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

Cushing's Disease Clinical Trial

— SEASCAPE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01582061
• Other study ID #: CSOM230B2406
• Status: Completed
• Phase: Phase 3
• Start date: August 16, 2011
• Est. completion date: January 26, 2017

Study information

• Verified date: May 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 104
• Est. completion date: January 26, 2017
• Est. primary completion date: January 26, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• ACTH-Secreting Pituitary Adenoma
• Cushing's Disease
• Pituitary ACTH Hypersecretion

Intervention

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

Locations

Country	Name	City	State
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	Joinville	SC
Brazil	Novartis Investigative Site	Londrina	PR
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Czechia	Novartis Investigative Site	Prague 2	Czech Republic
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Goettingen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Oldenburg
Germany	Novartis Investigative Site	Wurzburg
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki	GR
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Ashrafieh
Romania	Novartis Investigative Site	Bucharest
Romania	Novartis Investigative Site	Bucuresti
Romania	Novartis Investigative Site	Cluj
Romania	Novartis Investigative Site	Iasi
Russian Federation	Novartis Investigative Site	Moscow
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Granada	Andalucia
Spain	Novartis Investigative Site	Orense	Galicia
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Pontevedra	Galicia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Songkla
United States	University of New Mexico Hospital UNM	Albuquerque	New Mexico
United States	Emory University School of Medicine	Atlanta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	University of California at Los Angeles UCLA Tiverton	Los Angeles	California
United States	Mid South Endocrine Associates	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Mount Sinai School of Medicine	New York	New York
United States	Diabetes and Endocrinology Associates, PC	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Advanced Research, LLC	Peoria	Arizona
United States	University of Pennsylvania Medical Center Univ Penn	Philadelphia	Pennsylvania
United States	St Josephs Hospital & Medical Center St Joes	Phoenix	Arizona
United States	Allegheny Endocrinology Associates	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University OHSU 5	Portland	Oregon
United States	Swedish Cancer Institute Swedish Cancer Institute (SC)	Seattle	Washington
United States	LA Biomedical Research at Harbor UCLA Medical Center	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Brazil,  Czechia,  Germany,  Greece,  Korea, Republic of,  Lebanon,  Romania,  Russian Federation,  Spain,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percent Change in Cushing's Disease Clinical Signs and Symptoms - Temperature	degrees celius	Baseline week 12, 24 and 48
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percent Change From Baseline in Growth Hormone (GH) Values	Descriptive summary of the effect of pasireotide on GH.	Baseline, week 12, 24 and 48
Secondary	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