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

Anti-Dyskinesia Agents

Cardiotonic Agents

Cabergoline

Antiparkinson Agents

Dopamine

Dopamine Agonists

Dopamine Agents

Neurotransmitter Agents

The trial consisted of Pasireotide-untreated patients who started pasireotide 0.6mg twice a day for 8 weeks. If biochemical control was not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose was increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline was added and patients began combination treatment with cabergoline at the starting dose of 0.5mg once a day for 8 weeks. If biochemical control is still not achieved at the end of the third 8 week period, the dose of cabergoline was increased to 1.0mg once a day. Patients could also immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current maximal tolerated dose of pasireotide. Patients continued with the combination treatment for 8 weeks. If biochemical control was not not achieved by the end of the 8 week period, the dose of cabergoline was increased to 1mg once a day.

Pasireotide with or without cabergoline

The main purpose of this prospective, multicenter, open-label phase II study, was to evaluate the efficacy and safety of pasireotide alone or in combination with cabergoline in patients with Cushing's disease.

This was an open-label, multi-center, international, non-comparative study with adult patients with confirmed diagnosis of Cushing's disease. Given the fact that CD patients may need a multimodality treatment approach, the trial design aimed to mimic CD treatment by using a medical stepwise approach. Therefore, the whole patient population started treatment with Pasireotide and only in patients within this population who did not achieve biochemical control, cabergoline was added.

The whole patient population had never received pasireotide or had received it in the past (reasons of discontinuation not related to safety).

Core Phase

* Pasireotide naïve patients started pasireotide monotherapy at the dose of 0.6 mg s.c. bid. If at the end of the 8 week treatment period, the biochemical control was not achieved and the 0.6mg bid dose was well tolerated, the pasireotide dose was increased to 0.9mg bid. If the 0.9mg bid dose of pasireotide did not lead to biochemical control, cabergoline was added with a starting dose of 0.5mg qd. If the combination dose of 0.9mg bid of pasireotide plus 0.5mg qd cabergolinedid not achieve biochemical control, the cabergoline dose will be increased to 1.0mg qd.
* Patients who were currently being treated with maximal tolerated doses of pasireotide monotherapy for at least 8 weeks at screening without achieving normal mUFC, entered the study with a combination therapy starting with cabergoline 0.5mg qd.

Extension Phase

• After 35 weeks of treatment in core phase, patients had the option to continue study treatment if pasireotide was not yet approved for commercial use and/or reimbursed - if country reimbursement was applicable - in each respective country, or until 31st December 2017, or once an applicable roll over protocol became available, or whichever occurred first.

Novartis had a local transition plan in order to ensure that all trial patients had access to the study medication without any delay in their treatment

Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease

A Phase II Trial to Assess the Efficacy and Safety of Pasireotide s.c. Alone or in Combination With Cabergoline 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

Participants who attained mUFC ≤ 1.0 x ULN (upper limit of normal) with pasireotide alone or in combination with cabergoline. The 24h-UFC concentration results from three samples, collected during the screening period, were averaged to obtain the Baseline urinary free cortisol level. mean 24h-UFC was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit. Imputation: subjects who completed the end of treatment visit at Week 35, but had missing evaluation of mean urinary free cortisol (mUFC). The last available mUFC assessment at or after previous visit (week) before last week was carried forward as the last week mUFC assessment.

Mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.

Actual mean value of mUFC at each scheduled visit was determined from two 24-hour urine collections collected on two consecutive days that occurred before the visit when UFC was measured.

Duration of controlled or partially controlled response is defined as the period starting from the date of patient's first normalization (mUFC ≤ 1.0 x ULN) or at least 50% reduction from baseline up to the date when the patient's mUFC \> 1.0 x ULN and the reduction from baseline falls to less than 50% from the first time

A pre-dose blood draw for plasma ACTH sampling was taken at visits. Samples were analyzed by a central laboratory.

A pre-dose blood draw for an 8 am fasting serum cortisol measurement were taken at visits. Samples were analyzed by a central laboratory.

The mean arterial blood pressure determinations were obtained in the sitting position. Three measurements were taken with 5 minute intervals and the mean was used for study specific procedures

Weight was was one of the measures of clinical symptoms of CD

Body mass index was one of the measurements of clinical symptoms of CD. Body mass index=weight in kg divided by the square of the body height (in meters)

Waist circumference was one of the measurements of clinical signs of CD

LDL=Low density lipoprotein, HDL=high density llipoprotein and total protein were analyzed by a central laboratory

Patients who completed nine or more items for the 12-item Cushing's syndrome QoL questionaire were considered evaluable for that assessment. Raw scores were obtained for the 12 items using the following scoring: 1) always or very much, 2) often or quite a bit, 3) sometimes or somewhat, 4) rarely or very little, 5) never or not at all. Then the standardized score, Y, was calculated for each patient as follows: Y = 100\* (X - n) / n\*5 - n\*1) = 100 \* (X - n) / 4\*n where X denoted the raw score and n the number of questions answered by the patient. The higher the score, the better the QoL. The best possible standardized score was 100 and the worst possible standardized score was 0

SF-12v2 General Health Survey is a general patient reported outcome instrument over time. It is scored to provide eight health domain scores (Bodily Pain (BP), General Health (GH), Physical Functioning (PF), Role-Physical (RP), Social Functioning (SF), Role-Emotional (RE), Vitality (VT) and Mental Health (MH)). These eight domain scores can be combined to form two summary scores reflecting overall physical and mental health: the Physical Component Summary (PCS) and the Mental Component Summary (MCS). The analyses reported here focus on PCS and MCS scores. The domain scores use a norm-based score, which standardizes the scores with respect to the mean and standard deviation of a nationally representative sample of United States (US) adults. These are the scores on the original scale which have not been transformed in any way. The possible range of scores is 0 to 100, with higher scores representing better outcomes.

Clinical symptoms include: facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad. Two photographs, one frontal and one lateral from the shoulders up were taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position were taken to assess striae, and hirsutism. The photographs were assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

Facial rubor, hirsutism, striae, and supraclavicular and dorsal fat pad were assessed. Two photographs, one frontal and one lateral from the shoulders up will be taken to assess facial plethora, supraclavicular and dorsal fat pads. Two photographs, frontal and dorsal of the trunk with patient in standing position will be taken to assess striae, and hirsutism. The photographs must be assessed by a qualified physician at the site. Improvement=decrease in severity of symptom since baseline

To test proximal muscle strength patients should be placed in a low seated position (for instance on an examination room stool). They should be asked to extend the arms in front of them. From this seated position patients will be asked to stand up. Patients will be evaluated using the following scale: 3. - completely unable to stand 2. - able to stand only by using arms as assistance

1. - able to stand after several efforts without using arms as assistance 0. - able to stand easily with arms extended

Any sign or symptom that occurs during the study treatment plus 28 days post treatment

Pasireotide montherapy (0.6 mg bid to 0.9 mg bid) was administered until the biochemical control was achieved and if not achieved, a combination was administered: pasireotide (0.9 mg bid) + cabergoline (0.5 QD to 1 mg QD). Patients were able to add cabergoline at anytime during core and extension

< 65 years

≥ 65 years

Age, Customized

Caucasian

Asian

Native American

Black

Other

Race/Ethnicity, Customized

De novo

Persistent/recurrent

De novo = newly diagnosed and persistent/recurrent = xxxxxxxx

Cushing's disease status

None

Mild

Moderate

Severe

Not done

Clinical symptoms of CD for facial rubor by severity

Clinical symptoms of facial rubor

Clinical symptoms of CD for hirsutism by severity

Clinical symptoms of hirsutism

Clinical symptoms of CD for striae by severity

Clinical symptoms of striae

Clinical symptoms of CD for supraclavicular fat pad by severity

Clinical symptoms of supraclavicular fat pad

Clinical symptoms of CD for dorsal fat pad severity

Clinical symptoms of dorsal fat pad

Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35

Baseline

Core Week 2 n-8

Core Week 4 n=59

Core Week 8 n=58

Core Week 13 n=51

Core Week 17 n=57

Core Week 22 n=50

Core Week 26 n=54

Core Week 31 n=46

Full analysis set. The data beyond Week 139 should be interpreted with caution given that small number of subjects were monitored

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
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
Efficacy and Safety of Pasireotide Long Acting Release (LAR) Versus Octreotide LAR or Lanreotide Autogel (ATG) in Patients With Inadequately Controlled Acromegaly	NCT01137682	Acromegaly	Pasireotide octreotide LAR ... lanreotide ATG ...	18 Years -	Novartis
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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