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Cushings DiseasePhase 2NCT01331239

Safety and Efficacy of LCI699 in Cushing's Disease Patients

A Phase 2 study testing LCI699 in people with Cushings Disease and Cushing Disease, run by Novartis Pharmaceuticals at 10 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease. In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long… Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Cushings Disease, Cushing Disease
What is being tested?
LCI699
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
31 participants
Where
10 sitesin 4 countries
Study dates
23 Mar 2011to 22 Oct 2019
Phase
Phase 2
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

  • Patients with a confirmed diagnosis of Cushing's Disease (persistent or recurrent) as evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH.
  • Patients with de novo Cushing's disease can be included only if they are not considered candidate for surgery

Who cannot join

  • Patients treated with mitotane 6 months prior to Visit 1
  • Patients with compression of the optic chiasm
  • Patients with a known inherited syndrome as the cause for hormone over secretion
  • Patients with Cushing's syndrome due to ectopic ACTH secretion or adrenal Cushing's syndrome
  • Patients with pseudo-Cushing's syndrome
  • Patients who are not biochemically euthyroid
Show all 10Show fewer
  • Diabetic patients with poorly controlled diabetes (HbA1c >9%)
  • 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.
  • Patients who have received pituitary irradiation within five years prior to Visit 1.
  • Patients with risk factors for QTc prolongation or Torsade de Pointes.

Trial locations and contacts

10 sites in 4 countries.

10 sites in 4 countries

United States4 sites

  • Massachusetts General Hospital Neuroendocrine Unit

    Boston, Massachusetts, 02114

  • Northwestern University Endo, Metabolism and Molecular

    Chicago, Illinois, 60611-3308

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Oregon Health and Science University SC

    Portland, Oregon, 97239-3098

Other trials in United States

France2 sites

  • Novartis Investigative Site

    Le Kremlin-Bicêtre, 94275

  • Novartis Investigative Site

    Paris, 75014

Other trials in France

Italy2 sites

  • Novartis Investigative Site

    Ancona, L60020

  • Novartis Investigative Site

    Naples, 80131

Other trials in Italy

Japan2 sites

  • Novartis Investigative Site

    Chiba, 260 8677

  • Novartis Investigative Site

    Sapporo, Hokkaido, 060 8648

Other trials in Japan

About this study

Official title: A Proof of Concept, Open-label, Forced Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of 10-weeks Treatment of LCI699 in Patients With Cushing's Disease

This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.

In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.

A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.

Read the detailed description

The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.

The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.

Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was < Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.

The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.

Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.

On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.

Being tested
LCI699
Keywords
Cushing Disease, osilodrostat, LCI699, Pituitary Gland, Adrenocorticotropic Hormone
Medical subject headings
Adrenocortical Hyperfunction, Pituitary ACTH Hypersecretion, Pituitary Diseases

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • LCI699Drug

    Also called osilodrastat

    Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.

Study groups in NCT01331239
Study groupRoleWhat they receive
Part l: Core cohortExperimentalParticipants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study
Receives: Drug: LCI699
Part II Core: Expansion cohortExperimentalParticipants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study
Receives: Drug: LCI699
Part II Core: Follow-up cohortExperimentalParticipants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study
Receives: Drug: LCI699

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10

    A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced <50% decrease in UFC were classified as non-responders.

    Measured: 10 weeks

Secondary outcomes (26)

  1. Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)

    Change in Deoxycorticosterone over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  2. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)

    Change in Deoxycortisol over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  3. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)

    Change in aldosterone \& thyroxine, free over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  4. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)

    Change in Estradiol in females over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  5. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)

    Change in Estradiol in males over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  6. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)

    Change in FSH in females over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  7. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male)

    Change in FSH in males over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  8. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin

    Change in Renin, Insulin \& Thyrotropin over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  9. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Insulin-like Growth Factor-1

    Change in Insulin-like Growth Factor-1 over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  10. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female)

    Change in LH in females over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  11. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male)

    Change in LH in males over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  12. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female)

    Change in Testosterone in females over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  13. Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male)

    Change in Testosterone in males over time.

    Measured: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88

  14. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Fasting Glucose

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  15. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Hemoglobin A1C (HbA1C) (Glycosylated Hemoglobin)

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  16. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  17. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Sitting Diastolic Blood Pressure (DBP), Sitting Systolic Blood Pressure (SBP)

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  18. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  19. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Body Mass Index (BMI)

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  20. Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)

    Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. QUICKI is the quantitative insulin sensitivity check index and is derived using the inverse of the sum of algorithms (base 10) of the fasting insulin and fasting glucose: 1/(log(fasting insulin mU/mL)+log(fasting glucose mg/dL)).

    Values typically associated with the QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. So lower numbers reflect greater insulin resistance.

    Measured: Baseline, Week 22, Week 70, Last observed value, up to Month 88

  21. Pharmacokinetics (PK) Parameters: Area Under Curve (AUC)0-6h ss, AUC0-12h ss

    Trough PK concentrations and PK profiles at steady-state were collected. The AUC from time 0 to 12 h post dose at steady state, calculated by using the predose concentration (Ctrough,ss) as the 12 h concentration, assuming steady-state has been reached.

    Measured: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose

  22. PK Parameters: Cmax ss, Ctrough ss

    Trough PK concentrations and PK profiles at steady-state were collected.

    Measured: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose

  23. PK Parameters: Tmax ss,

    Trough PK concentrations and PK profiles at steady-state were collected.

    Measured: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose

  24. PK Parameters: T1/2 ss,

    Trough PK concentrations and PK profiles at steady-state were collected.

    Measured: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose

  25. Percentage of Participants Who Were Responders on 24-hour Urine Free Cortisol (UFC) at Week 22

    A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 22 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Participants with controlled or partially controlled UFC were defined as: Controlled UFC: mean UFC level <= upper limit of normal (ULN).

    Partially controlled UFC: mean UFC level > ULN but with >= 50% reduction from baseline.

    Measured: Week 22

  26. Number of Participants With Escape

    Escape is defined as loss of UFC control (i.e. UFC > ULN) on at least 2 consecutive visits at the highest tolerated dose after previously attaining UFC normalization)

    Measured: approx. 7 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Apr 2011 (estimated)
  2. Study start23 Mar 2011
  3. Primary completion22 Oct 2019
  4. Study completion22 Oct 2019

Resources

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 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
31 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01331239
Sponsor's protocol ID
CLCI699C2201
Other IDs
2010-022403-22
Status last verified
Jan 2021
First submitted
6 Apr 2011
Last updated
22 Jan 2021
Data monitoring committee
No
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 41052284

  • Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, Watson CE, Maldonado M, Hamrahian AH, Boscaro M, Biller BM. LCI699, a potent 11beta-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014 Apr;99(4):1375-83. doi: 10.1210/jc.2013-2117. Epub 2013 Dec 11.

    PubMed 24423285

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing LCI699 in people with Cushings Disease and Cushing Disease, run by Novartis Pharmaceuticals at 10 sites in 4 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 2 inclusion and 10 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 22 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in United States, France, Italy, Japan. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 22 Jan 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 Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10 (time frame: 10 weeks). 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 NCT01331239, which also lists 2 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 22 Jan 2021; AzTrials last refreshed its copy on 8 Nov 2026.

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