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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02697734
Recruitment Status : Active, not recruiting
First Posted : March 3, 2016
Last Update Posted : March 20, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE February 27, 2016
First Posted Date  ICMJE March 3, 2016
Last Update Posted Date March 20, 2020
Actual Study Start Date  ICMJE October 3, 2016
Actual Primary Completion Date June 19, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 27, 2016)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2016)
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease
Official Title  ICMJE 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
Brief Summary 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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Cushing's Disease
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • Experimental: osilodrostat Group
    Participants in this arm are receiving the study drug, osilodrostat and are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, respectively),
    Intervention: Drug: osilodrostat
  • Placebo Comparator: osilodrostat Placebo Group
    Participants in this arm are receiving osilodrostat placebo and are randomized in a 2:1 ratio to treatment with study drug (osilodrostat or placebo, respectively)
    Intervention: Drug: osilodrostat Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: January 13, 2020)
73
Original Estimated Enrollment  ICMJE
 (submitted: February 27, 2016)
69
Estimated Study Completion Date  ICMJE January 25, 2021
Actual Primary Completion Date June 19, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Brazil,   Canada,   China,   Costa Rica,   Greece,   Poland,   Portugal,   Russian Federation,   Spain,   Switzerland,   Thailand,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02697734
Other Study ID Numbers  ICMJE CLCI699C2302
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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

URL: https://www.clinicalstudydatarequest.com
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP