Cushing's DiseasePhase 3LINC-4NCT02697734
Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease
A Phase 3 study testing osilodrostat in people with Cushing's Disease, run by Novartis Pharmaceuticals at 36 sites in 14 countries.
Trial summary
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Cushing's Disease
- What is being tested?
- osilodrostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 73 participants
- Where
- 36 sitesin 14 countries
- Study dates
- 3 Oct 2016to 31 Dec 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c):
- 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.
- Morning plasma Adrenocorticotropic hormone (ACTH) above Lower Limit of Normal
- Confirmation (based on medical history) of pituitary source of excess
- ACTH as defined by any one or more of the following three criteria:
- Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. Magnetic resonance imaging (MRI) confirmation of pituitary adenoma > 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either corticotropic-releasing hormone (CRH) or desmopressin (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).
Who cannot join
- 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 QT corrected (QTc) prolongation or Torsade de Pointes, including:
- patients with a baseline QT corrected (Fridericia QT formula) (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).
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- 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.
- Combination of any two of the following (a+b or a+c, or b+c):
- 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
- Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- 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.
Trial locations and contacts
36 sites in 14 countries.
36 sites in 14 countries
United States6 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
University of Colorado Endocrinology Clinical Trials Unit
Aurora, Colorado, 80045
Columbia University Medical Center New York Presbyterian Neuroendocrine Unit
New York, New York, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, 10065
University of Pennsylvania Medical Center University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Oregon Health and Science University SC LCI699C2301
Portland, Oregon, 97239
Spain6 sites
Novartis Investigative Site
A Coruña, Galicia, 15006
Novartis Investigative Site
Alzira, Valencia, 46600
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Málaga, Andalusia, 29009
Novartis Investigative Site
Seville, Andalusia, 41013
Novartis Investigative Site
Valencia, Valencia, 46026
Brazil4 sites
Novartis Investigative Site
Fortaleza, Ceará, 60430-275
Novartis Investigative Site
Rio de Janeiro, Rio de Janeiro, 21941-590
Novartis Investigative Site
São Paulo, São Paulo, 04039 004
Novartis Investigative Site
São Paulo, São Paulo, 05403 000
China4 sites
Novartis Investigative Site
Beijing, 100034
Novartis Investigative Site
Beijing, 100730
Novartis Investigative Site
Chengdu, Sichuan, 610041
Novartis Investigative Site
Guangzhou, 510080
Canada3 sites
Novartis Investigative Site
Halifax, Nova Scotia, B3H 1V7
Novartis Investigative Site
Montreal, Quebec, H2W 1T8
Novartis Investigative Site
Sherbrooke, Quebec, J1H 5N4
Poland3 sites
Novartis Investigative Site
Krakow, 31-501
Novartis Investigative Site
Warsaw, Masovian Voivodeship, 04-305
Novartis Investigative Site
Warsaw, 03 242
Thailand2 sites
Novartis Investigative Site
Bangkok, THA, 10330
Novartis Investigative Site
Bangkok, 10700
Turkey (Türkiye)2 sites
Novartis Investigative Site
Istanbul, 34890
Novartis Investigative Site
Kocaeli, 41380
Costa Rica1 site
Novartis Investigative Site
San Pedro, San Jose, Costa Rica, 1406 1200
About this study
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
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.
Read the detailed description
The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.
Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).
After Week 48, patients could join an optional 48 week extension period.
- Conditions
- Cushing's Disease
- Being tested
- osilodrostat, osilodrostat Placebo
- Keywords
- Cushing's disease, LCI699, osilodrostat, Pituitary Gland, Adrenocorticotropic, Hormone, ACTH, UFC
- Medical subject headings
- Pituitary ACTH Hypersecretion, Pituitary Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
osilodrostatDrug
Also called LCI699
In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.
osilodrostat PlaceboDrug
Matching Placebo in the form of filmcoated tablets for oral administration
| Study group | Role | What they receive |
|---|---|---|
| osilodrostat Group | Experimental | Participants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration) Receives: Drug: osilodrostat |
| osilodrostat Placebo Group | Placebo comparator | Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration) Receives: Drug: osilodrostat Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Randomized Participants With a Complete Response
A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12.
Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
Measured: at Week 12
Secondary outcomes (35)
Percentage of Participants With mUFC ≤ ULN at Week 36
The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol <= upper limit of normal (mUFC <= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.
Measured: At Week 36
Change From Baseline in mUFC
To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
Measured: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
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.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
Measured: up to 12 weeks
Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
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.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Measured: up to 12 weeks
Time-to-first Control of mUFC - % Event Probability Estimates
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.
Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
% Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.
Measured: up to 12 weeks
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
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.
Measured: up to 48 weeks
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC
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.
