0)	4.93 ng/mL Geometric Coefficient of Variation 32.0	11.7 ng/mL Geometric Coefficient of Variation 78.9	—
Plasma Osilodrostat Concentrations (ng/mL) week 14 0 hrs pre dose (n=4,55,0)	0.974 ng/mL Geometric Coefficient of Variation 129.7	1.96 ng/mL Geometric Coefficient of Variation 74.9	—
Plasma Osilodrostat Concentrations (ng/mL) week 14 1-2 hrs post dose (n=6,49,6)	3.74 ng/mL Geometric Coefficient of Variation 161.4	9.69 ng/mL Geometric Coefficient of Variation 35.8	22.6 ng/mL Geometric Coefficient of Variation 37.8
Plasma Osilodrostat Concentrations (ng/mL) week 20 0 hrs pre dose (n=10,19,15)	1.63 ng/mL Geometric Coefficient of Variation 71.1	1.95 ng/mL Geometric Coefficient of Variation 68.1	6.21 ng/mL Geometric Coefficient of Variation 74.3
Plasma Osilodrostat Concentrations (ng/mL) week 20 1-2 hrs post dose (n=13,18,12)	6.09 ng/mL Geometric Coefficient of Variation 27.3	8.66 ng/mL Geometric Coefficient of Variation 94.0	26.0 ng/mL Geometric Coefficient of Variation 99.3

Adverse Events

Placebo Controlled Period - Osilodrostat Arm.

Serious events: 2 serious events

Other events: 45 other events

Deaths: 0 deaths

Placebo Controlled Period - Placebo Arm.

Serious events: 1 serious events

Other events: 21 other events

Deaths: 0 deaths

Overall Study Period - Osilodrostat Arm.

Serious events: 10 serious events

Other events: 47 other events

Deaths: 0 deaths

Overall Study Period - Placebo Arm.

Serious events: 0 serious events

Other events: 24 other events

Deaths: 0 deaths

Overall Study Period - All Participants.

Serious events: 10 serious events

Other events: 71 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Controlled Period - Osilodrostat Arm. n=48 participants at risk All data while on osilodrostat treatment up to week 12 in participants initially randomized to osilodrostat.	Placebo Controlled Period - Placebo Arm. n=25 participants at risk All data while on placebo treatment up to week 12 in participants initially randomized to placebo.	Overall Study Period - Osilodrostat Arm. n=48 participants at risk All data while on osilodrostat treatment from randomization up to end-of-study in participants initially randomized to osilodrostat.	Overall Study Period - Placebo Arm. n=25 participants at risk All data while on osilodrostat treatment from Week 12 up to end-of-study in participants initially randomized to placebo.	Overall Study Period - All Participants. n=73 participants at risk All data while on osilodrostat treatment up to end-of-study in all randomized participants, excluding data while on placebo from participants initially randomized to placebo.
Endocrine disorders Adrenal insufficiency	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Abdominal pain	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Erosive duodenitis	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Nausea	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Anal abscess	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Dengue fever	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Pneumonia	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Pyelonephritis	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Injury, poisoning and procedural complications Conjunctival laceration	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Injury, poisoning and procedural complications Eye injury	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Injury, poisoning and procedural complications Retinal injury	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Injury, poisoning and procedural complications Wrist fracture	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Electrocardiogram QT prolonged	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Electrocardiogram T wave inversion	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Periarthritis	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Nervous system disorders Cerebral vascular occlusion	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Nervous system disorders Hemiparesis	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Obstructive airways disorder	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Hypertension	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Hypotension	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Orthostatic hypotension	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	1.4% 1/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.

