Nervous System Diseases

Gland and Hormone Related Diseases

All Conditions

Neoplasms

Rare Diseases

Pituitary Diseases

Pituitary Neoplasms

ACTH-Secreting Pituitary Adenoma

Pituitary ACTH Hypersecretion

Adenoma

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Endocrine System Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine Gland Neoplasms

ACTH-secreting Pituitary Adenoma

Anti-Inflammatory Agents

All Drugs and Chemicals

Pharmaceutical Solutions

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Hormones

Pasireotide

Adrenocorticotropic Hormone

Melanocyte-Stimulating Hormones

beta-Endorphin

Hormone Antagonists

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 600 μg bid group includes all patients whose mean daily dose \< 1500 μg /day.

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined on the mean daily dose considering the following grouping rule: 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg, 600 μg, or 300 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg and 600 μg for glucose impaired metabolism patients

Pasireotide sub-cutaneous

Novartis Pharmaceuticals

This study provided access to pasireotide sc in patients with Cushing's disease.and provided additional information for safety and efficacy of pasireotide s.c.

Purpose of this study was to give access to pasireotide sc for patients with Cushing's disease as no medical treatment for Cushing's disease was approved at the time of the study initiation. The study population consisted of patients with persistent or recurrent Cushing's disease or patients with de novo Cushing's disease that were not considered candidates for pituitary surgery (poor surgery candidates, surgically unapproachable tumor, patients with no visible pituitary tumor, patients who refused surgery). A confirmed Cushing's disease diagnosis was required.

An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.

An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease (Seascape).

Only AEs occurring on or after the start of study treatment and no more than 28 days after the discontinuation of study treatment. A patient with multiple occurrences of an AE under one treatment is counted only once in the AE category for that treatment. A patient with multiple severity grades for an AE while on a treatment, is only counted under the maximum grade.

The 24h-UFC concentration results from three samples during screening were averaged to obtain baseline. After baseline, mean 24h UFC was determined at week 24. At Week 4, 8, 16 and 20, mean 24h UFC was determined from two 24 hour urine collections collected on two consecutive days occurring before the visit. At Week 12, 24 and 48, the mean 24h-UFC from three 24 hour urine collections, collected over the week before the visit, was determined. After Week 24, the mean 24h UFC was determined at 12-week intervals until end of study visit, from two 24 hour collections during two consecutive days prior to each respective visit (except at Week 48). UFC was determined by liquid chromatography tandem mass spectroscopy (LC/MS/MS). The normal ranges were determined by the central laboratory's own reference range. All samples, including screening samples, were analyzed by a central laboratory.

A 12-item Cushing's syndrome HRQoL questionnaire (CushingQoL, cf. Webb et al 2008) was implemented and patients who completed 9 or more items at a visit were considered evaluable for that visit. The standardized scores were calculated as follows: 1) Obtain raw scores, denoted by X, as the sum of all the ratings on all the HRQoL questions for a single patient and the score can range from 12 (worst HRQoL) to 60 points (best HRQoL). Therefore, the lower the score, greater the negative impact on HRQoL and 2) obtain standardized score, Y, for a single patient

• Y = 100 (X-12) / (60-12) = 100 (X-12)/48. For example, if a patient answers all 12 items with 'Sometimes' or 'Somewhat', X = 36 and Y = 100 ∙ 24/48 = 50 The WPAI-GH questionnaire was used to assess work productivity and activity impairment. However, there was very limited baseline data and therefore the results and outcomes of the objective, 'change from baseline in WPAI-GH scores' are not included.

Standing systolic and diastolic BP based on 1 assessment and sitting systolic and diastolic BP was mean of 3 assessments.

Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)\*100

Percent change in patients reducing by at least one class level. Class levels: \<25.0, 25.0 to \<30.0, ≥ 30.0. Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)\*100

Clinically relevant threshold (at any time point) was reduction of ≥ 5%

Direct observation of ability to stand unaided: 0=able to stand easily with arms extended, 1=able to stand after several efforts without using arms as assistance, 2=able to stand only by using arms as assistance 3=completely unable to stand

Clinically relevant threshold (at any time point). Reduction of ≥ 5%, Reduction of ≥ 10%

Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)\*100. Ferriman-Gallway scoring was used: 0=minimum and 36 was maximum in females only.

Descriptive summary of the effect of pasireotide on GH.

Descriptive summary of the effect of pasireotide on IGF-1

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events fields "number of deaths resulting from adverse events" all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator

600 µg Bid

900 µg Bid

All Patients

Pasireotide 600 μg

Pasireotide 900 μg

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

Any primary system organ class

Metabolism and nutrition disorders

Gastrointestinal disorders

Investigations

Hepatobiliary disorders

Endocrine disorders

Gen disorders,admin site conditions

Ear and labyrinth disorders

Infections and infestations

Musculoskeletal and connective tissue disorders

Neoplasms benign, malignant and unspecified

Nervous system disorders

Psychiatric disorders

Respiratory, thoracic, mediastinal disorders

All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose \< 1500 μg /day.

600 µg Bid - All Grades

Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients

600 μg - Grades 3/4

All grades of adverse events. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

900 μg - All Grades

Adverse event grades 3 and 4. Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg

900 μg - Grades 3/4

All grades of adverse events for all patients who received 600 µg bid or 900 µg bid of pasireotide sub-cutaneous.

All Patients - All Grades

All Patients - Grades 3/4

Three additional arms were created to display subset of subjects with specific criteria.

Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE)

Week 12

Week 24

Week 48

Week 24 (LOCF)

Week 48 (LOCF)

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 600 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 600 μg for glucose impaired metabolism patients. Mean daily dose category is defined: 600 μg bid group includes all patients whose mean daily dose \< 1500 μg /day.

Pasireotide sub-cutaneous was supplied in 1 ml ampoules containing 900 μg pasireotide per 1 ml of solution and was administered BID. Starting dose was 900 μg. Mean daily dose category is defined : 900 μg bid group includes all patients whose mean daily dose ≥ 1500 μg /day

Patients received pasireotide 600 μg or 900 μg BID

LOCF Week 24: last available mean 24h-UFC of at least two samples between and including week 12 and week 24; LOCF Week 48: last available mean 24h-UFC of at least two samples between and including week 12 and week 48. Two-sided 95% confidence intervals for proportions are calculated using the exact method

Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)

Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline

Only patients who completed at least 9 questions on questionnaire were included for that visit.

Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores

Sitting systolic Week 12

Sitting systolic Week 24

Sitting systolic Week 48

Standing systolic Week 12

Standing systolic Week 24

Standing systolic Week 48

Sitting diastolic Week 12

Sitting diastolic Week 24

Sitting diastolic Week 48

Standing diastolic Week 12

Standing diastolic Week 24

Standing diastolic Week 48

Number of patients with available data differed at visits

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP)

Sitting pulse Week 12

Sitting pulse Week 24

Sitting pulse Week 48

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI)

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference

Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism

Percent Change From Baseline in Growth Hormone (GH) Values

Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values

Overall Study

Gastrointestinal Agents

Lactitol

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

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

<65 years

Age, Customized

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.	NCT01582061	Cushing's Disea...	Pasireotide sub...	18 Years -	Novartis
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Evaluation of New Diagnostic Indicator of Subclinical Hypercortisolism	NCT04833192	Adrenal Inciden... Subclinical Hyp...	experimental gr...	18 Years - 75 Years	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease	NCT01915303	Cushings Diseas...	Pasireotide wit...	18 Years -	Novartis
Safety and Efficacy of LCI699 in Cushing's Disease Patients	NCT01331239	Cushings Diseas... Cushing Disease	LCI699	18 Years - 75 Years	Novartis
Evaluation of New Diagnostic Indicator of Subclinical Hypercortisolism	NCT04833192	Adrenal Inciden... Subclinical Hyp...	experimental gr...	18 Years - 75 Years	The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School
An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.	NCT01582061	Cushing's Disea...	Pasireotide sub...	18 Years -	Novartis

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