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

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

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.

Study Overview

• Status: Completed
• Conditions: Cushing's Disease
• Intervention / Treatment: Drug: Pasireotide sub-cutaneous

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • CE
    • Fortaleza, CE, Brazil, 04636-000
      • Novartis Investigative Site
  • PR
    • Londrina, PR, Brazil, 86015-520
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 21941-913
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90560-030
      • Novartis Investigative Site
  • SC
    • Joinville, SC, Brazil, 89201260
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 04029-000
      • Novartis Investigative Site
• Czechia
  • Czech Republic
    • Prague 2, Czech Republic, Czechia, 128 00
      • Novartis Investigative Site
• Germany
  • Aachen, Germany, 52074
    • Novartis Investigative Site
  • Augsburg, Germany, 86150
    • Novartis Investigative Site
  • Berlin, Germany, 10098
    • Novartis Investigative Site
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
  • Frankfurt, Germany, 60329
    • Novartis Investigative Site
  • Goettingen, Germany, 37075
    • Novartis Investigative Site
  • Hamburg, Germany, 22587
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Marburg, Germany, 35039
    • Novartis Investigative Site
  • Muenchen, Germany, 80804
    • Novartis Investigative Site
  • Oldenburg, Germany, 26122
    • Novartis Investigative Site
  • Wurzburg, Germany, 97080
    • Novartis Investigative Site
• Greece
  • Athens, Greece, 106 76
    • Novartis Investigative Site
  • Thessaloniki, Greece, 546 36
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 115 27
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 546 42
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seoul, Korea, Republic of, 03722
    • Novartis Investigative Site
  • Korea
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 02447
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania, 011461
    • Novartis Investigative Site
  • Bucuresti, Romania, 011863
    • Novartis Investigative Site
  • Cluj, Romania, 400006
    • Novartis Investigative Site
  • Iasi, Romania, 700106
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 129110
    • Novartis Investigative Site
• Spain
  • Andalucia
    • Cordoba, Andalucia, Spain, 14004
      • Novartis Investigative Site
    • Granada, Andalucia, Spain, 18003
      • Novartis Investigative Site
  • Catalunya
    • Badalona, Catalunya, Spain, 08916
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Novartis Investigative Site
  • Galicia
    • Orense, Galicia, Spain, 32005
      • Novartis Investigative Site
    • Pontevedra, Galicia, Spain, 36071
      • Novartis Investigative Site
  • Islas Baleares
    • Palma De Mallorca, Islas Baleares, Spain, 07120
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Songkla, Thailand, 90110
    • Novartis Investigative Site
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Advanced Research, LLC
    • Phoenix, Arizona, United States, 85013
      • St Josephs Hospital & Medical Center St Joes
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles UCLA Tiverton
    • Torrance, California, United States, 90502
      • LA Biomedical Research at Harbor UCLA Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School Of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60644
      • John H Stroger Jr Hospital of Cook County
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
    • Omaha, Nebraska, United States, 68131
      • Diabetes and Endocrinology Associates, PC
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Hospital UNM
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University OHSU 5
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Medical Center Univ Penn
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Endocrinology Associates
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center
    • Nashville, Tennessee, United States, 37203
      • Mid South Endocrine Associates
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute Swedish Cancer Institute (SC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Written informed consent obtained prior to any screening procedures
2. Male or female patients aged 18 years or greater
3. Patients with confirmed diagnosis of Cushing's disease as evidenced by mean urinary free cortisol of three 24-hour urine samples collected during the 3-week screening period above the upper limit of the laboratory normal range morning plasma ACTH within the normal or above normal range either MRI confirmation of pituitary adenoma (greater than or equal to 0.6 cm), or inferior petrosal sinus gradient >3 after CRH stimulation for those patients with a microadenoma less than 0.6 cm, or for patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma.
4. Patients with de novo Cushing's disease must not be considered as candidates for pituitary surgery (i.e. poor surgical candidates, surgically unapproachable tumors, patients with no visible pituitary tumor, patients who refuse to have surgical treatment)
5. Karnofsky performance status >60 (i.e. requires occasional assistance, but is able to care for most of his personal needs)

6. For patients on previous medical treatment for Cushing's disease the following washout periods must be completed before screening assessments are performed

   • Inhibitors of steroidogenesis (e.g. ketoconazole, metyrapone, rosiglitazone): 1 week
   • Dopamine agonists (e.g. bromocriptine, cabergoline): 4 weeks
   • Mitotane: 6 months
   • Octreotide LAR and Lanreotide autogel: 8 weeks
   • Lanreotide SR: 4 weeks
   • Octreotide (immediate release formulation): 1 week
   • Glucocorticoid receptor inhibitor (mifepristone): 4 weeks

Exclusion criteria:

1. Radiotherapy of the pituitary <4 weeks before screening or patient who has not recovered from side effects
2. Patients with compression of the optic chiasm causing acute clinically significant visual field defect
3. Patients with Cushing's syndrome due to ectopic ACTH secretion
4. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
5. Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1)
6. Patients with a diagnosis of glucocorticoid-remedial aldosteronism (GRA)
7. Patients who have undergone major surgery within 1 month prior to screening
8. Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)
9. Diabetic patients whose blood glucose is poorly controlled as evidenced by HbA1C >8%

10. Patients who have clinically significant impairment in cardiovascular function or are at risk thereof, as evidenced by congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, high grade AV block, history of acute MI less than one year prior to study entry

    • QTcF >450 msec at screening
    • History of syncope or family history of idiopathic sudden death
    • Risk factors for Torsades de Pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, cardiac failure
    • Concomitant disease(s) that could prolong the QT interval such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, cirrhosis, uncontrolled hypothyroidism, concomitant medication(s) with known risk for TdP
11. Patients with liver disease or history of liver disease such as cirrhosis, chronic active hepatitis B and C, or chronic persistent hepatitis, or patients with ALT or AST more than 2 x ULN, serum creatinine >2.0 x ULN, serum bilirubin >1.5 x ULN, serum albumin < 0.67 x LLN at screening

12. Patients who have any current or prior medical condition that can interfere with the conduct of the study or the evaluation of its results, such as

    • History of immunocompromise, including a positive HIV test result (Elisa and Western blot). An HIV test will not be required, however, previous medical history will be reviewed
    • Presence of active or suspected acute or chronic uncontrolled infection
    • History of, or current alcohol misuse/abuse in the 12 month period prior to screening
13. Female patients who are pregnant or lactating, or are of childbearing potential and not practicing a medically acceptable method of birth control. If a woman is participating in the trial then one form of contraception is sufficient (pill or diaphragm) and the partner should use a condom. If oral contraception is used in addition to condoms, the patient must have been practicing this method for at least two months prior to screening and must agree to continue the oral contraceptive throughout the course of the study and for one month after the study has ended. Male patients who are sexually active are required to use condoms during the study and for three month afterwards as a precautionary measure (available data do not suggest any increased reproductive risk with the study drugs)
14. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to screening or patients who have previously been treated with pasireotide
15. Known hypersensitivity to somatostatin analogues
16. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
17. Patients with presence of Hepatitis B surface antigen (HbsAg)
18. Patients with presence of Hepatitis C antibody test (anti-HCV)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Pasireotide 600 μg; 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.	Drug: Pasireotide sub-cutaneous; 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; Other Names: SOM230 sub-cutaneous
EXPERIMENTAL: Pasireotide 900 μg; 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	Drug: Pasireotide sub-cutaneous; 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; Other Names: SOM230 sub-cutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE)	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.	Baseline up to approximately 256 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)	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.	Baseline, week 12, 24 and 48
Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline	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.	Baseline, week 12, 24 and 48
Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores	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.	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP)	Standing systolic and diastolic BP based on 1 assessment and sitting systolic and diastolic BP was mean of 3 assessments.	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse	Change from baseline is shown as: Percent change from baseline (BL) =((Post BL value - BL value)/ BL value)*100	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature	degrees celius	Baseline week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI)	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	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight	Clinically relevant threshold (at any time point) was reduction of ≥ 5%	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength	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	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference	Clinically relevant threshold (at any time point). Reduction of ≥ 5%, Reduction of ≥ 10%	Baseline, week 12, 24 and 48
Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism	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.	Baseline, week 12, 24 and 48
Percent Change From Baseline in Growth Hormone (GH) Values	Descriptive summary of the effect of pasireotide on GH.	Baseline, week 12, 24 and 48
Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values	Descriptive summary of the effect of pasireotide on IGF-1	Baseline, week 12, 24 and 48

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Fleseriu M, Iweha C, Salgado L, Mazzuco TL, Campigotto F, Maamari R, Limumpornpetch P. Safety and Efficacy of Subcutaneous Pasireotide in Patients With Cushing's Disease: Results From an Open-Label, Multicenter, Single-Arm, Multinational, Expanded-Access Study. Front Endocrinol (Lausanne). 2019 Jul 16;10:436. doi: 10.3389/fendo.2019.00436. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 16, 2011
• Primary Completion (ACTUAL): January 26, 2017
• Study Completion (ACTUAL): January 26, 2017

Study Registration Dates

• First Submitted: April 12, 2012
• First Submitted That Met QC Criteria: April 19, 2012
• First Posted (ESTIMATE): April 20, 2012

Study Record Updates

• Last Update Posted (ACTUAL): June 19, 2018
• Last Update Submitted That Met QC Criteria: May 24, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: adult; Cortisol; SOM230; Pituitary tumor; Adrenocorticotropic hormone; Cushing's disease; Hormone disorder
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Hypothalamic Diseases; Hyperpituitarism; Pituitary Diseases; Adenoma; Pituitary Neoplasms; ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pasireotide
• Other Study ID Numbers: CSOM230B2406

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED