Clinical trial NCT01582061: An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease.
Official title: An Open-label, Multi-center, Expanded Access Study of Pasireotide s.c. in Patients With Cushing's Disease (Seascape).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cushing's Disease
Keywords: Cushing's disease
Hormone disorder
Cortisol
Adrenocorticotropic hormone
Pituitary tumor
SOM230
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-04-20
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: Percentage of Patients With a Drug-related Adverse Event That is Recorded as Grade 3 or 4 or as a Serious Adverse Event (SAE)
timeFrame: Baseline up to approximately 256 weeks
Secondary outcomes:
measure: Percentage of Patients With Mean Urinary Free Cortisol (UFC) ≤ Upper Limit of Normal (ULN)
timeFrame: Baseline, week 12, 24 and 48
measure: Percentage of Patients Achieving a Reduction of Mean UFC ≥ 50% From Baseline
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing Quality of Life and Work Productivity and Activity Impairment-General Health (WPAI-GH) Scores
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Blood Pressure (BP)
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Pulse
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature
timeFrame: Baseline week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Body Mass Index (BMI)
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Weight
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Muscle Strength
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Waist Circumference
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change in Cushing's Disease Clinical Signs and Symptoms - Hirsutism
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change From Baseline in Growth Hormone (GH) Values
timeFrame: Baseline, week 12, 24 and 48
measure: Percent Change From Baseline in Insulin Growth Factor - 1 (IGF - 1) Values
timeFrame: Baseline, week 12, 24 and 48
Other outcomes:
Locations:
city: Peoria
country: United States
facility: Advanced Research, LLC
state: Arizona
city: Phoenix
country: United States
facility: St Josephs Hospital & Medical Center St Joes
state: Arizona
city: Los Angeles
country: United States
facility: University of California at Los Angeles UCLA Tiverton
state: California
city: Torrance
country: United States
facility: LA Biomedical Research at Harbor UCLA Medical Center
state: California
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: John H Stroger Jr Hospital of Cook County
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Omaha
country: United States
facility: Diabetes and Endocrinology Associates, PC
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Hospital UNM
state: New Mexico
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Portland
country: United States
facility: Oregon Health and Science University OHSU 5
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center Univ Penn
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Endocrinology Associates
state: Pennsylvania
city: Nashville
country: United States
facility: Mid South Endocrine Associates
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Seattle
country: United States
facility: Swedish Cancer Institute Swedish Cancer Institute (SC)
state: Washington
city: Fortaleza
country: Brazil
facility: Novartis Investigative Site
state: CE
city: Londrina
country: Brazil
facility: Novartis Investigative Site
state: PR
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Joinville
country: Brazil
facility: Novartis Investigative Site
state: SC
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Prague 2
country: Czechia
facility: Novartis Investigative Site
state: Czech Republic
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Frankfurt
country: Germany
facility: Novartis Investigative Site
city: Goettingen
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Marburg
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Oldenburg
country: Germany
facility: Novartis Investigative Site
city: Wurzburg
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Bucharest
country: Romania
facility: Novartis Investigative Site
city: Bucuresti
country: Romania
facility: Novartis Investigative Site
city: Cluj
country: Romania
facility: Novartis Investigative Site
city: Iasi
country: Romania
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Granada
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Orense
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Pontevedra
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Palma De Mallorca
country: Spain
facility: Novartis Investigative Site
state: Islas Baleares
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Songkla
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.