Efficacy and Safety Evaluation of Osilodrostat in Cushing... | NCT02697734

Label	Type	Description	Intervention Names
osilodrostat Group	Experimental	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)	Drug: osilodrostat
osilodrostat Placebo Group	Placebo Comparator	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)	Drug: osilodrostat Placebo

Name	Type	Description	Arm Group Labels	Other Names
osilodrostat	Drug	In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.	osilodrostat Group

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

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

Eligibility Module

Eligibility Criteria

Key inclusion criteria:

Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c):
1. mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3 consecutive days, during screening after washout of prior medical therapy for CD (if applicable), confirmed by the central laboratory and available before Day 1), with ≥2 of the individual UFC values being > 1.3 x ULN.
2. Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal
3. Confirmation (based on medical history) of pituitary source of excess
  
  ACTH as defined by any one or more of the following three criteria:
i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. Magnetic resonance imaging (MRI) confirmation of pituitary adenoma > 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either corticotropic-releasing hormone (CRH) or desmopressin (DDAVP) stimulation for patients with a tumor ≤ 6mm. The criteria for a confirmatory BIPSS test are any of the following: Pre-dose central to peripheral ACTH gradient > 2; Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP stimulation
Patients that received glucocorticoid replacement therapy must have discontinued such therapy for at least seven days or 5 half-lives prior to screening, whichever is longer.
Patients with de novo CD can be included only if they are not considered candidates for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors, patients who refuse to have surgical treatment, or surgical treatment is not available).

Key exclusion criteria:

Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night salivary cortisol value collected during the screening period and after washout of prior CD medication.
Patients with risk factors for QT corrected (QTc) prolongation or Torsade de Pointes, including:

patients with a baseline QT corrected (Fridericia QT formula) (QTcF) > 450 ms for males and QTcF > 460 ms for females; personal or family history of long QT syndrome; concomitant medications known to prolong the QT interval; patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before pre-dose Day 1.

Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy during the placebo-controlled period (Weeks 1-12) for the treatment of severe hypercortisolism or pituitary tumor growth causing compression of the optic chiasm.
Patients with compression of the optic chiasm due to a macroadenoma or patients at high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm).
Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).
Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent (adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing. Highly effective contraception methods include: A. Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. B. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study drug. In case of bilateral oophorectomy, documentation is required (e.g. operative report, pelvic ultrasound or other reliable imaging method). C. Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.

D. Combination of any two of the following (a+b or a+c, or b+c):

Use of oral*, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
Placement of an intrauterine device (IUD) or intrauterine system (IUS)
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. *In the case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential.

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
University of Colorado Endocrinology Clinical Trials Unit		Aurora	Colorado	80045	United States
University of Michigan Comprehensive Cancer Center

PubMed Identifier	Type	Citation	Retractions
41052284	Derived	Fleseriu M, Pivonello R, Lacroix A, Biller BMK, Feelders R, Gadelha M, Bertherat J, Belaya Z, Piacentini A, Pedroncelli AM, Newell-Price J. Osilodrostat dose impact on efficacy/safety in Cushing's disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025 Oct 30;193(5):606-617. doi: 10.1093/ejendo/lvaf207.
39610378

ID	Title	Description
FG000	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).
FG001	Osilodrostat Placebo Group

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Dec 20, 2019	Jul 26, 2021

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Randomized Participants With a Complete Response

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.

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

Posted

Count of Participants

Participants

at Week 12

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants	OG00048 OG00125

Title

Denominators

Categories

Title	Measurements
	OG00037 OG0012

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Cochran-Mantel-Haenszel		<.0001		Odds Ratio (OR)	43.4			2-Sided	95	7.06	343.19					Superiority

Secondary

Percentage of Participants With mUFC ≤ ULN at Week 36

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.

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.'

Posted

Number

95% Confidence Interval

Percentage of participants

At Week 36

ID	Title	Description
OG000	All Participants Combined	Consisted of all randomized participants who received at least one dose of osilodrostat.

Units	Counts
Participants	OG000

Secondary

Change From Baseline in mUFC

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

Posted

Mean

Standard Deviation

nmol/24hr

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

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN

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.

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

Posted

Count of Participants

Participants

up to 12 weeks

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response

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).

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

Posted

Median

95% Confidence Interval

Days

up to 12 weeks

ID	Title	Description
OG000	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).
OG001	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).

Secondary

Time-to-first Control of mUFC - % Event Probability Estimates

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.

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

Posted

Number

95% Confidence Interval

Percent (event probability estimates)

up to 12 weeks

ID	Title	Description
OG000	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).
OG001	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).

Secondary

Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants

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.

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

Posted

Count of Participants

Participants

up to 48 weeks

ID	Title	Description
OG000	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).
OG001	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).
OG002	All Participants	All Participants

Secondary

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

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

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

Posted

Median

95% Confidence Interval

days

from week 26 to week 48

ID	Title	Description
OG000	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).
OG001	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).
OG002	All Participants

Secondary

Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates

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.

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

Posted

Number

95% Confidence Interval

Percent (event probability estimates)

week 26 and week 36

ID	Title	Description
OG000	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).
OG001	Osilodrostat Placebo Group

Secondary

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

Posted

Mean

Standard Deviation

g/cm2

Baseline, week 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts

Secondary

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

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"

Posted

Mean

Standard Deviation

scores on a scale

Baseline, week 48

ID	Title	Description
OG000	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).
OG001	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).

Secondary

Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48

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.

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

Posted

Count of Participants

Participants

baseline, week 12, 36 and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Fasting Plasma Glucose

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

Posted

Mean

Standard Deviation

mg/dL

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Hemoglobin A1C

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

Posted

Mean

Standard Deviation

percentage of Hemoglobin A1C

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Cholesterol

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

Posted

Mean

Standard Deviation

mmol/L

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in LDL Cholesterol

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

Posted

Mean

Standard Deviation

mmol/L

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in HDL Cholesterol

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

Posted

Mean

Standard Deviation

mmol/L

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Triglyceride

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

Posted

Mean

Standard Deviation

mmol/L

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Standing Systolic Blood Pressure

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

Posted

Mean

Standard Deviation

mmHg

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Supine Systolic Blood Pressure

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

Posted

Mean

Standard Deviation

mmHg

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Standing Diastolic Blood Pressure

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

Posted

Mean

Standard Deviation

mmHg

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Supine Diastolic Blood Pressure

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

Posted

Mean

Standard Deviation

mmHg

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Weight

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

Posted

Mean

Standard Deviation

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change in Waist Circumference

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

Posted

Mean

Standard Deviation

Baseline, weeks 12, 36, and 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease

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

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.

Posted

Count of Participants

Participants

baseline, Week 12, Week 36 and Week 48

ID	Title	Description
OG000	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).
OG001	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).

Secondary

Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

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.

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).

Secondary

Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).

Secondary

Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).

Secondary

Change From Baseline in EQ-5D-5L Utility Index

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.

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).
OG001	Osilodrostat Placebo Group

Secondary

Change From Baseline in EQ-5D VAS

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.

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).
OG001	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).

Secondary

Change From Baseline in Beck Depression Inventory-II - Total Score Derived

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.

Posted

Mean

Standard Deviation

Scores on a scale

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

ID	Title	Description
OG000	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).
OG001	Osilodrostat Placebo Group

Secondary

Change From Baseline in Serum Cortisol

Change from baseline in serum cortisol

Posted

Mean

Standard Deviation

nmol/L

Baseline, Week 12, Week 36, Week 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change From Baseline in Late Night Saliva Cortisol

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

Posted

Mean

Standard Deviation

nmol/L

Baseline, Week 12, Week 36, Week 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change From Baseline in Morning Saliva Cortisol

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

Posted

Mean

Standard Deviation

nmol/L

Baseline, Week 12, Week 36, Week 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Change From Baseline in Hair Cortisol Levels

Change from baseline in hair cortisol levels

Posted

Mean

Standard Deviation

pg/mg

Baseline, Week 26, Week 48

ID	Title	Description
OG000	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).
OG001	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).

Units	Counts
Participants

Secondary

Plasma Osilodrostat Concentrations (ng/mL)

Plasma osilodrostat concentrations (ng/mL)

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

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

ID	Title	Description
OG000	Osilodrostat Incident Dose 1mg	Participants received 1mg of osilodrostat.
OG001	Osilodrostat Incident Dose 2mg	Participants received 2mg of osilodrostat.
OG002	Osilodrostat Incident Dose 5mg	Participants received 5mg of osilodrostat.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Adrenal insufficiency	Endocrine disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG0030 affected25 at risk EG0043 affected73 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Erosive duodenitis	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Anal abscess	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Dengue fever	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Pneumonia	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0011 affected25 at risk EG0020 affected48 at risk EG003
Pyelonephritis	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Conjunctival laceration	Injury, poisoning and procedural complications	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Eye injury	Injury, poisoning and procedural complications	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Retinal injury	Injury, poisoning and procedural complications	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Wrist fracture	Injury, poisoning and procedural complications	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Electrocardiogram T wave inversion	Investigations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Periarthritis	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Cerebral vascular occlusion	Nervous system disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Hemiparesis	Nervous system disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Obstructive airways disorder	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Hypertension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Hypotension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Orthostatic hypotension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0012 affected25 at risk EG0022 affected48 at risk EG0031 affected25 at risk EG0043 affected73 at risk
Palpitations	Cardiac disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0012 affected25 at risk EG0022 affected48 at risk EG003
Tachycardia	Cardiac disorders	MedDRA (23.1)	Systematic Assessment	EG0006 affected48 at risk EG0010 affected25 at risk EG0028 affected48 at risk EG003
Adrenal insufficiency	Endocrine disorders	MedDRA (23.1)	Systematic Assessment	EG0007 affected48 at risk EG0010 affected25 at risk EG00212 affected48 at risk EG003
Abdominal distension	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0003 affected48 at risk EG0011 affected25 at risk EG0024 affected48 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0004 affected48 at risk EG0010 affected25 at risk EG00210 affected48 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0011 affected25 at risk EG0023 affected48 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG00010 affected48 at risk EG0010 affected25 at risk EG00214 affected48 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG00015 affected48 at risk EG0013 affected25 at risk EG00222 affected48 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (23.1)	Systematic Assessment	EG0005 affected48 at risk EG0010 affected25 at risk EG0029 affected48 at risk EG003
Asthenia	General disorders	MedDRA (23.1)	Systematic Assessment	EG00011 affected48 at risk EG0010 affected25 at risk EG00215 affected48 at risk EG003
Fatigue	General disorders	MedDRA (23.1)	Systematic Assessment	EG00012 affected48 at risk EG0014 affected25 at risk EG00223 affected48 at risk EG003
Oedema peripheral	General disorders	MedDRA (23.1)	Systematic Assessment	EG0005 affected48 at risk EG0010 affected25 at risk EG00212 affected48 at risk EG003
Pyrexia	General disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0025 affected48 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Influenza	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Laryngitis	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0011 affected25 at risk EG0022 affected48 at risk EG003
Oral herpes	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Pharyngitis	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0025 affected48 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0005 affected48 at risk EG0010 affected25 at risk EG00212 affected48 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (23.1)	Systematic Assessment	EG0004 affected48 at risk EG0010 affected25 at risk EG0028 affected48 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Alanine aminotransferase increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0012 affected25 at risk EG0023 affected48 at risk EG003
Aspartate aminotransferase increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0022 affected48 at risk EG003