Other adverse events

Measure	Placebo Controlled Period - Osilodrostat Arm. n=48 participants at risk All data while on osilodrostat treatment up to week 12 in participants initially randomized to osilodrostat.	Placebo Controlled Period - Placebo Arm. n=25 participants at risk All data while on placebo treatment up to week 12 in participants initially randomized to placebo.	Overall Study Period - Osilodrostat Arm. n=48 participants at risk All data while on osilodrostat treatment from randomization up to end-of-study in participants initially randomized to osilodrostat.	Overall Study Period - Placebo Arm. n=25 participants at risk All data while on osilodrostat treatment from Week 12 up to end-of-study in participants initially randomized to placebo.	Overall Study Period - All Participants. n=73 participants at risk All data while on osilodrostat treatment up to end-of-study in all randomized participants, excluding data while on placebo from participants initially randomized to placebo.
Blood and lymphatic system disorders Anaemia	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Cardiac disorders Palpitations	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.7% 2/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Cardiac disorders Tachycardia	12.5% 6/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.7% 8/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.3% 9/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Endocrine disorders Adrenal insufficiency	14.6% 7/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	25.0% 12/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.0% 6/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.7% 18/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Abdominal distension	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Abdominal pain	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	20.8% 10/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.4% 12/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Abdominal pain upper	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Diarrhoea	20.8% 10/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	29.2% 14/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	23.3% 17/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Nausea	31.2% 15/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	45.8% 22/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	20.0% 5/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	37.0% 27/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Gastrointestinal disorders Vomiting	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	18.8% 9/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.3% 9/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
General disorders Asthenia	22.9% 11/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	31.2% 15/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	23.3% 17/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
General disorders Fatigue	25.0% 12/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	47.9% 23/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.0% 6/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	39.7% 29/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
General disorders Oedema peripheral	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	25.0% 12/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.4% 12/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
General disorders Pyrexia	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.8% 5/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Gastroenteritis	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Influenza	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Laryngitis	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Nasopharyngitis	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Oral herpes	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Pharyngitis	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.2% 6/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Upper respiratory tract infection	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	25.0% 12/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	21.9% 16/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Infections and infestations Urinary tract infection	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.7% 8/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.4% 12/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Injury, poisoning and procedural complications Fall	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Alanine aminotransferase increased	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.2% 6/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Aspartate aminotransferase increased	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.8% 5/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Blood cholesterol increased	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Blood potassium decreased	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Blood pressure increased	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Blood testosterone increased	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	27.1% 13/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	20.0% 5/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.7% 18/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Electrocardiogram T wave inversion	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.7% 2/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Renin increased	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.8% 5/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Investigations Weight decreased	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Metabolism and nutrition disorders Decreased appetite	37.5% 18/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	50.0% 24/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	40.0% 10/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	46.6% 34/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Metabolism and nutrition disorders Hypercholesterolaemia	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.5% 6/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.2% 6/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Metabolism and nutrition disorders Hypoglycaemia	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Metabolism and nutrition disorders Hypokalaemia	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.5% 6/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	11.0% 8/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Arthralgia	35.4% 17/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	54.2% 26/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	28.0% 7/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	45.2% 33/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Back pain	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.7% 8/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	13.7% 10/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Muscle spasms	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Muscular weakness	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.2% 6/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Myalgia	20.8% 10/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	31.2% 15/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.7% 18/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Musculoskeletal and connective tissue disorders Pain in extremity	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.8% 5/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Nervous system disorders Dizziness	18.8% 9/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	39.6% 19/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	30.1% 22/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Nervous system disorders Headache	14.6% 7/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	24.0% 6/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	35.4% 17/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	32.0% 8/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	34.2% 25/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Nervous system disorders Paraesthesia	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Psychiatric disorders Anxiety	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Renal and urinary disorders Renal colic	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.7% 2/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	2.7% 2/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Respiratory, thoracic and mediastinal disorders Nasal congestion	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.1% 3/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Acne	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	18.8% 9/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	13.7% 10/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Alopecia	2.1% 1/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.8% 5/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Dry skin	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Eczema	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Hirsutism	0.00% 0/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.5% 6/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	9.6% 7/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Pruritus	12.5% 6/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	14.6% 7/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	8.0% 2/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.3% 9/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	4.2% 2/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	6.2% 3/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	5.5% 4/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Hypertension	14.6% 7/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	28.0% 7/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	25.0% 12/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.0% 4/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	21.9% 16/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Hypotension	10.4% 5/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	18.8% 9/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	12.0% 3/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	16.4% 12/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Vascular disorders Orthostatic hypotension	8.3% 4/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	0.00% 0/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	14.6% 7/48 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	4.0% 1/25 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.	11.0% 8/73 • Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: + 1 862 778 8300

Email: Novartis.email@Novartis.com

Results disclosure agreements

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

Restriction type: OTHER