a study to find out if a drug pasireotide used alone or used with cabergoline together is safe and beneficial for patients with Cushingâ??s disease(Cushingâ??s disease is a condition where the pituitary gland releases too much adrenocorticotropic hormone (ACTH).

• Register: CTRI
• Last refreshed on: 24 November 2021
• Main ID: CTRI/2014/06/004700
• Date of registration: 24-06-2014
• Prospective Registration: Yes
• Primary sponsor: Novartis Healthcare Pvt Ltd
• Public title: a study to find out if a drug pasireotide used alone or used with cabergoline together is safe and beneficial for patients with Cushingâ??s disease(Cushingâ??s disease is a condition where the pituitary gland releases too much adrenocorticotropic hormone (ACTH).
• Scientific title: A Phase II trial to assess the efficacy and safety of pasireotide s.c. alone or in combination with cabergoline in patients with Cushingâ??s disease
• Date of first enrolment: 30-07-2014
• Target sample size: 128
• Recruitment status: Completed
• URL: http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=7519
• Study type: Interventional
• Study design: Other; Method of generating randomization sequence:Computer generated randomization Method of allocation concealment:On-site computer system Blinding and masking:Open Label
• Phase: Phase 2

Countries of recruitment

Argentina, Austria, Belgium, Brazil, Bulgaria, Colombia, France, Germany, Greece, Hungary, India, Italy, Spain, Turkey, United Kingdom, United States of America, Venezuela (Bolivarian Republic of)

Contacts

• Name: Dr Manish Mistry
• Affiliation: Novartis India Ltd

• Name: Dr Manish Mistry
• Affiliation: Novartis India Ltd

Key inclusion & exclusion criteria

Inclusion criteria: 1. Written informed consent obtained prior to any screening procedures.

2. Adult patients with confirmed diagnosis of ACTH-dependent Cushingâ??s disease as evidenced by all of the following:

a. The mean of three 24-hour urine samples collected within 2 weeks greater than 1xULN with 2 out of 3 samples greater than ULN

b. Morning plasma ACTH within the normal or above normal range

c. Either MRI confirmation of pituitary adenoma greater than 6 mm, or inferior petrosal sinus

gradient greater than 3 after CRH stimulation for those patients with a tumor less than or equal to 6 mm (If IPSS had previously been performed without CRH (e.g. with DDAVP), then a

central to peripheral pre-stimulation gradient greater than 2 is required. If IPSS had not

previously been performed, IPSS with CRH stimulation is required.). For patients who have had prior pituitary surgery, histopathology confirming an ACTH staining adenoma

3. Patients with de novo Cushingâ??s disease can be included only if they are not considered

candidates for pituitary surgery (e.g. poor surgical candidates, surgically unapproachable

tumors, patients who refuse to have surgical treatment)

4. Karnofsky performance status >= 60 (i.e. requires occasional assistance, but is able to care for most of their personal needs)

5. Women of child-bearing potential, defined as all women physiologically capable of

becoming pregnant, if they are using highly effective methods of contraception during

dosing and for 30 days after stopping study medication. Highly effective contraception

methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyle of the

subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation

methods) and withdrawal are not acceptable methods of contraception

• Female sterilization (have had surgical bilateral oophorectomy with or without

hysterectomy) or tubal ligation at least six weeks before taking study treatment. In

case of oophorectomy alone, only when the reproductive status of the woman has

been confirmed by follow up hormone level assessment

• Male sterilization (at least 6 months prior to screening). For female subjects on the

study the vasectomized male partner should be the sole partner for that subject.

• Combination of any two of the following (a+b or a+c, or b+c):

a. Use of oral, injected or implanted hormonal methods of contraception or other

forms of hormonal contraception that have comparable efficacy (failure rate

<1%), for example hormone vaginal ring or transdermal hormone contraception.

b. Placement of an intrauterine device IUD or intrauterine system IUS

c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository

In case of use of oral contraception women should have been stable on the same pill

for a minimum of 3 months before taking study treatment.

Inclusion criteria for Group 1:

1. Patients on medical treatment for Cushingâ??s disease the following washout periods must

be completed before screening assessments are performed

• Inhibitors of steroidogenesis (ketoconazole, metyrapone): 1 week

• Pituitary directed agents: Dopamine agonist
Exclusion criteria: 1. Patients with compression of the optic chiasm causing any visual field defect that requires

surgical intervention

2. Diabetic patients with poor glycemic control as evidenced by HbA1c greater than 8%

3. Patients with risk factors for torsade de pointes, i.e. patients with a baseline QTcF greater than 450 ms in males, and greater than 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 Cushingâ??s syndrome due to ectopic ACTH secretion

6. Patients with hypercortisolism secondary to adrenal tumors or nodular (primary) bilateral

adrenal hyperplasia

7. Patients who have a known inherited syndrome as the cause for hormone over-secretion

(i.e. Carney Complex, McCune-Albright syndrome, MEN-1)

8. Patients who are hypothyroid and not on adequate replacement therapy

9. Patients with symptomatic cholelithiasis

10. Patients who have 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

11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent

hepatitis, or patients with ALT/AST greater than 2 X ULN, serum bilirubin greater than 2 X ULN

12. Patients with serum creatinine greater than 2 X ULN

13. Patients with WBC less than 3 X 10 raised to e 9/L; Hb 90% less than LLN; PLT less than 100 X 10 raised to e 9/L

14. Patients who have a history of alcohol or drug abuse in the 6 month period prior to

receiving pasireotide

15. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing

16. Patients with active malignant disease within the last five years (with the exception of

basal cell carcinoma or carcinoma in situ of the cervix)

17. Patients with the presence of active or suspected acute or chronic uncontrolled infection

18. 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

19. Patients with presence of Hepatitis B surface antigen (HbsAg)

20. Patients with presence of Hepatitis C antibody test (anti-HCV)

Age minimum:
Age maximum:
Gender:

Health Condition(s) or Problem(s) studied

Health Condition 1: null- Cushings disease

Intervention(s)

Intervention1: Paseriotide, Cabergoline: Group 1 consists of Pasireotide-untreated patients will start pasireotide sc 0.6mg twice a day for 8 weeks. If biochemical control is not achieved by the end of the 8 weeks, and the 0.6mg dose is well-tolerated, the dose will be increased to 0.9mg twice a day for another 8 weeks. If biochemical control is not achieved, cabergoline will be added and patients will begin 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 wlil be increased to 1.0mg once a day.


Group 2 patients will immediately start the combination treatment by adding cabergoline 0.5mg once a day at study entry to their current dose of pasireotide. Patients will continue with the combination treatment for 8 weeks. If biochemical control is not achieved by the end of the 8 week period, the dose of cabergoline will be increased to 1mg once a day.
Control Intervention1: NIL: NIL

Primary Outcome(s)

1. To evaluate the overall efficacy of the treatment regimen of pasireotide alone or in combination with cabergoline in patients who are pasireotide untreated at screening(Group1)

2. To evaluate the efficacy of pasireotide in combination

with cabergoline in patients treated with pasireotide at

screening but still with uncontrolled mUFC (Group 2)Timepoint: 1. Proportion of patients who attain mUFC less than or equal to 1xULN at week 35 with pasireotide alone or in combination with cabergoline in Group 1

2. Proportion of patients who attain a mUFC less than or equal to 1xULN at week 17 with pasireotide in Group 2

Secondary Outcome(s)

2. To assess overall efficacy of pasireotide alone or in combination with cabergoline as measured by normal mUFC levels at each scheduled visit when UFC is

measured in Group 1 and Group 2, separatelyTimepoint: 2. Proportion of patients that attain mUFC less than or equal to 1xULN as assessed at each scheduled visit when UFC is measured

7. To assess the effect on the categorical measures of

clinical signs of hypercortisolism in Group 1 and Group 2, separatelyTimepoint: 7. Shift from baseline in clinical signs over time: facial rubor, fat pads,

hirsutism, striae (via photographs) and muscle strength

3. To evaluate overall efficacy of pasireotide alone or in

combination with cabergoline as measured by controlled

and partially controlled mUFC levels at each scheduled

visit when UFC is measured in Group 1 and Group 2,

separatelyTimepoint: 3. Proportion of patients who attain mUFC less than or equal to 1xULN or have at least 50% reduction from baseline in mUFC as assessed at each scheduled visit when

UFC is measured

6. To assess the effect on the continuous measures of

clinical symptoms of hypercortisolism in Group 1 and Group 2, separatelyTimepoint: 6. Actual and percentage change from baseline in clinical symptoms over time:

blood pressure, body mass index, waist circumference, fasting serum lipid profile, and weight

4. To evaluate the duration of controlled or partially

controlled mUFC response in Group 1 and Group 2,

separatelyTimepoint: 4. Duration of controlled or partially controlled response is defined as the

period starting from the date of patientâ??s first normalization (mUFC less than or equal to 1xULN)

or at least 50% reduction from baseline up to the date when the patientâ??s

mUFC less than 1xULN and the reduction from baseline falls to less than 50% from

the first time

1. To assess the changes in mUFC from baseline to study

end at each scheduled visit where UFC is measured in

Group 1 and Group 2, separatelyTimepoint: 1. Actual and percentage change in mUFC from baseline to study end at each

scheduled visit when UFC is measured

8. To assess the improvement of health-related quality of

life in Group 1 and Group 2, separatelyTimepoint: 8. Change from baseline in standardized scores, as measured by the

Cushingâ??s QOL and SF-12v2 over time

5. To assess the effect on plasma ACTH and serum

cortisol in Group 1 and Group 2, separatelyTimepoint: 5. Change from baseline in plasma ACTH and serum cortisol over time

To evaluate the PK exposures of pasireotide alone and

in combination with cabergoline in Group 2 patientsTimepoint: Ctrough and Cmax at baseline, week 8 and week 17

To evaluate the safety profile of pasireotide alone or in combination with in Group 1 and Group 2, separatelyTimepoint: Toxicity will be assessed using National Cancer Institute-Common

Toxicology Criteria Adverse Events version 4 (NCI-CTCAE v.4) & for

laboratory assessments : special safety assessments that include regular monitoring & recording of blood glucose, insulin, HbA1c, GH and IGF-1, thyroid & liver function

tests, gallbladder examinations & ECGs. Concomitant medications/Significant nondrug therapies will be assessed from study

enrollment until safety follow-up visit.

To explore PK/PD relationship between pasireotide concentrations and PD/safety markersTimepoint: PK: Ctrough, Cmax

PD: mUFC, serum cortisol, plasma ACTH. Safety: glucose, HbA1c, ECG

Secondary ID(s)

CSOM230B2411 version number 00 release date 29 May 2013

NCT01915303

Source(s) of Monetary Support

Novartis Healthcare Pvt Ltd GDO Trial Monitoring, India 6 & 7 floor , Inspire BKC G Block, BKC Main Road Bandra Kurla Complex Bandra (East) Mumbai Mumbai MAHARASHTRA 400051 India

Ethics review

Status: Approved
Approval date: 06/03/2014
Contact:

AIIMS Ethics Committee , All India Institute Of Medical Sciences , New Delhi

Status: Approved
Approval date: 14/05/2014
Contact:

Institutional Review Borad, Christian Medical College

Status: Approved
Approval date: 21/08/2014
Contact:

Insitutional Ethics Committee, Postgraduate Institute Of Medical Education and Research (P.G.I.M.E.R)

Status: Not Approved
Approval date:
Contact:

Institutional Ethics Committee - I, Seth GSMC and KEM hospital

Results

• Date Completed: 07/09/2016