Blood cholesterol increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0011 affected25 at risk EG0023 affected48 at risk EG003
Blood potassium decreased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0011 affected25 at risk EG0022 affected48 at risk EG003
Blood pressure increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0011 affected25 at risk EG0023 affected48 at risk EG003
Blood testosterone increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0005 affected48 at risk EG0010 affected25 at risk EG00213 affected48 at risk EG003
Electrocardiogram T wave inversion	Investigations	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0011 affected25 at risk EG0020 affected48 at risk EG003
Renin increased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0021 affected48 at risk EG003
Weight decreased	Investigations	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (23.1)	Systematic Assessment	EG00018 affected48 at risk EG0014 affected25 at risk EG00224 affected48 at risk EG003
Hypercholesterolaemia	Metabolism and nutrition disorders	MedDRA (23.1)	Systematic Assessment	EG0003 affected48 at risk EG0011 affected25 at risk EG0026 affected48 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0026 affected48 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG00017 affected48 at risk EG0013 affected25 at risk EG00226 affected48 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0028 affected48 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG00010 affected48 at risk EG0011 affected25 at risk EG00215 affected48 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Dizziness	Nervous system disorders	MedDRA (23.1)	Systematic Assessment	EG0009 affected48 at risk EG0014 affected25 at risk EG00219 affected48 at risk EG003
Headache	Nervous system disorders	MedDRA (23.1)	Systematic Assessment	EG0007 affected48 at risk EG0016 affected25 at risk EG00217 affected48 at risk EG003
Paraesthesia	Nervous system disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Anxiety	Psychiatric disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0022 affected48 at risk EG003
Renal colic	Renal and urinary disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0011 affected25 at risk EG0020 affected48 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0024 affected48 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0022 affected48 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0020 affected48 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Acne	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0029 affected48 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0001 affected48 at risk EG0011 affected25 at risk EG0024 affected48 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0003 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Eczema	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0010 affected25 at risk EG0022 affected48 at risk EG003
Hirsutism	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0000 affected48 at risk EG0011 affected25 at risk EG0026 affected48 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0006 affected48 at risk EG0010 affected25 at risk EG0027 affected48 at risk EG003
Skin hyperpigmentation	Skin and subcutaneous tissue disorders	MedDRA (23.1)	Systematic Assessment	EG0002 affected48 at risk EG0010 affected25 at risk EG0023 affected48 at risk EG003
Hypertension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0007 affected48 at risk EG0017 affected25 at risk EG00212 affected48 at risk EG003
Hypotension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0005 affected48 at risk EG0010 affected25 at risk EG0029 affected48 at risk EG003
Orthostatic hypotension	Vascular disorders	MedDRA (23.1)	Systematic Assessment	EG0004 affected48 at risk EG0010 affected25 at risk EG0027 affected48 at risk EG003

ID	Term
D047748	Pituitary ACTH Hypersecretion
D010900	Pituitary Diseases

ID	Term
D006964	Hyperpituitarism
D007027	Hypothalamic Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D004700	Endocrine System Diseases

ID	Title	Description
BG000	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).
BG001	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).
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo Controlled Period - Osilodrostat Arm.	All data while on osilodrostat treatment up to week 12 in participants initially randomized to osilodrostat.	48	2	48	45	48
EG001	Placebo Controlled Period - Placebo Arm.	All data while on placebo treatment up to week 12 in participants initially randomized to placebo.	25	1	25	21	25
EG002	Overall Study Period - Osilodrostat Arm.	All data while on osilodrostat treatment from randomization up to end-of-study in participants initially randomized to osilodrostat.	48	10	48	47	48
EG003	Overall Study Period - Placebo Arm.	All data while on osilodrostat treatment from Week 12 up to end-of-study in participants initially randomized to placebo.	25	0	25	24	25
EG004	Overall Study Period - All Participants.	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.	73	10	73	71	73