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Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study

Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.

LCI699

Novartis Pharmaceuticals

This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.

In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.

A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.

The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.

The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.

Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was \< Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.

The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.

Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.

On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.

Safety and Efficacy of LCI699 in Cushing's Disease Patients

A Proof of Concept, Open-label, Forced Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of 10-weeks Treatment of LCI699 in Patients With 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 review 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 availability is according to the criteria and process described on www.clinicalstudydatarequest.com

A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.

Change in aldosterone \& thyroxine, free over time.

Change in Estradiol in females over time.

Change in Renin, Insulin \& Thyrotropin over time.

Change in Insulin-like Growth Factor-1 over time.

Change in Testosterone in females over time.

Change in Testosterone in males over time.

Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. QUICKI is the quantitative insulin sensitivity check index and is derived using the inverse of the sum of algorithms (base 10) of the fasting insulin and fasting glucose: 1/(log(fasting insulin mU/mL)+log(fasting glucose mg/dL)).

Values typically associated with the QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. So lower numbers reflect greater insulin resistance.

Trough PK concentrations and PK profiles at steady-state were collected. The AUC from time 0 to 12 h post dose at steady state, calculated by using the predose concentration (Ctrough,ss) as the 12 h concentration, assuming steady-state has been reached.

Trough PK concentrations and PK profiles at steady-state were collected.

A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 22 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Participants with controlled or partially controlled UFC were defined as: Controlled UFC: mean UFC level \<= upper limit of normal (ULN).

Partially controlled UFC: mean UFC level \> ULN but with \>= 50% reduction from baseline.

Escape is defined as loss of UFC control (i.e. UFC \> ULN) on at least 2 consecutive visits at the highest tolerated dose after previously attaining UFC normalization)

Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus the 28 days post treatment

Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part l of this study. 4 patients in this cohort moved to Part II of the study

Part l: Core Cohort

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study

Part ll Core: Expansion Cohort

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Follow-up of this study. These patients were patients who transferred from Part l Core phase of the study

Part ll Core: Follow-up Cohort

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.

Part II Core: Expansion Cohort

Total

<65 years

Age, Customized

Sex: Female, Male

White

Black or African American

Asian

Race/Ethnicity, Customized

Part l: Core cohort: safety analysis set (SAS): All subjects that received at least one dose of study drug.

Part 2: Expansion cohort: Full Analysis Set (FAS): All patients in Follow-up cohort.

Study Director

Primary Analysis Set: All patients with evaluable UFC data (at least two 24 hour measurements for both baseline and Week 10) were included in the primary efficacy analysis set. Of the 12 patients enrolled to this arm, 9 of the 12 patients met this criteria.

Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10

BL: 11-Deoxycorticosterone

WK 22: 11-Deoxycorticosterone

WK 70: 11-Deoxycorticosterone

LOV: 11-Deoxycorticosterone

Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Follow-up of this study. These patients were patients who transferred from Part l Core phase of the study.

Safety Analysis Set (SAS): All patients in the Core proof of concept (PoC) follow-up cohort who received at least one dose of study treatment after reentering the study and all patients in the Expansion cohort who received at least one dose of study treatment after Protocol amendment 04.

Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)

BL: 11-Deoxycortisol

WK 22: 11-Deoxycortisol

WK 70: 11-Deoxycortisol

LOV: 11-Deoxycortisol

Safety Analysis Set (SAS): All patients in the Core PoC follow-up cohort who received at least one dose of study treatment after reentering the study and all patients in the Expansion cohort who received at least one dose of study treatment after Protocol amendment 04.

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)

BL: Aldosterone

WK 22: Aldosterone

WK 70: Aldosterone

LOV: Aldosterone

BL: Thyroxine, free

WK 22: Thyroxine, free

WK 70: Thyroxine, free

LOV: Thyroxine, free

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)

BL: Female Estradiol

WK 22: Female Estradiol

WK 70: Female Estradiol

LOV: Female Estradiol

Safety Analysis Set (SAS): All patients in the Core PoC follow-up cohort who received at least one dose of study treatment after reentering the study and all patients in the Expansion cohort who received at least one dose of study treatment after Protocol amendment 04. This analysis was on the female patients only.

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)

BL: Male Estradiol

WK 22: Male Estradiol

WK 70: Male Estradiol

LOV: Male Estradiol

Safety Analysis Set (SAS): All patients in the Core PoC follow-up cohort who received at least one dose of study treatment after reentering the study and all patients in the Expansion cohort who received at least one dose of study treatment after Protocol amendment 04. This analysis was on the male patients only.

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)

BL: Female FSH

WK 22: Female FSH

WK 70: Female FSH

LOV: Female FSH

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)

BL: Male FSH

WK 22: Male FSH

WK 70: Male FSH

LOV: Male FSH

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male)

BL: Renin

WK 22: Renin

WK 70: Renin

LOV: Renin

BL: Insulin

WK 22: Insulin

WK 70: Insulin

LOV: Insulin

BL: Thyrotropin

WK 22: Thyrotropin

WK 70: Thyrotropin

LOV: Thyrotropin

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin

BL: Insulin-like Growth Factor-1

WK 22: Insulin-like Growth Factor-1

WK 70: Insulin-like Growth Factor-1

LOV: Insulin-like Growth Factor-1

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Insulin-like Growth Factor-1

BL: Female LH

WK 22: Female LH

WK 70: Female LH

LOV: Female LH

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female)

BL: Male LH

WK 22: Male LH

WK 70: Male LH

LOV: Male LH

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male)

BL: Female Testosterone

WK 22: Female Testosterone

WK 70: Female Testosterone

LOV: Female Testosterone

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female)

BL: Male Testosterone

WK 22: Male Testosterone

WK 70: Male Testosterone

LOV: Male Testosterone

Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male)

WK 22

WK 70

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Fasting Glucose

Part II Core: Follow-up Cohort

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Hemoglobin A1C (HbA1C) (Glycosylated Hemoglobin)

BL Cholesterol

WK 22 Cholesterol

WK 70 Cholesterol

LOV Cholesterol

BL LDL Cholesterol

WK 22 LDL Cholesterol

WK 70 LDL Cholesterol

LOV LDL Cholesterol

BL HDL Cholesterol

WK 22 HDL Cholesterol

WK 70 HDL Cholesterol

LOV HDL Cholesterol

BL Triglycerides

WK 22 Triglycerides

WK 70 Triglycerides

LOV Triglycerides

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides

BL DBP

WK 22 DPB

WK 70 DPB

LOV DPB

BL SBP

WK 22 SPB

WK 70 SPB

LOV SPB

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Sitting Diastolic Blood Pressure (DBP), Sitting Systolic Blood Pressure (SBP)

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Body Mass Index (BMI)

Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)

AUC0-6h,ss

AUC0-12h,ss

Participants in the Expansion cohort who took 2mg of osilodrostat

2mg Bid

Participants in the Expansion cohort who took 5mg of osilodrostat

5mg Bid

Participants in the Expansion cohort who took 10mg of osilodrostat

10mg Bid

Participants in the Expansion cohort who took 20mg of osilodrostat

20mg Bid

Participants in the Expansion cohort who took 30mg of osilodrostat

30mg Bid

Pharmacokinetic Analysis Set (PAS): all enrolled patients with at least 1 dose of study drug and at least 1 post-dose PK assessment after Protocol Amendment 4 or after re-entering the study.

Pharmacokinetics (PK) Parameters: Area Under Curve (AUC)0-6h ss, AUC0-12h ss

Cmax,ss

PAS: all enrolled patients with at least 1 dose of study drug and at least 1 post-dose PK assessment after Protocol Amendment 4 or after re-entering the study.

PK Parameters: Cmax ss, Ctrough ss

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Study of Efficacy and Safety of Osilodrostat in Cushing's Syndrome	NCT02468193	Cushing's Syndr... Ectopic Cortico... Adrenal Adenoma Adrenal Carcino... AIMAH PPNAD	Osilodrostat	18 Years - 85 Years	Novartis
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease	NCT02180217	Cushings Diseas...	osilodrostat LCI699 matching...	18 Years - 75 Years	Novartis
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease	NCT02180217	Cushings Diseas...	osilodrostat LCI699 matching...	18 Years - 75 Years	Novartis
Pharmacokinetic (PK), Pharmacodynamic (PD) and Tolerability of Osilodrostat in Pediatric Patients With Cushing's Disease	NCT03708900	Cushing's Disea...	LCI699	6 Years - 17 Years	RECORDATI GROUP

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