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Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease (LINC-4)

This study is currently recruiting participants.
Verified November 2017 by Novartis ( Novartis Pharmaceuticals )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02697734
First Posted: March 3, 2016
Last Update Posted: November 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
  Purpose
Purpose of study is to aim to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy

Condition Intervention Phase
Cushing's Disease Drug: osilodrostat Drug: osilodrostat Placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study With an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients With Cushing's Disease

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Percentage of randomized participants with a complete response [ Time Frame: at Week 12 ]
    To demonstrate the superiority of osilodrostat compared to placebo in achieving a complete response mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12.


Secondary Outcome Measures:
  • Percentage of participants with mUFC ≤ ULN [ Time Frame: At Week 36 ]
    To assess the complete response rate in both arms combined at Week 36 in patients receiving osilodrostat treatment.

  • Percentage of patients with complete response mUFC ≤ ULN and partial response with mUFC decrease ≥ 50% from baseline and > ULN) [ Time Frame: At Week 12, Week 36, and Week 48 ]
    The assess the percentage of patients with a complete response (mUFC ≤ ULN) or a partial response (mUFC decrease ≥ 50% from baseline and >ULN) at Week 12, Week 36, and Week 48.

  • Percentage change in mUFC [ Time Frame: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96 ]
    To assess the complete response by treatment arm from baseline to week 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96 by treatment arm for all participants.

  • Time-to-first control of mUFC [ Time Frame: At randomization, day 1,15,36,57,85. ]
    To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period.

  • Time-to-escape from collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN [ Time Frame: At week 48 ]
    To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC > 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks.

  • Percent change in fasting plasma glucose, HbA1c, fasting lipid profile, blood pressure, weight and waist circumference) [ Time Frame: Baseline, weeks 12, 36, and 48 ]
    To assess percent change from baseline in fasting plasma glucose, HbA1c, fasting lipid profile, blood pressure, weight and waist circumference at Week12, Week 36, and Week 48 by treatment arm and for the overall participant population.

  • Change from baseline in bone mineral density (BMD) by Dual-energy X-ray absorptiometry (DXA) scan at the lumbar spine and total hip [ Time Frame: Baseline, week 48 ]
    The change from baseline in bone mineral density, and BMD T- score, at the lumbar spine (L1-L4) and total hip at Week 48 by treatment arm and for overall participant population.

  • Change from baseline in Health Related Quality of Life, using Cushing Disease-specific Quality of Life, Beck Depression Inventory II (BDI-I), EQ-5D-5L [ Time Frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48. ]
    Change in standardized score of CushingQoL, Beck Depression Inventory-II, and EQ-5D-5L, from baseline to Week 12 and Week 48, from Week 12 to Week 36, and from Week 36 to Week 48, or the last measurement prior to early discontinuation, whichever occurs earlier in treatment arm and overall participant population.

  • Percent of patients with a complete response (mUFC ≤ ULN) or a partial response (mUFC decrease ≥ 50% from baseline and >ULN) at week 12, 36 and 48 [ Time Frame: Baseline, week 12, 36 and 48 ]
    To assess the overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and >ULN) at week 12, 36, 48 by treatment arms for all patients.


Estimated Enrollment: 69
Actual Study Start Date: October 3, 2016
Estimated Study Completion Date: October 25, 2019
Estimated Primary Completion Date: October 25, 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: osilodrostat Group
Participants are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, respectively),
Drug: osilodrostat
In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. Each strength has a unique size and color. The osilodrostat 1 mg, 5 mg, 10 mg and 20 mg film coated tablets are approximately 6 mm, 7 mm, 9 mm, and 11 mm respectively in diameter and pale yellow, yellow, pale orange brown and light brown respectively in color.
Other Name: LCI699
Placebo Comparator: osilodrostat Placebo Group
Participants are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, respectively)
Drug: osilodrostat Placebo
Matching Placebo in the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. Each strength has a unique size and color.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key inclusion criteria:

  • Confirmed CD that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c):

    1. mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3 consecutive days, during screening after washout of prior medical therapy for CD (if applicable), confirmed by the central laboratory and available before Day 1), with ≥2 of the individual UFC values being > 1.3 x ULN.
    2. Morning plasma ACTH above Lower Limit of Normal
    3. Confirmation (based on medical history) of pituitary source of excess

      ACTH as defined by any one or more of the following three criteria:

    i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. MRI confirmation of pituitary adenoma > 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or DDAVP stimulation for patients with a tumor ≤ 6mm. The criteria for a confirmatory BIPSS test are any of the following: Pre-dose central to peripheral ACTH gradient > 2; Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP stimulation

  • Patients that received glucocorticoid replacement therapy must have discontinued such therapy for at least seven days or 5 half-lives prior to screening, whichever is longer.
  • Patients with de novo CD can be included only if they are not considered candidates for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors, patients who refuse to have surgical treatment, or surgical treatment is not available).

Key exclusion criteria:

  • Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night salivary cortisol value collected during the screening period and after washout of prior CD medication.
  • Patients with risk factors for QTc prolongation or Torsade de Pointes, including:

patients with a baseline QTcF > 450 ms for males and QTcF > 460 ms for females; personal or family history of long QT syndrome; concomitant medications known to prolong the QT interval; patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before pre-dose Day 1.

  • Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy during the placebo-controlled period (Weeks 1-12) for the treatment of severe hypercortisolism or pituitary tumor growth causing compression of the optic chiasm.
  • Patients with compression of the optic chiasm due to a macroadenoma or patients at high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm).
  • Patients who have a known inherited syndrome as the cause for hormone over secretion (i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).
  • Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent (adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing. Highly effective contraception methods include: A. 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. B. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study drug. In case of bilateral oophorectomy, documentation is required (e.g. operative report, pelvic ultrasound or other reliable imaging method). C. 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.

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

  1. 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
  2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
  3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. *In the case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study drug. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential. Other protocol-defined inclusion/exclusion criteria may apply.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02697734


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

  Show 32 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02697734     History of Changes
Other Study ID Numbers: CLCI699C2302
First Submitted: February 27, 2016
First Posted: March 3, 2016
Last Update Posted: November 14, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Cushing's disease
LCI699
osilodrostat
Pituitary Gland
Adrenocorticotropic
Hormone
ACTH
UFC

Additional relevant MeSH terms:
Pituitary ACTH Hypersecretion
ACTH-Secreting Pituitary Adenoma
Hyperpituitarism
Pituitary Diseases
Hypothalamic Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Endocrine System Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pituitary Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site