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

Anti-Dyskinesia Agents

Cardiotonic Agents

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Hormones

Cabergoline

Pasireotide

Adrenocorticotropic Hormone

Melanocyte-Stimulating Hormones

beta-Endorphin

Hormone Antagonists

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

Novartis Pharmaceuticals

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

All Patients

< 65 years

≥ 65 years

Age, Customized

Sex: Female, Male

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

Study Director

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

Core Week 35 n=45

Ext Week 43 n=22

Ext Week 51 n=20

Ext Week 59 n=24

Ext Week 67 n=17

Ext Week 75 n=18

Ext Week 83 n=20

Ext Week 91 n=18

Ext Week 99 n=13

Ext Week 107 n=12

Ext Week 115 n=13

Ext Week 123 n=13

Ext Week 131 n=11

Ext Week 139 n=9

Ext Week 147 n=9

Ext Week 155 n=4

Ext Week 163 n=6

Ext Week 171 n=6

Ext Week 179 n=4

Ext Week 187 n=4

Ext Week 195 n=3

Ext Week 203 n=4

Ext Week 211 n=3

Ext Week 219 n=2

Ext Week 227 n=2

Ext Week 235 n=3

Ext Week 243 n=1

Ext Week 251 n=1

Ext Week 267 n=1

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

Spots Global Cancer Trial Database for pasireotide with or without cabergoline