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Epinephrine

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Patients in this arm took the study drug, osilodrostat.

Osirodrostat 1mg, 5mg \& 10mg in the form of film-coated tablets was used for oral administration.

Osilodrostat

Novartis Pharmaceuticals

The study aim was to investigate the efficacy and safety of Osilodrostat in patients with Cushing's syndrome due to causes other than Cushing's disease in Japan.

This was a Phase II, single arm, open-label, dose titration, multi-center study which consisted of two distinct Study Periods plus an optional extension period in non-CD patients with CS. The 3 Study Periods (two distinct Study Periods plus an optional extension period) were as follows:

Study Period I \[Week 0 (Day 1) to Week-12\]: Study Period I was the dose titration period to achieve a stable therapeutic dose and to assess the efficacy and safety of osilodrostat.

The dosing regimen of osilodrostat in this study was titrated according to the following escalation sequence: osilodrostat 2 mg bid, 5 mg bid, 10 mg bid, 20 mg bid, and 30 mg bid. Dose adjustments were based on the serum cortisol values measured by the local lab at each site. Osilodrostat titration was done weekly for the initial 4-weeks, up to a maximum dose of 10 mg bid.

The mean of three 24-hour UFC (mUFC) values were measured to evaluate the efficacy in this period.

Study Period II (After Week-12 to Week-48): Study Period II was the period to assess the sustainability of efficacy and long term safety.

During Study Period II, only patients who tolerated and agreed to continue osilodrostat treatment continued on the study. The patient was administered with the stable therapeutic dose which was achieved in the Study Period I.

Optional extension period (After Week-48): Patients who continued to receive clinical benefit, as assessed by the study Investigator and who wished to enter the extension period were reconsented at Week-48. Patients who entered the extension period continued to be treated with the study drug without interruption to be assessed for efficacy and safety. Patients who continued to benefit from study treatment as assessed by the study investigator and who completed Week-72 were offered to participate in a separate long-term safety follow-up study. The optional extension period ended after all patients had completed Week-72 or had discontinued early.

Post-treatment Follow-up: All patients had 30 days safety follow-up after the last dose of study treatment.

Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome

A Phase II, Open-label, Dose Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of Osilodrostat in Patients With All Types of Endogenous Cushing's Syndrome Except Cushing's Disease

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data is currently available according to the process described on www.clinicalstudydatarequest.com

Percent change from baseline in the mUFC at the individual patient level

Absolute change from baseline in the mUFC

Complete response rate = percentage of participants who had mUFC≤ ULN; Partial response rate = Percentage of participants who had mUFC\>ULN and at least 50% reduction from baseline in mUFC. Overall response rate = Percentage of participants who had mUFC ≤ ULN or at least 50% reduction from baseline.

Absolute change from baseline in morning serum cortisol at the individual patient level

Percentage change from baseline in morning serum cortisol at the individual patient level

Absolute change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol

Percent change from baseline in several steroid hormones at individual levels: ACTH, Serum 11-deoxycorticosterone, Aldosterone, Estradiol

Absolute change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone

Percent change from baseline in several steroid hormones at individual levels: Serum 11-deoxycortisol, Testosterone

Absolute change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)

Percentasge change in cardiovascular-related metabolic parameter fasting glucose, associated with Cushing's syndrome (CS)

Absolute change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)

Percentage change in cardiovascular-related metabolic parameter HbA1c associated with Cushing's syndrome (CS)

Absolute change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol \& triglycerides, associated with Cushing's syndrome (CS)

Percent change in cardiovascular-related metabolic parameters: cholesterol, HDL cholesterol, LDL cholesterol \& triglycerides, associated with Cushing's syndrome (CS)

Absolute change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)

Percent change in cardiovascular-related metabolic parameter: BMI, associated with Cushing's syndrome (CS)

Absolute change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)

Percent change in cardiovascular-related metabolic parameter: Waist circumference, associated with Cushing's syndrome (CS)

Absolute change in cardiovascular-related metabolic parameter: sitting systolic BP \& sitting diastolic BP, associated with Cushing's syndrome (CS)

Percentage change in cardiovascular-related metabolic parameter: sitting systolic BP \& sitting diastolic BP, associated with Cushing's syndrome

The Cushing's Disease Health-Related Quality of Life Questionnaire (Cushing QoL) (version 1.0) was developed to evaluate quality of life in patients with Cushing's syndrome (Webb et al 2008). The Cushing QoL is comprised of 12 items that capture patient responses on seven concepts: daily activities, healing and pain, mood and self-confidence, social concerns, physical appearance, memory and concern about the future. Each questionnaire of the Cushing QOL has a scale of 1-5 where '1' corresponding to 'Always' or 'Very much' and '5' to 'Never' or 'Not at all'. The lower the score, the greater the impact on HRQoL. The score is the sum of all the item response and can range from 12 (worst) to 60 points (best).

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 \& 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. Each of 21 items corresponds to a symptom of depression and the sum of total score will be calculated where each item has a four-point scale ranging from 0 to 3, leading to a total score from zero to 63.

Osilodrostat plasma concentration data at each time-point were summarized by incident dose. About a half of pre-dose concentration data were excluded from analysis due to deviation from the pre-defined acceptable time window.

AE description; Any sign or symptom that occurs during the study treatment plus the 30 days post treatment

Age, Continuous

Sex: Female, Male

Japanese

Race/Ethnicity, Customized

ACTH-Independent Macronodular Adrena;l Hyperplasia

Adrenal Adenoma

Ectopic Corticotropin Syndrome

Type of disease

Full Analysis Set (FAS): Comprised of all enrolled patients who received at least one dose of osilodrostat.

Study Director

AIMAH- Patient 1 (n=1)

Adrenal adenoma - Patient 1 (n=1)

Adrenal adenoma - Patient 2 (n=1)

Adrenal adenoma - Patient 3 (n=1)

Adrenal adenoma - Patient 4 (n=1)

Adrenal adenoma - Patient 5 (n=1)

Ectopic corticotropin syndrome - Patient 1 (n=1)

Ectopic c orticotropin syndrome - Patient 2(n=0)

Ectopic corticotropin syndrome - Patient 3 (n=0)

Percent Change in the Mean Urine Free Cortisol (mUFC) at the Individual Level at Week 12

AIMAH-Patient (Pt) 1: Week (Wk) 24 (n=1)

AIMAH-Patient 1:Wk 48 (n=1)

Adrenal adenoma-Patient 1: Wk 24(n=0)

Adrenal adenoma-Patient 1: Wk 48(n=0)

Adrenal adenoma-Patient 2: Wk 24(n=1)

Adrenal adenoma-Patient 2: Wk 48(n=0)

Adrenal adenoma-Patient 3: Wk 24(n=0)

Adrenal adenoma-Patient 3: Wk 48(n=0)

Adrenal adenoma-Patient 4: Wk 24(n=0)

Adrenal adenoma-Patient 4: Wk 48(n=0)

Adrenal adenoma-Patient 5: Wk 24(n=0)

Adrenal adenoma-Patient 5: Wk 48(n=0)

Ectopic corticotropin syndrome-Pt 1: Wk 24(n=1)

Ectopic corticotropin syndrome-Pt 1: Wk 48(n=1)

Ectopic corticotropin syndrome-Pt 2: Wk 24(n=0)

Ectopic corticotropin syndrome-Pt 2: Wk 48(n=0)

Ectopic corticotropin syndrome-Pt 3: Wk 24(n=0)

Ectopic corticotropin syndrome-Pt 3: Wk 48(n=0)

Percent Change From Baseline in the mUFC at Individual Patient Level at Week 24 (Day 169) and Week 48 (Day 337)

Week 12 (day 85)( n = 7)

Week 24 (day 169) (n = 3)

Week 48 (day 337) (n = 2)

Absolute Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)

Percentage Change From Baseline in the mUFC at Week 12 (Day 85), Week 24 (Day 169) and Week 48 (Day 337)

Week 12: Complete responders

Week 12: Partial responders

Week 12: Overall responders

Week 24: Complete responders (n =3)

Week 24: Partial responders (n = 3)

Week 24: Overall responders (n = 3)

Week 48: Complete responders (n = 2)

Week 48: Partial responders (n = 2)

Week 48: Overall responders (n = 2)

Percentage of Participants With mUFC Response of Complete, Partial, and Overall Response

AIMAH-Patient (Pt) 1: Week (Wk) 12 (n = 1)

AIMAH-Patient 1: Wk 24 (n = 1)

AIMAH-Patient 1: Wk 48 (n = 1)

Adrenal adenoma-Patient 1: Wk 12 (n =1)

Adrenal adenoma-Patient 1:Wk 24 (n =0)

Adrenal adenoma-Patient 1: Wk 48 (n =0)

Adrenal adenoma-Patient 2: Wk 12(n =1)

Adrenal adenoma-Patient 2: Wk 24 (n =1)

Adrenal adenoma-Patient 2: Wk 48 (n =0)

Adrenal adenoma-Patient 3: Wk 12 (n =1)

Adrenal adenoma-Patient 3: Wk 24 (n =0)

Adrenal adenoma-Patient 3: Wk 48 (n =0)

Adrenal adenoma-Patient 4: Wk 12 (n =1)

Adrenal adenoma-Patient 4: Wk 24 (n =0)

Adrenal adenoma-Patient 4: Wk 48 (n =0)

Adrenal adenoma-Patient 5: Wk 12 (n =1)

Adrenal adenoma-Patient 5: Wk 24 (n =0)

Adrenal adenoma-Patient 5: Wk 48 (n =0)

Ectopic corticotropin syndrome-Pt 1: Wk 12 (n =1)

Ectopic corticotropin syndrome-Pt 1: Wk24 (n=1)

Ectopic corticotropin syndrome-Pt 1: Wk48 (n=1)

Ectopic corticotropin syndrome-Pt 2: Wk 12 (n =0)

Ectopic corticotropin syndrome-Pt 2: Wk 24 (n=0)

Ectopic corticotropin syndrome-Pt 2: Wk48 (n=0)

Ectopic corticotropin syndrome-Pt 3: Wk 12 (n =0)

Ectopic corticotropin syndrome-Pt 3: Wk24 (n=0)

Ectopic corticotropin syndrome-Pt 3: Wk48 (n=0)

Absolute Change From Baseline in Morning Serum Cortisol at Individual Level

Ectopic corticotropin syndrome-Pt 2: Wk24 (n=0)

Percentage Change From Baseline in Morning Serum Cortisol at Individual Level

AIMAH-Patient (Pt) 1 Wk 12 (n=1,1,1,1)

AIMAH-Pt 1 Wk 24 (n=1,1,1,1)

AIMAH-Pt 1 Wk 48 (n=1,1,1,1)

Adrenal adenoma-Pt 1 Wk 12 (n=1,1,1,1)

Adrenal adenoma-Pt 1 Wk 24 (n =0,0,0,0)

Adrenal adenoma-Pt 1 Wk 48 (n=0,0,0,0)

Adrenal adenoma-Pt 2 Wk 12 (n=1,1,1,1)

Adrenal adenoma-Pt 2 Wk 24(n=1,1,1,1)

Adrenal adenoma-Pt 2 Wk 48 (n=0,0,0,0)

Adrenal adenoma-Pt 3 Wk 12 (n=1,1,1,1)

Adrenal adenoma-Pt 3 Wk 24 (n=0, 0,0,0)

Adrenal adenoma-Pt 3 Wk 48(n=0,0,0,0)

Adrenal adenoma-Pt 4 Wk 12 (n=1,1,1,1)

Adrenal adenoma-Pt 4 Wk 24 (n=0,0,0,0)

Adrenal adenoma-Pt 4 Wk 48 (n=0,0,0,0)

Adrenal adenoma-Pt 5 Wk 12 (n=1,1,1,1)

Adrenal adenoma-Pt 5 Wk 24 (n=0,0,0,0)

Adrenal adenoma-Pt 5 Wk 48 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 1: Wk 12 (n=1,1,1,1)

Ectopic ACTH syndrome-Pt 1: Wk 24 (n=1,1,1,1)

Ectopic ACTH syndrome-Pt 1: Wk 48 (n=1,1,1,1)

Ectopic ACTH syndrome-Pt 2: Wk 12 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 2: Wk 24 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 2: Wk 48 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 3: Wk 12 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 3: Wk 24 (n=0,0,0,0)

Ectopic ACTH syndrome-Pt 3: Wk 48 (n=0,0,0,0)

ACTH

adrenal steroid hormones: Serum 11-deoxycorticosterone

Serum 11-deoxycorticosterone

Aldosterone

Estradiol

Absolute Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level

AIMAH-Patient (Pt) 1 Wk 12 (n =0,1,0,1)

AIMAH-Pt 1 Wk 24 (n=0,1,0,1)

Percentage Change From Baseline in ACTH and Other Adrenal Steroid Hormones at Individual Level

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