Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease (LINC-4)

• ClinicalTrials.gov Identifier: NCT02697734
• Recruitment Status: Completed
• First Posted: March 3, 2016
• Results First Posted: October 19, 2021
• Last Update Posted: November 1, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Cushing's Disease
• Interventions: Drug: osilodrostat; Drug: osilodrostat Placebo
• Enrollment: 73

Participant Flow

Recruitment Details
Pre-assignment Details	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.

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description	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).	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).
Period Title: Core Phase - up to Week 48
Started [1]	48	25
Completed	42	23
Not Completed	6	2
Reason Not Completed
Withdrawal by Subject	4	0
Adverse Event	1	2
Physician Decision	1	0
[1] treated
Period Title: Optional Extension Phase
Started	38	22
Completed	33	20
Not Completed	5	2
Reason Not Completed
Adverse Event	5	1
Physician Decision	0	1

Baseline Characteristics

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group	Total
Arm/Group Description		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).	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 of all reporting groups
Overall Number of Baseline Participants		48	25	73
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants	25 participants	73 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	46 95.8%	25 100.0%	71 97.3%
	>=65 years	2 4.2%	0 0.0%	2 2.7%
Age, Continuous [1]; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	48 participants	25 participants	73 participants
		42.3 (13.82)	38.9 (12.33)	41.2 (13.35)
		[1] Measure Analysis Population Description: Participants
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants	25 participants	73 participants
	Female	43 89.6%	18 72.0%	61 83.6%
	Male	5 10.4%	7 28.0%	12 16.4%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	48 participants	25 participants	73 participants
	American Indian or Alaska Native	1 2.1%	0 0.0%	1 1.4%
	Asian	9 18.8%	8 32.0%	17 23.3%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	2 4.2%	0 0.0%	2 2.7%
	White	34 70.8%	15 60.0%	49 67.1%
	More than one race	0 0.0%	1 4.0%	1 1.4%
	Unknown or Not Reported	2 4.2%	1 4.0%	3 4.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Randomized Participants With a Complete Response
Description	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.
Time Frame	at Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	48	25
Measure Type: Count of Participants; Unit of Measure: Participants
	37 77.1%	2 8.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Osilodrostat Group, Osilodrostat Placebo Group
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	43.4
	Confidence Interval	(2-Sided) 95%; 7.06 to 343.19
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Participants With mUFC ≤ ULN at Week 36
Description	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.
Time Frame	At Week 36

Outcome Measure Data

Analysis Population Description

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.'

Arm/Group Title	All Participants Combined
Arm/Group Description:	Consisted of all randomized participants who received at least one dose of osilodrostat.
Overall Number of Participants Analyzed	73
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percentage of participants
	80.8; (69.9 to 89.1)

3. Secondary Outcome

Title	Change From Baseline in mUFC
Description	To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
Time Frame	Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: nmol/24hr
actual - baseline	Number Analyzed	48 participants	25 participants
		421.4 (291.25)	451.5 (535.09)
change from baseline at week 2 (n=47,24)	Number Analyzed	47 participants	24 participants
		-139.3 (404.45)	164.9 (543.82)
change from baseline at week 5 (n=46,25)	Number Analyzed	46 participants	25 participants
		-252.8 (338.48)	-37.3 (280.84)
change from baseline at week 8 (n=44,25)	Number Analyzed	44 participants	25 participants
		-330.2 (303.35)	-35.0 (325.30)
change from baseline at week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-332.7 (315.50)	-49.1 (332.29)
change from baseline at week 14 (n=45,25)	Number Analyzed	45 participants	25 participants
		-191.7 (446.77)	-209.5 (407.62)
change from baseline at week 17 (n=45,25)	Number Analyzed	45 participants	25 participants
		-238.8 (362.46)	-284.5 (557.47)
change from baseline at week 20 (n=44,24)	Number Analyzed	44 participants	24 participants
		-294.5 (316.65)	-355.1 (538.96)
change from baseline at week 23 (n=44,25)	Number Analyzed	44 participants	25 participants
		-314.1 (307.60)	-387.8 (466.15)
change from baseline at week 26 (n=43,25)	Number Analyzed	43 participants	25 participants
		-345.2 (306.35)	-365.4 (458.28)
change from baseline at week 29 (n=43,25)	Number Analyzed	43 participants	25 participants
		-331.4 (299.63)	-391.4 (534.57)
change from baseline at week 32 (n=44,25)	Number Analyzed	44 participants	25 participants
		-341.3 (298.96)	-298.0 (655.52)
change from baseline at week 36 (n=43,25)	Number Analyzed	43 participants	25 participants
		-349.6 (310.46)	-372.9 (519.17)
change from baseline at week 40 (n=43,23)	Number Analyzed	43 participants	23 participants
		-333.4 (307.63)	-364.7 (542.28)
change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-325.1 (314.30)	-367.5 (554.16)
change from baseline at week 60 (n=33,19)	Number Analyzed	33 participants	19 participants
		-364.4 (339.57)	-335.2 (571.06)
change from baseline at week 72 (n=31,17)	Number Analyzed	31 participants	17 participants
		-381.2 (338.68)	-372.4 (624.69)
change from baseline at week 84 (n=23,17)	Number Analyzed	23 participants	17 participants
		-398.6 (377.81)	-196.0 (916.83)
change from baseline at week 96 (n=6,7)	Number Analyzed	6 participants	7 participants
		-414.5 (347.83)	-616.4 (881.92)

4. Secondary Outcome

Title	Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
Description	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.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	48	25
Measure Type: Count of Participants; Unit of Measure: Participants
	45 93.8%	8 32.0%

5. Secondary Outcome

Title	Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
Description	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).
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	48	25
Median (95% Confidence Interval); Unit of Measure: Days
	35; (34.0 to 52.0)	NA [1]; (87.0 to NA)

[1]

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.

6. Secondary Outcome

Title	Time-to-first Control of mUFC - % Event Probability Estimates
Description	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.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	48	25
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percent (event probability estimates)
2 Weeks	25.0; (15.0 to 39.8)	16.0; (6.3 to 37.2)
5 Weeks	60.4; (47.0 to 74.1)	20.0; (8.9 to 41.6)
8 Weeks	79.4; (67.0 to 89.4)	28.0; (14.5 to 49.9)
12 Weeks	NA [1]; (NA to NA)	28.0; (14.5 to 49.9)

[1]

Not estimable as not reached

7. Secondary Outcome

Title	Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
Description	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.
Time Frame	up to 48 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group	All Participants
Arm/Group Description:	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).	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
Overall Number of Participants Analyzed	48	25	73
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	2 8.0%	2 2.7%

8. Secondary Outcome

Title	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
Description	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).
Time Frame	from week 26 to week 48

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group	All Participants
Arm/Group Description:	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).	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
Overall Number of Participants Analyzed	48	25	73
Median (95% Confidence Interval); Unit of Measure: days
	NA [1]; (NA to NA)	NA [1]; (116.0 to NA)	NA [1]; (NA to NA)

[1]

Not estimable as not reached due to the low number of events.

9. Secondary Outcome

Title	Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
Description	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.
Time Frame	week 26 and week 36

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group	All Participants
Arm/Group Description:	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).	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
Overall Number of Participants Analyzed	48	25	73
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percent (event probability estimates)
% Event probability estimates (95% CI) at 26 Weeks	0 [1]; (NA to NA)	21.3; (5.7 to 61.9)	15.6; (4.1 to 49.6)
% Event probability estimates (95% CI) at 36 Weeks	0 [1]; (NA to NA)	NA [1]; (NA to NA)	15.6; (4.1 to 49.6)

[1]

Not estimable as not reached due to the low number of events

10. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		43	24
Mean (Standard Deviation); Unit of Measure: g/cm2
FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)	Number Analyzed	43 participants	24 participants
		0.8 (0.16)	0.8 (0.14)
FEMORAL NECK QC CORRECTED - week 48 - Actual change from baseline (n=28,19)	Number Analyzed	28 participants	19 participants
		0.0 (0.04)	0.0 (0.03)
HIP QC CORRECTED - baseline - Actual (n=43,24)	Number Analyzed	43 participants	24 participants
		0.9 (0.14)	0.9 (0.11)
HIP QC CORRECTED - week 48 - Actual change from baseline (n=28,19)	Number Analyzed	28 participants	19 participants
		0.0 (0.03)	0.0 (0.02)
SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)	Number Analyzed	42 participants	23 participants
		1.0 (0.15)	1.0 (0.18)
SPINAL CORD QC CORRECTED - week 48 - Actual change from baseline (n=28,18)	Number Analyzed	28 participants	18 participants
		0.0 (0.04)	0.0 (0.04)

11. Secondary Outcome

Title	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
Description	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"
Time Frame	Baseline, week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		43	24
Mean (Standard Deviation); Unit of Measure: scores on a scale
FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)	Number Analyzed	43 participants	24 participants
		-1.2 (1.06)	-1.3 (0.89)
FEMORAL NECK QC CORRECTED - Actual change from baseline at week 48 (n=28,19)	Number Analyzed	28 participants	19 participants
		0.1 (0.30)	0.1 (0.21)
HIP QC CORRECTED - baseline - Actual (n=43,24)	Number Analyzed	43 participants	24 participants
		-0.7 (1.08)	-0.8 (0.84)
HIP QC CORRECTED - Actual change from baseline at week 48 (n=28,19)	Number Analyzed	28 participants	19 participants
		0.0 (0.27)	0.0 (0.16)
SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)	Number Analyzed	42 participants	23 participants
		-1.2 (1.10)	-1.1 (1.40)
SPINAL CORD QC CORRECTED - Actual change from baseline at week 48 (n=28,18)	Number Analyzed	28 participants	18 participants
		0.1 (0.32)	0.1 (0.33)

12. Secondary Outcome

Title	Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
Description	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.
Time Frame	baseline, week 12, 36 and 48

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:	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).	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).
Overall Number of Participants Analyzed	48	25
Measure Type: Count of Participants; Unit of Measure: Participants
week 12 Complete responders	37 77.1%	2 8.0%
week 12 Partial responders	2 4.2%	2 8.0%
week 12 Overall responders (complete or partial responders)	39 81.3%	4 16.0%
week 12 Non-responders	9 18.8%	21 84.0%
week 36 Complete responders	38 79.2%	21 84.0%
week 36 Partial responders	2 4.2%	3 12.0%
week 36 Overall responders (complete or partial responders)	40 83.3%	24 96.0%
week 36 Non-responders	8 16.7%	1 4.0%
week 48 Complete responders	34 70.8%	16 64.0%
week 48 Partial responders	5 10.4%	3 12.0%
week 48 Overall responders (complete or partial responders)	39 81.3%	19 76.0%
week 48 Non-responders	9 18.8%	6 24.0%

13. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		47	24
Mean (Standard Deviation); Unit of Measure: mg/dL
Fasting glucose (mg/dL) - baseline - actual (n=47,24)	Number Analyzed	47 participants	24 participants
		97.3 (18.14)	91.4 (15.15)
Fasting glucose (mg/dL) - change from baseline at week 12 (n=44,23)	Number Analyzed	44 participants	23 participants
		-4.3 (14.84)	-1.7 (10.59)
Fasting glucose (mg/dL) - change from baseline at week 36 (n=43,24)	Number Analyzed	43 participants	24 participants
		-6.7 (12.48)	-1.1 (12.93)
Fasting glucose (mg/dL) - change from baseline at week 48 (n=41,21)	Number Analyzed	41 participants	21 participants
		-5.6 (14.13)	1.8 (13.92)

14. Secondary Outcome

Title	Change in Hemoglobin A1C
Description	Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: percentage of Hemoglobin A1C
Hemoglobin A1C (%) - Actual - baseline	Number Analyzed	48 participants	25 participants
		6.0 (0.92)	5.7 (0.56)
Hemoglobin A1C (%) - Actual change from baseline at week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-0.2 (0.44)	0.0 (0.27)
Hemoglobin A1C (%) Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-0.2 (0.54)	-0.1 (0.46)
Hemoglobin A1C (%) Actual change from baseline at week 48 (n=41,21)	Number Analyzed	41 participants	21 participants
		-0.2 (0.58)	0.1 (0.37)

15. Secondary Outcome

Title	Change in Cholesterol
Description	Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		45	25
Mean (Standard Deviation); Unit of Measure: mmol/L
Cholesterol (mmol/L) - actual - baseline (n=45,25)	Number Analyzed	45 participants	25 participants
		5.7 (1.30)	5.3 (1.15)
Cholesterol (mmol/L) - change from baseline at week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-0.8 (0.95)	0.0 (0.65)
Cholesterol (mmol/L) - change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-1.0 (1.28)	-0.4 (0.89)
Cholesterol (mmol/L) - change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-0.6 (1.36)	-0.4 (1.18)

16. Secondary Outcome

Title	Change in LDL Cholesterol
Description	Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		45	24
Mean (Standard Deviation); Unit of Measure: mmol/L
LDL Cholesterol (mmol/L) - Actual - baseline (n=45,24)	Number Analyzed	45 participants	24 participants
		3.4 (1.12)	3.0 (1.07)
LDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,23)	Number Analyzed	44 participants	23 participants
		-0.5 (0.80)	0.1 (0.47)
LDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,24)	Number Analyzed	44 participants	24 participants
		-0.6 (1.08)	-0.2 (0.70)
LDL Cholesterol (mmol/L) - Actual change from baseline at week 48 (n=41,21)	Number Analyzed	41 participants	21 participants
		-0.5 (0.99)	-0.2 (0.92)

17. Secondary Outcome

Title	Change in HDL Cholesterol
Description	Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		45	25
Mean (Standard Deviation); Unit of Measure: mmol/L
HDL Cholesterol (mmol/L) - Actual - baseline (n=45,25)	Number Analyzed	45 participants	25 participants
		1.6 (0.35)	1.5 (0.38)
HDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-0.3 (0.29)	0.0 (0.28)
HDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-0.3 (0.27)	-0.2 (0.25)
HDL Cholesterol (mmol/L) - Actual - change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-0.2 (0.27)	-0.1 (0.29)

18. Secondary Outcome

Title	Change in Triglyceride
Description	Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		45	25
Mean (Standard Deviation); Unit of Measure: mmol/L
Triglyceride (mmol/L) - Actual - baseline (n=45,25)	Number Analyzed	45 participants	25 participants
		1.5 (0.79)	1.7 (0.85)
Triglyceride (mmol/L) - Actual change from baseline at week 12(n=44,24)	Number Analyzed	44 participants	24 participants
		0.0 (0.53)	-0.2 (0.54)
Triglyceride (mmol/L) - Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-0.1 (0.55)	-0.1 (0.71)
Triglyceride (mmol/L) - Actual change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		0.1 (0.92)	-0.2 (0.62)

19. Secondary Outcome

Title	Change in Standing Systolic Blood Pressure
Description	Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		46	25
Mean (Standard Deviation); Unit of Measure: mmHg
Standing Systolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)	Number Analyzed	46 participants	25 participants
		132.4 (19.16)	130.0 (17.72)
Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-7.1 (18.08)	-0.9 (11.77)
Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	Number Analyzed	42 participants	25 participants
		-9.3 (19.09)	-7.0 (21.04)
Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-9.1 (19.45)	-11.0 (22.30)

20. Secondary Outcome

Title	Change in Supine Systolic Blood Pressure
Description	Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: mmHg
Supine Systolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		131.7 (18.33)	127.8 (18.69)
Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-8.0 (17.54)	2.3 (15.91)
Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	Number Analyzed	42 participants	25 participants
		-9.7 (19.88)	-4.4 (17.43)
Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-7.4 (19.38)	-7.5 (18.91)

21. Secondary Outcome

Title	Change in Standing Diastolic Blood Pressure
Description	Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		46	25
Mean (Standard Deviation); Unit of Measure: mmHg
Standing Diastolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)	Number Analyzed	46 participants	25 participants
		87.2 (12.74)	88.2 (10.83)
Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-4.8 (11.14)	-1.4 (9.84)
Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)	Number Analyzed	42 participants	25 participants
		-6.0 (12.09)	-4.4 (13.98)
Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-4.4 (11.64)	-3.9 (13.36)

22. Secondary Outcome

Title	Change in Supine Diastolic Blood Pressure
Description	Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: mmHg
Supine Diastolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		83.9 (11.71)	81.4 (11.21)
Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-6.3 (11.05)	-0.1 (8.31)
Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-7.7 (11.92)	-3.4 (11.37)
Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-5.8 (11.60)	-3.7 (10.92)

23. Secondary Outcome

Title	Change in Weight
Description	Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: kg
Weight (kg) - Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		78.8 (17.46)	77.3 (16.90)
Weight (kg) - Actual change from baseline at week 12(n=46,24)	Number Analyzed	46 participants	24 participants
		-0.8 (3.09)	-0.1 (2.12)
Weight (kg) - Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-3.0 (5.53)	-4.8 (5.63)
Weight (kg) - Actual change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-3.6 (6.53)	-5.5 (6.38)

24. Secondary Outcome

Title	Change in Waist Circumference
Description	Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
Time Frame	Baseline, weeks 12, 36, and 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: cm
Waist Circumference (cm)) - Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		102.5 (17.01)	103.4 (15.52)
Waist Circumference (cm) - Actual change from baseline at week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-1.0 (4.43)	-0.5 (3.35)
Waist Circumference (cm)) - Actual change from baseline at week 36 (n=44,25)	Number Analyzed	44 participants	25 participants
		-3.9 (6.36)	-2.1 (8.60)
Waist Circumference (cm) - Actual change from baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-4.1 (6.10)	-5.3 (5.68)

25. Secondary Outcome

Title	Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
Description	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
Time Frame	baseline, Week 12, Week 36 and Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		42	24
Measure Type: Count of Participants; Unit of Measure: Participants
Facial Rubor - week 12 (n=42,20)	Number Analyzed	42 participants	20 participants
		36 85.7%	19 95.0%
Hirsutism - week 12 (n=36,16)	Number Analyzed	36 participants	16 participants
		34 94.4%	15 93.8%
Striae - week 12 (n=41,20)	Number Analyzed	41 participants	20 participants
		38 92.7%	19 95.0%
Supraclavicular Fat Pad - week 12 (n=42,21)	Number Analyzed	42 participants	21 participants
		41 97.6%	19 90.5%
Dorsal Fat Pad - week 12 (n=41,21)	Number Analyzed	41 participants	21 participants
		35 85.4%	17 81.0%
Proximal Muscle Atrophy - week 12 (n=42,21)	Number Analyzed	42 participants	21 participants
		38 90.5%	20 95.2%
Central Obesity - week 12 (n=42,21)	Number Analyzed	42 participants	21 participants
		37 88.1%	21 100.0%
Ecchymoses - week 12 (n=42,20)	Number Analyzed	42 participants	20 participants
		39 92.9%	19 95.0%
Facial Rubor - week 36 (n=41,23)	Number Analyzed	41 participants	23 participants
		39 95.1%	22 95.7%
Hirsutism - week 36 (n=34,17)	Number Analyzed	34 participants	17 participants
		28 82.4%	16 94.1%
Striae - week 36 (n=40,23)	Number Analyzed	40 participants	23 participants
		38 95.0%	23 100.0%
Supraclavicular Fat Pad - week 36 (n=41,24)	Number Analyzed	41 participants	24 participants
		40 97.6%	24 100.0%
Dorsal Fat Pad - week 36 (n=40,24)	Number Analyzed	40 participants	24 participants
		36 90.0%	22 91.7%
Proximal Muscle Atrophy - week 36 (n=41,23)	Number Analyzed	41 participants	23 participants
		37 90.2%	22 95.7%
Central Obesity - week 36 (n=41,24)	Number Analyzed	41 participants	24 participants
		37 90.2%	21 87.5%
Ecchymoses - week 36 (n=41,23)	Number Analyzed	41 participants	23 participants
		39 95.1%	22 95.7%
Facial Rubor - week 48 (n=39,21)	Number Analyzed	39 participants	21 participants
		37 94.9%	21 100.0%
Hirsutism - week 48 (n=33,15)	Number Analyzed	33 participants	15 participants
		29 87.9%	15 100.0%
Striae - week 48 (n=38,21)	Number Analyzed	38 participants	21 participants
		38 100.0%	21 100.0%
Supraclavicular Fat Pad - week 48 (n=39,22)	Number Analyzed	39 participants	22 participants
		38 97.4%	22 100.0%
Dorsal Fat Pad - week 48 (n=38,22)	Number Analyzed	38 participants	22 participants
		36 94.7%	20 90.9%
Proximal Muscle Atrophy - week 48 (n=39,22)	Number Analyzed	39 participants	22 participants
		35 89.7%	21 95.5%
Central Obesity - week 48 (n=39,22)	Number Analyzed	39 participants	22 participants
		35 89.7%	21 95.5%
Ecchymoses - week 48 (n=39,21)	Number Analyzed	39 participants	21 participants
		38 97.4%	20 95.2%

26. Secondary Outcome

Title	Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - Baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		49.1 (19.60)	56.9 (18.99)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		6.2 (14.85)	8.6 (12.06)
Actual Change from Baseline at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		11.7 (16.30)	12.8 (14.24)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		4.7 (9.01)	-0.5 (9.99)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		0.1 (8.43)	2.5 (7.52)

27. Secondary Outcome

Title	Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		49.9 (20.34)	56.7 (21.11)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		6.1 (17.21)	9.6 (13.61)
Actual Change from Baseline at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		11.1 (17.84)	13.0 (16.30)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		4.1 (9.94)	-1.3 (12.36)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		0.1 (9.60)	2.4 (8.96)

28. Secondary Outcome

Title	Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		46.9 (22.32)	57.7 (21.91)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		6.3 (13.29)	5.6 (13.38)
Actual Change from Baseline at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		13.3 (19.83)	12.1 (15.59)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		6.6 (12.40)	2.2 (12.11)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		23.59 (11.27)	2.7 (12.17)

29. Secondary Outcome

Title	Change From Baseline in EQ-5D-5L Utility Index
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	24
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - baseline (n=48,24)	Number Analyzed	48 participants	24 participants
		0.825 (0.1486)	0.903 (0.1125)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-0.000 (0.1402)	0.021 (0.0771)
Actual Change from Baseline at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		0.044 (0.1393)	0.033 (0.0826)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		0.025 (0.1283)	0.010 (0.0487)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		0.023 (0.0762)	-0.008 (0.0367)

30. Secondary Outcome

Title	Change From Baseline in EQ-5D VAS
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	24
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - baseline (n=48,23)	Number Analyzed	48 participants	23 participants
		70.3 (17.26)	76.7 (17.88)
Actual Change from Baseline at week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		0.5 (13.57)	-0.3 (10.52)
Actual Change from Baseline at week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		9.4 (13.13)	5.8 (9.45)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		6.0 (11.08)	3.7 (9.29)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		3.2 (8.40)	-0.8 (4.44)

31. Secondary Outcome

Title	Change From Baseline in Beck Depression Inventory-II - Total Score Derived
Description	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.
Time Frame	Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: Scores on a scale
Actual - baseline (n=48,25)	Number Analyzed	48 participants	25 participants
		12.2 (10.22)	8.4 (7.82)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-1.4 (7.99)	-3.9 (5.42)
Actual Change from Baseline at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-4.3 (7.52)	-4.0 (7.70)
Actual Change from Week 12 at Week 36 (n=44,23)	Number Analyzed	44 participants	23 participants
		-2.0 (4.70)	0.6 (6.29)
Actual Change from Week 36 at Week 48 (n=42,22)	Number Analyzed	42 participants	22 participants
		-1.1 (4.83)	-0.4 (3.39)

32. Secondary Outcome

Title	Change From Baseline in Serum Cortisol
Description	Change from baseline in serum cortisol
Time Frame	Baseline, Week 12, Week 36, Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		47	25
Mean (Standard Deviation); Unit of Measure: nmol/L
Baseline - actual (n=47,25)	Number Analyzed	47 participants	25 participants
		565.8 (169.01)	486.1 (198.12)
Actual Change from Baseline at Week 12 (n=44,24)	Number Analyzed	44 participants	24 participants
		-276.0 (178.43)	73.0 (185.29)
Actual Change from Baseline at Week 36 (n=42,25)	Number Analyzed	42 participants	25 participants
		-267.0 (174.18)	-157.8 (225.56)
Actual Change from Baseline at Week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-210.7 (161.07)	-131.0 (236.88)

33. Secondary Outcome

Title	Change From Baseline in Late Night Saliva Cortisol
Description	Change from baseline in late night saliva cortisol (nmol/L)
Time Frame	Baseline, Week 12, Week 36, Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: nmol/L
Baseline - actual (n=48,25)	Number Analyzed	48 participants	25 participants
		11.7 (28.68)	9.0 (6.74)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-8.5 (29.60)	1.3 (8.87)
Actual Change from Baseline at Week 36 (n=42,25)	Number Analyzed	42 participants	25 participants
		-9.6 (30.82)	-5.8 (6.84)
Actual Change from Baseline at Week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-9.3 (29.05)	-5.0 (5.75)

34. Secondary Outcome

Title	Change From Baseline in Morning Saliva Cortisol
Description	Change from baseline in morning saliva cortisol (nmol/L)
Time Frame	Baseline, Week 12, Week 36, Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		48	25
Mean (Standard Deviation); Unit of Measure: nmol/L
Baseline - actual (n=48,25)	Number Analyzed	48 participants	25 participants
		17.2 (30.00)	14.1 (12.29)
Actual Change from Baseline at Week 12 (n=46,24)	Number Analyzed	46 participants	24 participants
		-11.6 (30.05)	-0.3 (11.21)
Actual Change from Baseline at Week 36 (n=40,25)	Number Analyzed	40 participants	25 participants
		-11.8 (30.74)	-9.3 (11.82)
Actual Change from Baseline at Week 48 (n=41,22)	Number Analyzed	41 participants	22 participants
		-11.8 (31.74)	-6.0 (10.97)

35. Secondary Outcome

Title	Change From Baseline in Hair Cortisol Levels
Description	Change from baseline in hair cortisol levels
Time Frame	Baseline, Week 26, Week 48

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Group	Osilodrostat Placebo Group
Arm/Group Description:		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).	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).
Overall Number of Participants Analyzed		19	9
Mean (Standard Deviation); Unit of Measure: pg/mg
Baseline - actual (n=19,9)	Number Analyzed	19 participants	9 participants
		38.9 (37.48)	10.5 (10.47)
Actual Change from Baseline at Week 26 (n=16,7)	Number Analyzed	16 participants	7 participants
		-15.8 (32.83)	-1.1 (12.72)
Actual Change from Baseline at Week 48 (n=14,6)	Number Analyzed	14 participants	6 participants
		-17.8 (26.66)	-9.7 (8.90)

36. Secondary Outcome

Title	Plasma Osilodrostat Concentrations (ng/mL)
Description	Plasma osilodrostat concentrations (ng/mL)
Time Frame	pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		Osilodrostat Incident Dose 1mg	Osilodrostat Incident Dose 2mg	Osilodrostat Incident Dose 5mg
Arm/Group Description:		Participants received 1mg of osilodrostat.	Participants received 2mg of osilodrostat.	Participants received 5mg of osilodrostat.
Overall Number of Participants Analyzed		16	55	29
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
week 1 1-2 hrs post dose (n=1,43,0)	Number Analyzed	1 participants	43 participants	0 participants
		3.85 [1]; (NA%)	7.29; (101.0%)
week 2 0 hrs pre dose (n=0,41,0)	Number Analyzed	0 participants	41 participants	0 participants
			2.19; (107.5%)
week 2 1-2 hrs post dose (n=0,42,0)	Number Analyzed	0 participants	42 participants	0 participants
			9.76; (53.4%)
week 5 pre dose (n=2,18,17)	Number Analyzed	2 participants	18 participants	17 participants
		0.576; (141.9%)	2.07; (82.1%)	5.06; (109.6%)
week 5 1-2 hrs post dose (n=2,9,29)	Number Analyzed	2 participants	9 participants	29 participants
		3.64; (60.5%)	11.1; (31.5%)	25.8; (84.4%)
week 8 0 hrs pre dose (n=2,4,13)	Number Analyzed	2 participants	4 participants	13 participants
		0.971; (76.7%)	2.64; (53.7%)	4.99; (55.6%)
week 8 1-2 hrs post dose (n=3,6,14)	Number Analyzed	3 participants	6 participants	14 participants
		3.70; (47.6%)	8.31; (45.6%)	23.3; (68.1%)
week 12 0 hrs pre dose (n=2,8,11)	Number Analyzed	2 participants	8 participants	11 participants
		1.55; (3.7%)	2.45; (39.2%)	5.03; (74.6%)
week 12 1-2 hrs post dose (n=4,34,0)	Number Analyzed	4 participants	34 participants	0 participants
		4.93; (32.0%)	11.7; (78.9%)
week 14 0 hrs pre dose (n=4,55,0)	Number Analyzed	4 participants	55 participants	0 participants
		0.974; (129.7%)	1.96; (74.9%)
week 14 1-2 hrs post dose (n=6,49,6)	Number Analyzed	6 participants	49 participants	6 participants
		3.74; (161.4%)	9.69; (35.8%)	22.6; (37.8%)
week 20 0 hrs pre dose (n=10,19,15)	Number Analyzed	10 participants	19 participants	15 participants
		1.63; (71.1%)	1.95; (68.1%)	6.21; (74.3%)
week 20 1-2 hrs post dose (n=13,18,12)	Number Analyzed	13 participants	18 participants	12 participants
		6.09; (27.3%)	8.66; (94.0%)	26.0; (99.3%)
week 26 0 hrs pre dose (n=12,13,10)	Number Analyzed	12 participants	13 participants	10 participants
		1.77; (86.4%)	2.12; (77.8%)	6.89; (85.1%)
week 26 1-2 hrs post dose (n=16,14,10)	Number Analyzed	16 participants	14 participants	10 participants
		5.28; (31.5%)	8.04; (50.7%)	33.1; (31.4%)

[1]

Geometric Coefficient of Variation is not applicable when 1 participant is analyzed

Adverse Events

Time Frame	Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo Controlled Period - Osilodrostat Arm.	Placebo Controlled Period - Placebo Arm.	Overall Study Period - Osilodrostat Arm.	Overall Study Period - Placebo Arm.	Overall Study Period - All Participants.
Arm/Group Description	All data while on osilodrostat treatment up to week 12 in participants initially randomized to osilodrostat.	All data while on placebo treatment up to week 12 in participants initially randomized to placebo.	All data while on osilodrostat treatment from randomization up to end-of-study in participants initially randomized to osilodrostat.	All data while on osilodrostat treatment from Week 12 up to end-of-study in participants initially randomized to placebo.	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.
All-Cause Mortality
	Placebo Controlled Period - Osilodrostat Arm.	Placebo Controlled Period - Placebo Arm.	Overall Study Period - Osilodrostat Arm.	Overall Study Period - Placebo Arm.	Overall Study Period - All Participants.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/48 (0.00%)	0/25 (0.00%)	0/48 (0.00%)	0/25 (0.00%)	0/73 (0.00%)
Serious Adverse Events
	Placebo Controlled Period - Osilodrostat Arm.	Placebo Controlled Period - Placebo Arm.	Overall Study Period - Osilodrostat Arm.	Overall Study Period - Placebo Arm.	Overall Study Period - All Participants.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	2/48 (4.17%)	1/25 (4.00%)	10/48 (20.83%)	0/25 (0.00%)	10/73 (13.70%)
Endocrine disorders
Adrenal insufficiency † 1	0/48 (0.00%)	0/25 (0.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Gastrointestinal disorders
Abdominal pain † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Erosive duodenitis † 1	1/48 (2.08%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Nausea † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Infections and infestations
Anal abscess † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Dengue fever † 1	1/48 (2.08%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Pneumonia † 1	0/48 (0.00%)	1/25 (4.00%)	0/48 (0.00%)	0/25 (0.00%)	0/73 (0.00%)
Pyelonephritis † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Injury, poisoning and procedural complications
Conjunctival laceration † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Eye injury † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Retinal injury † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Wrist fracture † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Investigations
Electrocardiogram QT prolonged † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Electrocardiogram T wave inversion † 1	1/48 (2.08%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Musculoskeletal and connective tissue disorders
Myalgia † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Periarthritis † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Nervous system disorders
Cerebral vascular occlusion † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Hemiparesis † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Obstructive airways disorder † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Vascular disorders
Hypertension † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Hypotension † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
Orthostatic hypotension † 1	0/48 (0.00%)	0/25 (0.00%)	1/48 (2.08%)	0/25 (0.00%)	1/73 (1.37%)
1 Term from vocabulary, MedDRA (23.1); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo Controlled Period - Osilodrostat Arm.	Placebo Controlled Period - Placebo Arm.	Overall Study Period - Osilodrostat Arm.	Overall Study Period - Placebo Arm.	Overall Study Period - All Participants.
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	45/48 (93.75%)	21/25 (84.00%)	47/48 (97.92%)	24/25 (96.00%)	71/73 (97.26%)
Blood and lymphatic system disorders
Anaemia † 1	2/48 (4.17%)	2/25 (8.00%)	2/48 (4.17%)	1/25 (4.00%)	3/73 (4.11%)
Cardiac disorders
Palpitations † 1	0/48 (0.00%)	2/25 (8.00%)	2/48 (4.17%)	0/25 (0.00%)	2/73 (2.74%)
Tachycardia † 1	6/48 (12.50%)	0/25 (0.00%)	8/48 (16.67%)	1/25 (4.00%)	9/73 (12.33%)
Endocrine disorders
Adrenal insufficiency † 1	7/48 (14.58%)	0/25 (0.00%)	12/48 (25.00%)	6/25 (24.00%)	18/73 (24.66%)
Gastrointestinal disorders
Abdominal distension † 1	3/48 (6.25%)	1/25 (4.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Abdominal pain † 1	4/48 (8.33%)	0/25 (0.00%)	10/48 (20.83%)	2/25 (8.00%)	12/73 (16.44%)
Abdominal pain upper † 1	1/48 (2.08%)	1/25 (4.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Diarrhoea † 1	10/48 (20.83%)	0/25 (0.00%)	14/48 (29.17%)	3/25 (12.00%)	17/73 (23.29%)
Nausea † 1	15/48 (31.25%)	3/25 (12.00%)	22/48 (45.83%)	5/25 (20.00%)	27/73 (36.99%)
Vomiting † 1	5/48 (10.42%)	0/25 (0.00%)	9/48 (18.75%)	0/25 (0.00%)	9/73 (12.33%)
General disorders
Asthenia † 1	11/48 (22.92%)	0/25 (0.00%)	15/48 (31.25%)	2/25 (8.00%)	17/73 (23.29%)
Fatigue † 1	12/48 (25.00%)	4/25 (16.00%)	23/48 (47.92%)	6/25 (24.00%)	29/73 (39.73%)
Oedema peripheral † 1	5/48 (10.42%)	0/25 (0.00%)	12/48 (25.00%)	0/25 (0.00%)	12/73 (16.44%)
Pyrexia † 1	2/48 (4.17%)	0/25 (0.00%)	5/48 (10.42%)	0/25 (0.00%)	5/73 (6.85%)
Infections and infestations
Gastroenteritis † 1	1/48 (2.08%)	0/25 (0.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Influenza † 1	2/48 (4.17%)	0/25 (0.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Laryngitis † 1	0/48 (0.00%)	0/25 (0.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Nasopharyngitis † 1	1/48 (2.08%)	1/25 (4.00%)	2/48 (4.17%)	2/25 (8.00%)	4/73 (5.48%)
Oral herpes † 1	1/48 (2.08%)	0/25 (0.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Pharyngitis † 1	1/48 (2.08%)	0/25 (0.00%)	5/48 (10.42%)	1/25 (4.00%)	6/73 (8.22%)
Upper respiratory tract infection † 1	5/48 (10.42%)	0/25 (0.00%)	12/48 (25.00%)	4/25 (16.00%)	16/73 (21.92%)
Urinary tract infection † 1	4/48 (8.33%)	0/25 (0.00%)	8/48 (16.67%)	4/25 (16.00%)	12/73 (16.44%)
Injury, poisoning and procedural complications
Fall † 1	2/48 (4.17%)	0/25 (0.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Investigations
Alanine aminotransferase increased † 1	2/48 (4.17%)	2/25 (8.00%)	3/48 (6.25%)	3/25 (12.00%)	6/73 (8.22%)
Aspartate aminotransferase increased † 1	1/48 (2.08%)	0/25 (0.00%)	2/48 (4.17%)	3/25 (12.00%)	5/73 (6.85%)
Blood cholesterol increased † 1	2/48 (4.17%)	1/25 (4.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Blood potassium decreased † 1	1/48 (2.08%)	1/25 (4.00%)	2/48 (4.17%)	2/25 (8.00%)	4/73 (5.48%)
Blood pressure increased † 1	1/48 (2.08%)	1/25 (4.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Blood testosterone increased † 1	5/48 (10.42%)	0/25 (0.00%)	13/48 (27.08%)	5/25 (20.00%)	18/73 (24.66%)
Electrocardiogram T wave inversion † 1	0/48 (0.00%)	1/25 (4.00%)	0/48 (0.00%)	2/25 (8.00%)	2/73 (2.74%)
Renin increased † 1	1/48 (2.08%)	0/25 (0.00%)	1/48 (2.08%)	4/25 (16.00%)	5/73 (6.85%)
Weight decreased † 1	2/48 (4.17%)	0/25 (0.00%)	3/48 (6.25%)	1/25 (4.00%)	4/73 (5.48%)
Metabolism and nutrition disorders
Decreased appetite † 1	18/48 (37.50%)	4/25 (16.00%)	24/48 (50.00%)	10/25 (40.00%)	34/73 (46.58%)
Hypercholesterolaemia † 1	3/48 (6.25%)	1/25 (4.00%)	6/48 (12.50%)	0/25 (0.00%)	6/73 (8.22%)
Hypoglycaemia † 1	1/48 (2.08%)	0/25 (0.00%)	3/48 (6.25%)	1/25 (4.00%)	4/73 (5.48%)
Hypokalaemia † 1	1/48 (2.08%)	0/25 (0.00%)	6/48 (12.50%)	2/25 (8.00%)	8/73 (10.96%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	17/48 (35.42%)	3/25 (12.00%)	26/48 (54.17%)	7/25 (28.00%)	33/73 (45.21%)
Back pain † 1	2/48 (4.17%)	0/25 (0.00%)	8/48 (16.67%)	2/25 (8.00%)	10/73 (13.70%)
Muscle spasms † 1	2/48 (4.17%)	0/25 (0.00%)	3/48 (6.25%)	1/25 (4.00%)	4/73 (5.48%)
Muscular weakness † 1	2/48 (4.17%)	0/25 (0.00%)	4/48 (8.33%)	2/25 (8.00%)	6/73 (8.22%)
Myalgia † 1	10/48 (20.83%)	1/25 (4.00%)	15/48 (31.25%)	3/25 (12.00%)	18/73 (24.66%)
Pain in extremity † 1	2/48 (4.17%)	0/25 (0.00%)	3/48 (6.25%)	2/25 (8.00%)	5/73 (6.85%)
Nervous system disorders
Dizziness † 1	9/48 (18.75%)	4/25 (16.00%)	19/48 (39.58%)	3/25 (12.00%)	22/73 (30.14%)
Headache † 1	7/48 (14.58%)	6/25 (24.00%)	17/48 (35.42%)	8/25 (32.00%)	25/73 (34.25%)
Paraesthesia † 1	0/48 (0.00%)	0/25 (0.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Psychiatric disorders
Anxiety † 1	0/48 (0.00%)	0/25 (0.00%)	2/48 (4.17%)	2/25 (8.00%)	4/73 (5.48%)
Renal and urinary disorders
Renal colic † 1	0/48 (0.00%)	1/25 (4.00%)	0/48 (0.00%)	2/25 (8.00%)	2/73 (2.74%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	0/48 (0.00%)	0/25 (0.00%)	4/48 (8.33%)	0/25 (0.00%)	4/73 (5.48%)
Dyspnoea † 1	1/48 (2.08%)	0/25 (0.00%)	2/48 (4.17%)	2/25 (8.00%)	4/73 (5.48%)
Epistaxis † 1	0/48 (0.00%)	0/25 (0.00%)	0/48 (0.00%)	2/25 (8.00%)	2/73 (2.74%)
Nasal congestion † 1	1/48 (2.08%)	0/25 (0.00%)	3/48 (6.25%)	0/25 (0.00%)	3/73 (4.11%)
Skin and subcutaneous tissue disorders
Acne † 1	2/48 (4.17%)	0/25 (0.00%)	9/48 (18.75%)	1/25 (4.00%)	10/73 (13.70%)
Alopecia † 1	1/48 (2.08%)	1/25 (4.00%)	4/48 (8.33%)	1/25 (4.00%)	5/73 (6.85%)
Dry skin † 1	3/48 (6.25%)	0/25 (0.00%)	3/48 (6.25%)	1/25 (4.00%)	4/73 (5.48%)
Eczema † 1	0/48 (0.00%)	0/25 (0.00%)	2/48 (4.17%)	2/25 (8.00%)	4/73 (5.48%)
Hirsutism † 1	0/48 (0.00%)	1/25 (4.00%)	6/48 (12.50%)	1/25 (4.00%)	7/73 (9.59%)
Pruritus † 1	6/48 (12.50%)	0/25 (0.00%)	7/48 (14.58%)	2/25 (8.00%)	9/73 (12.33%)
Skin hyperpigmentation † 1	2/48 (4.17%)	0/25 (0.00%)	3/48 (6.25%)	1/25 (4.00%)	4/73 (5.48%)
Vascular disorders
Hypertension † 1	7/48 (14.58%)	7/25 (28.00%)	12/48 (25.00%)	4/25 (16.00%)	16/73 (21.92%)
Hypotension † 1	5/48 (10.42%)	0/25 (0.00%)	9/48 (18.75%)	3/25 (12.00%)	12/73 (16.44%)
Orthostatic hypotension † 1	4/48 (8.33%)	0/25 (0.00%)	7/48 (14.58%)	1/25 (4.00%)	8/73 (10.96%)
1 Term from vocabulary, MedDRA (23.1); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: + 1 862 778 8300
• EMail: Novartis.email@Novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.

• Responsible Party: Novartis ( Novartis Pharmaceuticals )
• ClinicalTrials.gov Identifier: NCT02697734
• Other Study ID Numbers: CLCI699C2302
• First Submitted: February 27, 2016
• First Posted: March 3, 2016
• Results First Submitted: July 26, 2021
• Results First Posted: October 19, 2021
• Last Update Posted: November 1, 2021