Clinical trial NCT01915303: Study of the Efficacy and Safety of Pasireotide s.c. +/- Cabergoline in Patients With Cushing's Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cushings Disease
Keywords: pituitary tumors
pasireotide
cabergoline
combination treatment
UFC
hormone disorder
cortisol
adrenocorticotropic hormone
Cushing Disease
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-08-02
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Eligibility criteria: Inclusion criteria:

1. Written informed consent obtained prior to screening procedures
2. Adult patients with confirmed diagnosis of ACTH-dependent Cushing's disease as evidenced by all of the following:

   1. The mean of three 24-hour urine samples collected within 2 weeks \> 1xULN with 2 out of 3 samples \>ULN
   2. Morning plasma ACTH within the normal or above normal range
   3. Either MRI confirmation of pituitary adenoma \> 6 mm, or inferior petrosal sinus gradient \>3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm\*. For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma \*If IPSS had previously been performed without CRH (e.g. with DDAVP), then a central to peripheral pre-stimulation gradient \> 2 was required. If IPSS had not previously been performed, IPSS with CRH stimulation was required.
3. Patients with de novo Cushing's disease could only be included only if they were not considered candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable tumors, patients who refused to have surgical treatment)
4. Male or female patients aged 18 years or greater
5. Karnofsky performance status ≥ 60 (i.e. required occasional assistance, but was able to care for most of their personal needs)
6. Patients on medical treatment for Cushing's disease the following washout periods must have been completed before screening assessments were performed

   * Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week
   * Pituitary directed agents: Dopamine agonists (bromocriptine, cabergoline) and PPARγ agonists (rosiglitazone or pioglitazone): 4 weeks
   * Octreotide LAR, Lanreotide SR and Lanreotide autogel: 14 weeks
   * Octreotide (immediate release formulation): 1 week
   * Progesterone receptor antagonist (mifepristone): 4 weeks
7. Patients could have been considered to enter the trial if they met any one of the following criteria: 1) They were naive to pasireotide 2) They had received pasireotide in the past and have been discontinued because of lack of efficacy (2 weeks for washout prior to screening for patients treated with pasireotide subcutaneously and 12 weeks of washout prior to screening for patients treated with pasireotide LAR) 3) Patients who were on maximal tolerated dose but had not achieved biochemical control
8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, if they were using highly effective methods of contraception during dosing and for 30 days after stopping study medication.
9. Male participants in the trial must have agreed to use a condom during intercourse, and not to father a child during the study and for the period of 30 days following stopping of the study treatment.

Exclusion criteria:

1. Patients with compression of the optic chiasm that caused any visual field defect that required surgical intervention
2. Diabetic patients with poor glycemic control as evidenced by HbA1c \>8%
3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF \>450 ms in males, and \> 460 ms in females. hypokalemia, hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval.
4. Patients with clinically significant valvular disease.
5. Patients with Cushing's syndrome due to ectopic ACTH secretion
6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral adrenal hyperplasia
7. Patients who had congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute MI less than one year prior to study entry or clinically significant impairment in cardiovascular function
8. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST \> 2 X ULN, serum bilirubin \>2.0 X ULN
9. Patients with serum creatinine \>2.0 X ULN
10. Patients with WBC \<3 X 10e9/L; Hb 90% \< LLN; PLT \<100 X 10e9/L
11. Patients with presence of Hepatitis B surface antigen (HbsAg)
12. Patients with presence of Hepatitis C antibody test (anti-HCV)
13. Patients with severe hepatic impairment (Child Pugh C) and hypersensitivity to pasireotide or cabergoline
14. Patients with lung, pericardial, and retroperitoneal fibrosis; gastro-duodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynauds syndrome.
15. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/ml)
16. Patients with end-stage renal failure and/or hemodialysis
17. Patients with presence of active or suspected acute or chronic uncontrolled infection
18. Patients with a history of non-complance to medical regimens or who were considered potentially unreliable or were unable to complete the entire study
19. Patients with presence of Hepatitis B surface antigen (HbsAg)
20. Patients with presence of Hepatitis C antibody test (anti-HCV)
21. Patients with severe hepatic impairment (Child Pugh C) and hpersensitivity to pasireotide or cabergoline
22. Patients with lung, pericardial, and retroperitoneal fibrosis; gastroduodenal ulcer or digestive haemorrhage, galactose intolerance, Parkinson's disease, uncontrolled hypertension and Raynaud's syndrome
23. Pregnant or nursing (lactating) women where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5mIU/mL)
24. Patients with end-stage renal failure and/or hemodialysis

Primary outcomes:
measure: Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN Collected or Imputed at Week 35
timeFrame: Baseline up to week 35
Secondary outcomes:
measure: Mean Urinary Free Cortisol (mUFC) at Scheduled Visits
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
measure: Percentage of Responders With Mean Urinary Free Cortisol (mUFC) ≤ 1.0xULN
timeFrame: Baseline up to week 235
measure: Percentage of Participants Who Attain mUFC ≤ 1.0 x ULN or Have at Least 50% Reduction From Baseline in mUFC
timeFrame: Baseline up to week 235
measure: Duration (Weeks) of Controlled or Partially Controlled Response
timeFrame: from the date patient's first normalization (mUFC ≤ 1.0xULN) or at least 50% reduction from baseline up to the date when the patient's mUFC > 1.0 x ULN
measure: Plasma Adrenocorticotropic Hormone (ACTH)
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
measure: Serum Cortisol Levels
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
measure: Sitting Systolic Blood Pressure at Week 35
timeFrame: Baseline and week 35
measure: Sitting Diastolic Blood Pressure at Week 35
timeFrame: Baseline and week 35
measure: Body Weight at Week 35
timeFrame: Baseline and week 35
measure: Body Mass Index at Week 35
timeFrame: Baseline and week 35
measure: Waist Circumference at Week 35
timeFrame: Baseline and week 35
measure: LDL, HDL and Total Cholesterol at Week 35
timeFrame: Baseline and week 35
measure: Mean Scores of Cushing QoL Standardized Score at Week 17 and 35
timeFrame: Baseline and week 17 and 35
measure: Mean Scores of SF-12v2 Domain Scores at Week 17 and 35
timeFrame: Baseline, week 17 and 35
measure: Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Facial Rubor
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
measure: Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Hirsutism
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
measure: Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Striae
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
measure: Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Supraclavicular Fat Pad
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
measure: Number of Participants With Improvement in Clinical Symptom of Hypercortisolism From Baseline - Dorsal Fat Pad
timeFrame: Baseline, weeks 2, 4, every 4 or 5 weeks during core, every 16 weeks during extension
measure: Number of Participants With Shift From Mild to Severe in Clinical Signs of Hypercortisolism
timeFrame: Baseline, weeks 1, 2, 4, every 4 or 5 weeks during core, every 8 weeks during extension
measure: Number of Patients With Shift From Standing Easily to Not Being Able to Stand
timeFrame: Baseline up to week 267
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham The Kirklin Clinic
state: Alabama
city: Portland
country: United States
facility: Oregon Health and Science University SOM230B2411
state: Oregon
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Curitiba
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: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Vandoeuvre Cedex
country: France
facility: Novartis Investigative Site
city: Erlangen
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Vellore
country: India
facility: Novartis Investigative Site
state: Tamil Nadu
city: Chandigarh
country: India
facility: Novartis Investigative Site
city: New Delhi
country: India
facility: Novartis Investigative Site
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Wilayah Persekutuan
country: Malaysia
facility: Novartis Investigative Site
city: México
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Durango
country: Mexico
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Alzira
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
state: TUR
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Pendik / Istanbul
country: Turkey
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: