Neoplasms

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ACTH-Secreting Pituitary Adenoma

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Pituitary Diseases

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pituitary Neoplasms

Endocrine Gland Neoplasms

ACTH-secreting Pituitary Adenoma

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period.

Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period.

Osilodrostat comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat was 30 mg bid.

osilodrostat

Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid.

LCI699 matching placebo

Novartis Pharmaceuticals

The study aimed to confirm long-term efficacy and safety of LCI699 for the treatment of patients with Cushing's disease. It was a pivotal trial which supported the registration of LCI699 for the treatment of patients with Cushing's disease in the US and the EU.

This is a phase lll, multi-center, double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period which evaluated the safety and efficacy of LCI699 for the treatment of patients with Cushing's disease.

The primary objective compared the complete response rate at the end of the 8-week period of randomized withdrawal (Week 34) between patients randomized to continued osilodrostat therapy vs.

placebo. The key secondary objective assessed the complete response rate at the end of individual dose titration and treatment with osilodrostat in the initial single-arm, open label period (Week 24).

Eligible patients were randomized in a double-blinded fashion at Week 26 at a 1:1 ratio either to continue treatment with osilodrostat at the same dose or to matching placebo. Randomization was stratified by osilodrostat dose at Week 24 (≤ 5mg bid vs. \>5mg bid); and history of pituitary irradiation (yes/no).

The study had four periods combined in the Core Period (Study Period 1 to 4) and an optional Extension Period. The optional Extension Period starting at Week 48.

Study Period 1 consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients (Week 1 to Week 12). Dose adjustments were based on the mean of three 24-hour UFC (mUFC) values as measured by the central laboratory.

During study Period 2 (Week 13 to Week 24), osilodrostat efficacy and safety were assessed at the therapeutic dose determined during study Period 1. Patients whose mUFC became elevated during this period had their osilodrostat dose increased further, if it was tolerated, up to 30 mg bid. Such patients were followed for long-term safety and efficacy and were not considered responders for the key secondary endpoint, hence were not randomized in Study Period 3.

Study Period 3 was a double-blind, placebo-controlled randomized withdrawal (RW) Period (Week 26 to Week 34). In order to be eligible for randomization in study Period 3, patients had to have completed dose titration during study Period 1, and had to be classified as complete responders at Week 24 of study Period 2. Patients not eligible for randomization received open-label osilodrostat until the end of the Core Period (Week 48), unless there was a reason to discontinue from the study prematurely.

During study Period 3, mUFC was measured at scheduled visits every 2 weeks. However, patients were also allowed to have unscheduled visits at any time during the RW if they reported symptoms of hypercortisolism or hypocortisolism.

The dose of study drug remained unchanged for patients who maintained a normal mUFC and did not develop adverse events (AEs) related to study drug during RW. The Investigator could reduce or temporally withhold a dose of study drug for safety reasons at any time during the study, including the RW Period.

During this study period, a patient was discontinued from the RW Period and declared a nonresponder, if the mUFC increased to \>1.5×ULN. After discontinuation from RW treatment, or at the end of the RW Period (Week 34), whichever came first, the patient resumed open-label osilodrostat at a dose selected by the Investigator.

Patients who discontinued from the study during the RW Period were no longer in the study, and consequently were not permitted to receive open-label osilodrostat and could not move to study Period 4.

Patients who discontinued from RW treatment due to lack of efficacy resumed open-label osilodrostat at the time of discontinuation, which could occur before Week 34. Patients who were not discontinued during RW resumed open-label osilodrostat at the end of RW (Week 34) and continued osilodrostat thereafter (study Period 4).

The Novartis study team, the patient, the Investigator, and all other site staff remained blinded to treatment assignment from the time of randomization to the time of database lock at the end of the Core Period. Novartis Drug Supply Management department members were unblinded in order to prepare the study drug supplies.

Study Period 4 was a single-arm, open-label therapy (end of Week 34 to Week 48). At the end of Week 34, all patients received open-label osilodrostat treatment. The Investigator had the discretion to select the dose during this period.

Patients continued open-label therapy until Week 48. At Week 48, patients had the option to enter an Extension Period, or discontinue osilodrostat at Week 48 to conclude with an end of Core Period visit 4 weeks off study drug (at Week 52).

Patients who continued to receive clinical benefit, as assessed by the study Investigator, and who wished to enter the Extension Period were re-consented at Week 48. Patients entered the Extension period without interruption of study drug or assessments. At the end of the study, patients who continued to benefit from treatment were offered to participate in a separate long-term safety follow-up study. The optional Extension Period ended after all patients completed Week 72 or discontinued early.

It is a double-blind, randomized withdrawal study of LCI699 following a 24 week, single-arm, open-label dose titration and treatment period.

Safety and Efficacy of LCI699 for the Treatment of Patients With Cushing's Disease

Phase III, Multi-center, Double-blind, Randomized Withdrawal Study of LCI699 Following a 24 Week, Single-arm, Open-label Dose Titration and Treatment Period to Evaluate the Safety and Efficacy of LCI699 for the Treatment of 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

To compare the complete response rate at the end of the 8-week period of randomized withdrawal between randomized patients.A primary efficacy responder is defined as a randomized patient who has mUFC ≤ ULN at Week 34 and who was neither discontinued (study or RW treatment) nor had osilodrostat dose increase above the level at Week 26 during the RW Period of the study. mUFC: mean urinary free cortisol; ULN: Upper Limit of Normal

To assess the complete response rate at the end of individual dose-titration and treatment with LCI699 in the initial single-arm, open label period. A Key secondary efficacy responder is defined as a patient in FAS who has mUFC ≤ ULN at Week 24 and the dose of osilodrostat during Study Period 2 (Weeks 13-24) was not increased above the level established at the end of Study Period 1 (Week 12). Patients who had missing mUFC assessment at Week 24 will be counted as non-responders for the key secondary endpoint.

Time-to-loss of control of mUFC during the RW Period, defined as the time (in days) from randomization to the first evidence of loss of control (defined as mUFC assessment \>1.5 ULN based on central laboratory result \& at least 2 of the associated individual urine samples showing UFC \>1.5×ULN) within the RW period. A patient without evidence of loss of control was censored at the date of the last assessment with mUFC ≤ 1.5 ULN. If a patient discontinued randomized treatment without having a UFC assessment, they were censored at the date of randomization. The measure type (number) refers to an Event probability estimate 8 weeks after randomization.

Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN

Actual change in fasting glucose from baseline.

Actual change in glycosylated hemoglobin (HbA1c) from baseline.

Actual change in Cholesterol, LDL Cholesterol, HDL Cholesterol \& Triglyceride from baseline.

Actual change in sitting SBP \& DBP from baseline.

Actual change in waist circumference from baseline.

Cushing's Disease Health-Related Quality of Life Questionnaire was developed to evaluate quality of life in patients with Cushing's syndrome. It is comprised of 12 items that capture patient responses on 7 concepts: daily activities, healing \& pain, mood \& self-confidence, social concerns, physical appearance, memory \& concern about the future. These items are measured on a 5- 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 4 weeks. 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. Content reliability, sensitivity to change \& psychometric properties have been validated in patients with Cushing's disease. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. Increases from baseline are indicative of an improvement.

BDI-II is a patient-reported instrument developed to measure the severity of depression in adults \& adolescents aged 13 years \& older. It is designed to be completed by the patient on paper \& takes approximately 5 minutes to complete. The BDI-II consists of 21 items designed to assess the intensity of depression in clinical \& normal patients in the preceding 2 weeks. Items are rated on a 4-point severity scale of 0 ('not at all') to 3 ('extreme' form of each symptom) with differing response options for each item. A global score ranging from 0 to 63 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. Patients were asked to complete the questionnaire prior to clinical assessments being undertaken. A reduction from baseline in BDI-II is indicative of an improvement.

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. It is cognitively undemanding, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire. 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, \& 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.

The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with on 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 VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.

Improvement from baseline to Weeks 48, 72 and End of Treatment (Extension period) in each of the following clinical signs of Cushing's disease by photography: facial rubor, hirsutism, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises).

Actual change from baseline to Week 48 and the LOV in bone mineral density as measured by DXA scan at the lumbar spine and total hip. An increase in bone mineral density is indicative of an improvement..

Escape was defined as the time (in days) from the first mUFC ≤ ULN to the first mUFC results \> 1.5 x ULN with at least 2 individual UFC results \> 1.5 x ULN the loss happened beyond 12-week dose titration period. Participants randomized to placebo were not included in the analysis.

To evaluate exposures of LCI699 in patients with Cushing's disease. Plasma concentrations (predose, 0.75 h, 1.5 h, and 4 h post-dose) of LCI699. These are the maximum number of PAS subjects analyzed for each incident dose.

Complete response rate is defined as percentage of enrolled participants with mUFC ≤ ULN.

Partial response rate is defined as percentage of enrolled participants with ≥ 50% reduction from baseline in mUFC, but mUFC\>ULN)

Overall response rate is defined as percentage of enrolled participants with mUFC ≤ ULN or at least 50% reduction from baseline.

Adverse Event: Any sign or symptom that occurs during the study treatment plus up to 30 days after the last dose administration.

Osilodrostat

LCI699 Placebo

All participants in this group took open label osilodrostat, before and after randomization.

Non-randomized

Consisted of all participants who were enrolled and treated with open label osilodrostat.

All Participants

Osilodrostat (LCI699)

Total

Age, Continuous

Sex: Female, Male

Caucasian

Black

Asian

Other

Race/Ethnicity, Customized

Full analysis set (FAS): comprises all enrolled patients who received at least one dose of osilodrostat.

The first 12 weeks of the study consisted of an individual dose-titration period.

Study Director

Randomized analysis set (RAS): comprises all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).

Percentage of Primary Efficacy Responder at Week 34 by Randomized Treatment and Strata

Consisted of all participants who were enrolled and treated in the open label osilodrostat.

Percentage of Secondary Efficacy Responder at Week 24 (Key Secondary Endpoint)

Randomized analysis set (RAS): comprised all randomized patients who received at least one dose of randomized drug (osilodrostat or placebo).

Time-to-loss of Control of Mean Urinary Free Cortisol (mUFC) by Randomized Treatment Group

Week 12

Week 24

Week 48

Week 72

Last observed value

Complete Response Rate (CRR)

Actual Baseline (BL)

Wk 12: Act. change from BL

Wk 24: Act. change from BL

Wk 48: Act. change from BL

Wk 72: Act. change from BL

Last avail. assess.: Act. change from BL

Actual Change From Baseline in mUFC

Baseline

Wk 48

Wk 72

Last avail. assessment

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Fasting Glucose

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Hemoglobin A1C (HbA1C)

Cholesterol: BL

Cholesterol: Wk 48

Cholesterol: Wk 72

Cholesterol: Last avail. assessment

LDL Cholesterol: BL

LDL Cholesterol: Wk 48

LDL Cholesterol: Wk 72

LDL Cholesterol: Last avail asses

HDL Cholesterol: BL

HDL Cholesterol: Wk 48

HDL Cholesterol: Wk 72

HDL Cholesterol: Last avail assess

Triglyceride: BL

Triglyceride: Wk 48

Triglyceride: Wk 72

Triglyceride: Last avail. assess

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Cholesterol, LDL Cholesterol, HDL Cholesterol & Triglyceride

SBP: Baseline

SBP: Wk 48

SBP: Wk 72

SBP: Last avail. assessment

DBP: Baseline

DBP: Wk 48

DBP: Wk 72

DBP: Last avail. assessment

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Sitting Systolic Blood Pressure (SBP) & Sitting Diastolic Blood Pressure (DBP)

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Weight

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Body Mass Index (BMI)

Actual Change From Baseline in Cardiovascular-related Parameter Associated With Cushing's Disease: Waist Circumference

Last available assess.

FAS: Comprised all enrolled patients who received at least one dose of osilodrostat.

Actual Change From Baseline in Patient-Reported Outcomes (Cushing's Health-Related Quality of Life (QoL)) - Total Score

Last avail. assess.

FAS comprised all enrolled patients who received at least one dose of osilodrostat.

Actual Change From Baseline in Patient-Reported Outcomes: Beck Depression Inventory-II (BDI-II)

Actual Change in Patient-Reported Outcomes: EQ-5D-5L Utility Index

Actual Change in Patient-Reported Outcomes: EQ-5D-5L Vascular Analog Scale (VAS)

W48: Facial rubor

W48: Striae

W48:Supraclavicular fat pad

W48: Dorsal fat pad

W48: Proximal muscle atrophy

W48: Central obesity

W48: Ecchymoses

W72: Facial rubor

W72: Striae

W72:Supraclavicular fat pad

W72: Dorsal fat pad

W72: Proximal muscle atrophy

W72: Central obesity

W72: Ecchymoses

End of Trial (EOT):Facial rubor

EOT: Striae

EOT:Supraclavicular fat pad

EOT: Dorsal fat pad

EOT: Proximal muscle atrophy

EOT: Central obesity

EOT: Ecchymoses

Change From Baseline in the Physical Features of Cushing's Disease by Photography

Baseline (L1-L4 Lumbar Spine)

W48 (L1-L4 Lumbar Spine)

LOV (L1-L4 Lumbar Spine)

Baseline (Total Hip)

W48 (Total Hip)

LOV (Total Hip)

Change From Baseline in Bone Mineral Density - All Participants

Consisted of all participants in the study under osilodrostat treatment

FAS comprised all enrolled patients who received at least one dose of osilodrostat. This is a subset of the FAS participants who met all the criteria for Escape. The placebo patients + patients that did not reach mUFC \<= ULN at some stage during the study are excluded from the denominator.

Time-to-escape

Week (Wk) 2: Predose

Wk 2: 0.75h

Wk 2: 1.5h

Wk 2: 4h

Wk 4: Predose

Wk 4: 0.75h

Wk 4: 1.5h

Wk 4: 4h

Wk 6: Predose

Wk 6: 0.75h

Wk 6: 1.5h

Wk 6: 4h

Wk 8: Predose

Wk 8: 0.75h

Wk 8: 1.5h

Wk 8: 4h

Wk 10: Predose

Wk 10: 0.75h

Wk 10: 1.5h

Wk 10: 4h

Participants received 2mg of osilodrostat

Osilodrostat (LCI699) 2 mg

Participants received 3mg of osilodrostat

Osilodrostat (LCI699) 3 mg

Participants received 5 mg of osilodrostat

Osilodrostat (LCI699) 5 mg

Participants received 7 mg of osilodrostat

Osilodrostat (LCI699) 7 mg

Pharmacokinetics analysis set (PAS) consists of all enrolled patients who receive at least one dose of osilodrostat and have at least one evaluable post-dosing PK assessment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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 for the Treatment of Patients With Cushing's Disease	NCT02180217	Cushings Diseas...	osilodrostat LCI699 matching...	18 Years - 75 Years	Novartis

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