The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Measured: from week 26 to week 48
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
Escape is defined as the first loss of control of urinary free cortisol (UFC) that meets all of the following criteria: 1. prior normalization of UFC has occurred (median urinary free cortisol (mUFC)≤ upper limit of normal (ULN)); 2. patient reached the highest tolerated dose of osilodrostat; 3. 2 consecutive mUFC (collected at scheduled visits) were above 1.3x ULN; 4. the loss of control of UFC is not related to a dose interruption or dose reduction due to safety reasons; 5. happened beyond Week 26 when the patients have a chance to be treated with doses as high as 30 mg bid.
- Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point.
- Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CI of KM estimates.
Measured: week 26 and week 36
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement.
Measured: Baseline, week 48
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement. T-score is the number of standard deviations above or below the mean for a healthy 30-year-old adult of the same sex and ethnicity as the patient. The WHO criteria are: Normal is a T-score of -1.0 or higher"
Measured: Baseline, week 48
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
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.
Measured: baseline, week 12, 36 and 48
Change in Fasting Plasma Glucose
Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Hemoglobin A1C
Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Cholesterol
Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in LDL Cholesterol
Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in HDL Cholesterol
Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Triglyceride
Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Standing Systolic Blood Pressure
Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Supine Systolic Blood Pressure
Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Standing Diastolic Blood Pressure
Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Supine Diastolic Blood Pressure
Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Weight
Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change in Waist Circumference
Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
Measured: Baseline, weeks 12, 36, and 48
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
Change from baseline to Week 12, Week 36, and Week 48 in each of the following clinical signs of Cushing's disease, captured by: a semi-quantitative Likert scale for facial rubor, striae, supraclavicular fat pad, dorsal fat pad, proximal muscle wasting (atrophy), central (abdominal) obesity, and ecchymoses (bruises) by randomized treatment arm. The number/proportion of participants with an improvement or no change compared to baseline are reported
Measured: baseline, Week 12, Week 36 and Week 48
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness').
The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in EQ-5D-5L Utility Index
EQ-5D-5L Utility Index:
The EQ-5D-5L questionnaire is a standardized measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L measures 5 items on mobility, self-care, usual activities, pain/discomfort, anxiety/depression, measured on 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. A utility index can be computed from the EQ 5D-5L descriptive system with utility scores ranging from -0.281 (worst imaginable health state) to 1 (best imaginable health state), with -0.281 representing an "unconscious" health state. A single index value is analyzed for the EQ-5D-5L score. An increase from baseline in the EQ-ED-5L utility index is indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in EQ-5D VAS
The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100='the best health you can imagine' and 0='the worst health you can imagine'. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Beck Depression Inventory-II - Total Score Derived
The Beck Depression Inventory II (BDI-II) is a patient reported instrument that consists of 21 items designed to assess the intensity of depression in clinical and normal patients in the preceding two weeks. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression. A global score ranges from 0 to 63 and is calculated with a higher score representing a greater level of depression. The following scoring guidelines for interpretation of BDI-II have been suggested (Smarr, 2011): Minimal range =0-13, Mild depression =14-19, Moderate depression =20-28 and Severe depression = 29-63. A reduction from baseline in BDI-II is indicative of an improvement.
Measured: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Serum Cortisol
Change from baseline in serum cortisol
Measured: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Late Night Saliva Cortisol
Change from baseline in late night saliva cortisol (nmol/L)
Measured: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Morning Saliva Cortisol
Change from baseline in morning saliva cortisol (nmol/L)
Measured: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Hair Cortisol Levels
Change from baseline in hair cortisol levels
Measured: Baseline, Week 26, Week 48
Plasma Osilodrostat Concentrations (ng/mL)
Plasma osilodrostat concentrations (ng/mL)
Measured: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2016 (estimated)
- Study start3 Oct 2016
- Primary completion19 Jun 2019
- Study completion31 Dec 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Cushing's DiseaseStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02697734
- Sponsor's protocol ID
- CLCI699C2302
- Acronym
- LINC-4
- Status last verified
- Oct 2021
- First submitted
- 27 Feb 2016
- Last updated
- 1 Nov 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Publications
Fleseriu M, Pivonello R, Lacroix A, Biller BMK, Feelders R, Gadelha M, Bertherat J, Belaya Z, Piacentini A, Pedroncelli AM, Newell-Price J. Osilodrostat dose impact on efficacy/safety in Cushing's disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025 Oct 30;193(5):606-617. doi: 10.1093/ejendo/lvaf207.
PubMed 41052284Newell-Price J, Fleseriu M, Pivonello R, Feelders RA, Gadelha MR, Lacroix A, Witek P, Heaney AP, Piacentini A, Pedroncelli AM, Biller BMK. Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol. J Endocr Soc. 2024 Nov 12;9(1):bvae201. doi: 10.1210/jendso/bvae201. eCollection 2024 Nov 26.
PubMed 39610378Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.
PubMed 35325149
Study at a glance
From the registry record, last updated by the sponsor on 1 Nov 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02697734
- Acronym / sponsor ID
- LINC-4 / CLCI699C2302
- Conditions
- Cushing's Disease
- Keywords
- Cushing's disease, LCI699, osilodrostat, Pituitary Gland, Adrenocorticotropic, Hormone, ACTH, UFC
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 3 Oct 2016 (actual)
- Primary completion
- 19 Jun 2019 (actual)
- Study completion
- 31 Dec 2020 (actual)
- First posted
- 3 Mar 2016 (estimated)
- Results
- Posted 19 Oct 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.
Detailed description
The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.
Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).
After Week 48, patients could join an optional 48 week extension period.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| osilodrostat Group | Experimental | Drug: osilodrostatParticipants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration) |
| osilodrostat Placebo Group | Placebo comparator | Drug: osilodrostat PlaceboParticipants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration) |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Confirmed Cushing's Disease (CD) that is persistent or recurrent as evidenced by all of the following criteria being met (i.e., a, b and c):
- 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 (11 listed)
- 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 QT corrected (QTc) prolongation or Torsade de Pointes, including:
- patients with a baseline QT corrected (Fridericia QT formula) (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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| osilodrostatAlso: LCI699In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. | Drug | osilodrostat Group |
| osilodrostat PlaceboMatching Placebo in the form of filmcoated tablets for oral administration | Drug | osilodrostat Placebo Group |
Primary outcome
Percentage of Randomized Participants With a Complete Response
Time frame: at Week 12
A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
35 secondary outcomes
Percentage of Participants With mUFC ≤ ULN at Week 36
Time frame: At Week 36
Change From Baseline in mUFC
Time frame: Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
Time frame: up to 12 weeks
Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
Time frame: up to 12 weeks
Time-to-first Control of mUFC - % Event Probability Estimates
Time frame: up to 12 weeks
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
Time frame: up to 48 weeks
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC
Time frame: from week 26 to week 48
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
Time frame: week 26 and week 36
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
Time frame: Baseline, week 48
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
Time frame: Baseline, week 48
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
Change in Fasting Plasma Glucose
Time frame: Baseline, weeks 12, 36, and 48
Change in Hemoglobin A1C
Time frame: Baseline, weeks 12, 36, and 48
Change in Cholesterol
Time frame: Baseline, weeks 12, 36, and 48
Change in LDL Cholesterol
Time frame: Baseline, weeks 12, 36, and 48
Change in HDL Cholesterol
Time frame: Baseline, weeks 12, 36, and 48
Change in Triglyceride
Time frame: Baseline, weeks 12, 36, and 48
Change in Standing Systolic Blood Pressure
Time frame: Baseline, weeks 12, 36, and 48
Change in Supine Systolic Blood Pressure
Time frame: Baseline, weeks 12, 36, and 48
Change in Standing Diastolic Blood Pressure
Time frame: Baseline, weeks 12, 36, and 48
Change in Supine Diastolic Blood Pressure
Time frame: Baseline, weeks 12, 36, and 48
Change in Weight
Time frame: Baseline, weeks 12, 36, and 48
Change in Waist Circumference
Time frame: Baseline, weeks 12, 36, and 48
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
Time frame: baseline, Week 12, Week 36 and Week 48
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in EQ-5D-5L Utility Index
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in EQ-5D VAS
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Beck Depression Inventory-II - Total Score Derived
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Serum Cortisol
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Late Night Saliva Cortisol
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Morning Saliva Cortisol
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Hair Cortisol Levels
Time frame: Baseline, Week 26, Week 48
Plasma Osilodrostat Concentrations (ng/mL)
Time frame: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Nov 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41052284Fleseriu M, Pivonello R, Lacroix A, Biller BMK, Feelders R, Gadelha M, Bertherat J, Belaya Z, Piacentini A, Pedroncelli AM, Newell-Price J. Osilodrostat dose impact on efficacy/safety in Cushing's disease: large, pooled analysis of LINC 2, 3, and 4. Eur J Endocrinol. 2025 Oct 30;193(5):606-617. doi: 10.1093/ejendo/lvaf207.
- Derived from this study: PubMed 39610378Newell-Price J, Fleseriu M, Pivonello R, Feelders RA, Gadelha MR, Lacroix A, Witek P, Heaney AP, Piacentini A, Pedroncelli AM, Biller BMK. Improved Clinical Outcomes During Long-term Osilodrostat Treatment of Cushing Disease With Normalization of Late-night Salivary Cortisol and Urinary Free Cortisol. J Endocr Soc. 2024 Nov 12;9(1):bvae201. doi: 10.1210/jendso/bvae201. eCollection 2024 Nov 26.
- Derived from this study: PubMed 35325149Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Yu Y, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Pedroncelli AM, Snyder PJ. Randomized Trial of Osilodrostat for the Treatment of Cushing Disease. J Clin Endocrinol Metab. 2022 Jun 16;107(7):e2882-e2895. doi: 10.1210/clinem/dgac178.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
36 sites in 14 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing osilodrostat in people with Cushing's Disease, run by Novartis Pharmaceuticals at 36 sites in 14 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 36 sites in United States, Spain, Brazil, China, Canada and 9 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 19 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Randomized Participants With a Complete Response (time frame: at Week 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02697734, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Nov 2021.