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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02697734
Collaborator
(none)
73
Enrollment
36
Locations
2
Arms
50.9
Actual Duration (Months)
2
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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

Study Type:
Interventional
Actual Enrollment :
73 participants
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
Actual Study Start Date :
Oct 3, 2016
Actual Primary Completion Date :
Jun 19, 2019
Actual Study Completion Date :
Dec 31, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: osilodrostat Group

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)

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.
Other Names:
  • LCI699

    		•
    Placebo Comparator: osilodrostat Placebo Group

    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)

    Drug: osilodrostat Placebo
    Matching Placebo in the form of filmcoated tablets for oral administration

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Randomized Participants With a Complete Response [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.

    Secondary Outcome Measures

    1. Percentage of Participants With mUFC ≤ ULN at Week 36 [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.

    2. Change From Baseline in mUFC [Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96]

      To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.

    3. Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN [up to 12 weeks]

      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.

    4. Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response [up to 12 weeks]

      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).

    5. Time-to-first Control of mUFC - % Event Probability Estimates [up to 12 weeks]

      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.

    6. Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants [up to 48 weeks]

      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.

    7. 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 [from week 26 to 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. The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).

    8. Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates [week 26 and week 36]

      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.

    9. 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 [Baseline, week 48]

      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.

    10. 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 [Baseline, week 48]

      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"

    11. Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48 [baseline, 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.

    12. Change in Fasting Plasma Glucose [Baseline, weeks 12, 36, and 48]

      Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm

    13. Change in Hemoglobin A1C [Baseline, weeks 12, 36, and 48]

      Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm

    14. Change in Cholesterol [Baseline, weeks 12, 36, and 48]

      Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

    15. Change in LDL Cholesterol [Baseline, weeks 12, 36, and 48]

      Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

    16. Change in HDL Cholesterol [Baseline, weeks 12, 36, and 48]

      Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

    17. Change in Triglyceride [Baseline, weeks 12, 36, and 48]

      Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm

    18. Change in Standing Systolic Blood Pressure [Baseline, weeks 12, 36, and 48]

      Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

    19. Change in Supine Systolic Blood Pressure [Baseline, weeks 12, 36, and 48]

      Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

    20. Change in Standing Diastolic Blood Pressure [Baseline, weeks 12, 36, and 48]

      Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

    21. Change in Supine Diastolic Blood Pressure [Baseline, weeks 12, 36, and 48]

      Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm

    22. Change in Weight [Baseline, weeks 12, 36, and 48]

      Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm

    23. Change in Waist Circumference [Baseline, weeks 12, 36, and 48]

      Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm

    24. Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease [baseline, Week 12, Week 36 and Week 48]

      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

    25. Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    26. Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    27. Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    28. Change From Baseline in EQ-5D-5L Utility Index [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    29. Change From Baseline in EQ-5D VAS [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    30. Change From Baseline in Beck Depression Inventory-II - Total Score Derived [Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.]

      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.

    31. Change From Baseline in Serum Cortisol [Baseline, Week 12, Week 36, Week 48]

      Change from baseline in serum cortisol

    32. Change From Baseline in Late Night Saliva Cortisol [Baseline, Week 12, Week 36, Week 48]

      Change from baseline in late night saliva cortisol (nmol/L)

    33. Change From Baseline in Morning Saliva Cortisol [Baseline, Week 12, Week 36, Week 48]

      Change from baseline in morning saliva cortisol (nmol/L)

    34. Change From Baseline in Hair Cortisol Levels [Baseline, Week 26, Week 48]

      Change from baseline in hair cortisol levels

    35. Plasma Osilodrostat Concentrations (ng/mL) [pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26]

      Plasma osilodrostat concentrations (ng/mL)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key inclusion criteria:
    • 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):

    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 Adrenocorticotropic hormone (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:
    1. 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).

    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 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).

    • 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Colorado Endocrinology Clinical Trials Unit Aurora Colorado United States 80045
    2 University of Michigan Comprehensive Cancer Center Ann Arbor Michigan United States 48109
    3 Columbia University Medical Center New York Presbyterian Neuroendocrine Unit New York New York United States 10032
    4 Memorial Sloan Kettering Cancer Center New York New York United States 10065
    5 Oregon Health and Science University SC LCI699C2301 Portland Oregon United States 97239
    6 University of Pennsylvania Medical Center University of Pennsylvania Philadelphia Pennsylvania United States 19104
    7 Novartis Investigative Site Leuven Belgium 3000
    8 Novartis Investigative Site Fortaleza CE Brazil 60430-275
    9 Novartis Investigative Site Rio de Janeiro RJ Brazil 21941-590
    10 Novartis Investigative Site Sao Paulo SP Brazil 04039 004
    11 Novartis Investigative Site Sao Paulo SP Brazil 05403 000
    12 Novartis Investigative Site Halifax Nova Scotia Canada B3H 1V7
    13 Novartis Investigative Site Montreal Quebec Canada H2W 1T8
    14 Novartis Investigative Site Sherbrooke Quebec Canada J1H 5N4
    15 Novartis Investigative Site Chengdu Sichuan China 610041
    16 Novartis Investigative Site Beijing China 100034
    17 Novartis Investigative Site Beijing China 100730
    18 Novartis Investigative Site Guang Zhou China 510080
    19 Novartis Investigative Site San Pedro San Jose, Costa Rica Costa Rica 1406 1200
    20 Novartis Investigative Site Athens Greece 106 76
    21 Novartis Investigative Site Warszawa Mazowieckie Poland 04-305
    22 Novartis Investigative Site Krakow Poland 31-501
    23 Novartis Investigative Site Warszawa Poland 03 242
    24 Novartis Investigative Site Porto Portugal 4200-319
    25 Novartis Investigative Site Moscow Russian Federation 117036
    26 Novartis Investigative Site Malaga Andalucia Spain 29009
    27 Novartis Investigative Site Sevilla Andalucia Spain 41013
    28 Novartis Investigative Site Alzira Comunidad Valenciana Spain 46600
    29 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46026
    30 Novartis Investigative Site La Coruna Galicia Spain 15006
    31 Novartis Investigative Site Madrid Spain 28009
    32 Novartis Investigative Site Luzern Switzerland 6000
    33 Novartis Investigative Site Bangkok THA Thailand 10330
    34 Novartis Investigative Site Bangkok Thailand 10700
    35 Novartis Investigative Site Istanbul Turkey 34890
    36 Novartis Investigative Site Kocaeli Turkey 41380

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02697734
    Other Study ID Numbers:
    • CLCI699C2302
    First Posted:
    Mar 3, 2016
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Cushing's disease
    LCI699
    osilodrostat
    Pituitary Gland
    Adrenocorticotropic
    Hormone
    ACTH
    UFC
    Additional relevant MeSH terms:
    ACTH-Secreting Pituitary Adenoma
    Pituitary ACTH Hypersecretion

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). There are 73 participants in the FAS who were randomized and received treatment.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Period Title: Core Phase - up to Week 48
    STARTED 48 25
    COMPLETED 42 23
    NOT COMPLETED 6 2
    Period Title: Core Phase - up to Week 48
    STARTED 38 22
    COMPLETED 33 20
    NOT COMPLETED 5 2

    Baseline Characteristics

    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group Total
    Arm/Group Description 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). 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). Total of all reporting groups
    Overall Participants 48 25 73
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    46
    95.8%
    25
    100%
    71
    97.3%
    >=65 years
    2
    4.2%
    0
    0%
    2
    2.7%
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    42.3
    (13.82)
    38.9
    (12.33)
    41.2
    (13.35)
    Sex: Female, Male (Count of Participants)
    Female
    43
    89.6%
    18
    72%
    61
    83.6%
    Male
    5
    10.4%
    7
    28%
    12
    16.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    2.1%
    0
    0%
    1
    1.4%
    Asian
    9
    18.8%
    8
    32%
    17
    23.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    4.2%
    0
    0%
    2
    2.7%
    White
    34
    70.8%
    15
    60%
    49
    67.1%
    More than one race
    0
    0%
    1
    4%
    1
    1.4%
    Unknown or Not Reported
    2
    4.2%
    1
    4%
    3
    4.1%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Randomized Participants With a Complete Response
    Description 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.
    Time Frame at Week 12

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Count of Participants [Participants]
    37
    77.1%
    2
    8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Osilodrostat Group, Osilodrostat Placebo Group
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <.0001
    Comments
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Odds Ratio (OR)
    Estimated Value 43.4
    Confidence Interval (2-Sided) 95%
    7.06 to 343.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Percentage of Participants With mUFC ≤ ULN at Week 36
    Description 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.
    Time Frame At Week 36

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set participants: comprises all randomized participants who received at least one dose of osilodrostat. Only a single arm is reported since the endpoint is 'To assess the complete response rate in both arms combined at Week 36 in patients receiving osilodrostat treatment.'
    Arm/Group Title All Participants Combined
    Arm/Group Description Consisted of all randomized participants who received at least one dose of osilodrostat.
    Measure Participants 73
    Number (95% Confidence Interval) [Percentage of participants]
    80.8
    168.3%
    3. Secondary Outcome
    Title Change From Baseline in mUFC
    Description To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
    Time Frame Baseline, weeks 2,5,8,12,14,17,20,23,26,29,32,36,40,48,60,72,84,96

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    actual - baseline
    421.4
    (291.25)
    451.5
    (535.09)
    change from baseline at week 2 (n=47,24)
    -139.3
    (404.45)
    164.9
    (543.82)
    change from baseline at week 5 (n=46,25)
    -252.8
    (338.48)
    -37.3
    (280.84)
    change from baseline at week 8 (n=44,25)
    -330.2
    (303.35)
    -35.0
    (325.30)
    change from baseline at week 12 (n=44,24)
    -332.7
    (315.50)
    -49.1
    (332.29)
    change from baseline at week 14 (n=45,25)
    -191.7
    (446.77)
    -209.5
    (407.62)
    change from baseline at week 17 (n=45,25)
    -238.8
    (362.46)
    -284.5
    (557.47)
    change from baseline at week 20 (n=44,24)
    -294.5
    (316.65)
    -355.1
    (538.96)
    change from baseline at week 23 (n=44,25)
    -314.1
    (307.60)
    -387.8
    (466.15)
    change from baseline at week 26 (n=43,25)
    -345.2
    (306.35)
    -365.4
    (458.28)
    change from baseline at week 29 (n=43,25)
    -331.4
    (299.63)
    -391.4
    (534.57)
    change from baseline at week 32 (n=44,25)
    -341.3
    (298.96)
    -298.0
    (655.52)
    change from baseline at week 36 (n=43,25)
    -349.6
    (310.46)
    -372.9
    (519.17)
    change from baseline at week 40 (n=43,23)
    -333.4
    (307.63)
    -364.7
    (542.28)
    change from baseline at week 48 (n=42,22)
    -325.1
    (314.30)
    -367.5
    (554.16)
    change from baseline at week 60 (n=33,19)
    -364.4
    (339.57)
    -335.2
    (571.06)
    change from baseline at week 72 (n=31,17)
    -381.2
    (338.68)
    -372.4
    (624.69)
    change from baseline at week 84 (n=23,17)
    -398.6
    (377.81)
    -196.0
    (916.83)
    change from baseline at week 96 (n=6,7)
    -414.5
    (347.83)
    -616.4
    (881.92)
    4. Secondary Outcome
    Title Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
    Description 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.
    Time Frame up to 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo)
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Count of Participants [Participants]
    45
    93.8%
    8
    32%
    5. Secondary Outcome
    Title Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
    Description 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).
    Time Frame up to 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Median (95% Confidence Interval) [Days]
    35
    NA
    6. Secondary Outcome
    Title Time-to-first Control of mUFC - % Event Probability Estimates
    Description 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.
    Time Frame up to 12 weeks

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    2 Weeks
    25.0
    16.0
    5 Weeks
    60.4
    20.0
    8 Weeks
    79.4
    28.0
    12 Weeks
    NA
    28.0
    7. Secondary Outcome
    Title Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
    Description 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.
    Time Frame up to 48 weeks

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group All Participants
    Arm/Group Description 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). 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). All Participants
    Measure Participants 48 25 73
    Count of Participants [Participants]
    0
    0%
    2
    8%
    2
    2.7%
    8. Secondary Outcome
    Title 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
    Description 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).
    Time Frame from week 26 to week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group All Participants
    Arm/Group Description 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). 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). All Participants
    Measure Participants 48 25 73
    Median (95% Confidence Interval) [days]
    NA
    NA
    NA
    9. Secondary Outcome
    Title Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
    Description 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.
    Time Frame week 26 and week 36

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group All Participants
    Arm/Group Description 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). 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). All Participants
    Measure Participants 48 25 73
    % Event probability estimates (95% CI) at 26 Weeks
    0
    21.3
    15.6
    % Event probability estimates (95% CI) at 36 Weeks
    0
    NA
    15.6
    10. Secondary Outcome
    Title 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
    Description 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.
    Time Frame Baseline, week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 43 24
    FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)
    0.8
    (0.16)
    0.8
    (0.14)
    FEMORAL NECK QC CORRECTED - week 48 - Actual change from baseline (n=28,19)
    0.0
    (0.04)
    0.0
    (0.03)
    HIP QC CORRECTED - baseline - Actual (n=43,24)
    0.9
    (0.14)
    0.9
    (0.11)
    HIP QC CORRECTED - week 48 - Actual change from baseline (n=28,19)
    0.0
    (0.03)
    0.0
    (0.02)
    SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)
    1.0
    (0.15)
    1.0
    (0.18)
    SPINAL CORD QC CORRECTED - week 48 - Actual change from baseline (n=28,18)
    0.0
    (0.04)
    0.0
    (0.04)
    11. Secondary Outcome
    Title 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
    Description 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"
    Time Frame Baseline, week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 43 24
    FEMORAL NECK QC CORRECTED - baseline - Actual (n=43,24)
    -1.2
    (1.06)
    -1.3
    (0.89)
    FEMORAL NECK QC CORRECTED - Actual change from baseline at week 48 (n=28,19)
    0.1
    (0.30)
    0.1
    (0.21)
    HIP QC CORRECTED - baseline - Actual (n=43,24)
    -0.7
    (1.08)
    -0.8
    (0.84)
    HIP QC CORRECTED - Actual change from baseline at week 48 (n=28,19)
    0.0
    (0.27)
    0.0
    (0.16)
    SPINAL CORD QC CORRECTED - baseline - Actual (n=42,23)
    -1.2
    (1.10)
    -1.1
    (1.40)
    SPINAL CORD QC CORRECTED - Actual change from baseline at week 48 (n=28,18)
    0.1
    (0.32)
    0.1
    (0.33)
    12. Secondary Outcome
    Title Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
    Description 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.
    Time Frame baseline, week 12, 36 and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo).
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    week 12 Complete responders
    37
    77.1%
    2
    8%
    week 12 Partial responders
    2
    4.2%
    2
    8%
    week 12 Overall responders (complete or partial responders)
    39
    81.3%
    4
    16%
    week 12 Non-responders
    9
    18.8%
    21
    84%
    week 36 Complete responders
    38
    79.2%
    21
    84%
    week 36 Partial responders
    2
    4.2%
    3
    12%
    week 36 Overall responders (complete or partial responders)
    40
    83.3%
    24
    96%
    week 36 Non-responders
    8
    16.7%
    1
    4%
    week 48 Complete responders
    34
    70.8%
    16
    64%
    week 48 Partial responders
    5
    10.4%
    3
    12%
    week 48 Overall responders (complete or partial responders)
    39
    81.3%
    19
    76%
    week 48 Non-responders
    9
    18.8%
    6
    24%
    13. Secondary Outcome
    Title Change in Fasting Plasma Glucose
    Description Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 47 24
    Fasting glucose (mg/dL) - baseline - actual (n=47,24)
    97.3
    (18.14)
    91.4
    (15.15)
    Fasting glucose (mg/dL) - change from baseline at week 12 (n=44,23)
    -4.3
    (14.84)
    -1.7
    (10.59)
    Fasting glucose (mg/dL) - change from baseline at week 36 (n=43,24)
    -6.7
    (12.48)
    -1.1
    (12.93)
    Fasting glucose (mg/dL) - change from baseline at week 48 (n=41,21)
    -5.6
    (14.13)
    1.8
    (13.92)
    14. Secondary Outcome
    Title Change in Hemoglobin A1C
    Description Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Hemoglobin A1C (%) - Actual - baseline
    6.0
    (0.92)
    5.7
    (0.56)
    Hemoglobin A1C (%) - Actual change from baseline at week 12 (n=46,24)
    -0.2
    (0.44)
    0.0
    (0.27)
    Hemoglobin A1C (%) Actual change from baseline at week 36 (n=44,25)
    -0.2
    (0.54)
    -0.1
    (0.46)
    Hemoglobin A1C (%) Actual change from baseline at week 48 (n=41,21)
    -0.2
    (0.58)
    0.1
    (0.37)
    15. Secondary Outcome
    Title Change in Cholesterol
    Description Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 45 25
    Cholesterol (mmol/L) - actual - baseline (n=45,25)
    5.7
    (1.30)
    5.3
    (1.15)
    Cholesterol (mmol/L) - change from baseline at week 12 (n=44,24)
    -0.8
    (0.95)
    0.0
    (0.65)
    Cholesterol (mmol/L) - change from baseline at week 36 (n=44,25)
    -1.0
    (1.28)
    -0.4
    (0.89)
    Cholesterol (mmol/L) - change from baseline at week 48 (n=42,22)
    -0.6
    (1.36)
    -0.4
    (1.18)
    16. Secondary Outcome
    Title Change in LDL Cholesterol
    Description Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 45 24
    LDL Cholesterol (mmol/L) - Actual - baseline (n=45,24)
    3.4
    (1.12)
    3.0
    (1.07)
    LDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,23)
    -0.5
    (0.80)
    0.1
    (0.47)
    LDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,24)
    -0.6
    (1.08)
    -0.2
    (0.70)
    LDL Cholesterol (mmol/L) - Actual change from baseline at week 48 (n=41,21)
    -0.5
    (0.99)
    -0.2
    (0.92)
    17. Secondary Outcome
    Title Change in HDL Cholesterol
    Description Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 45 25
    HDL Cholesterol (mmol/L) - Actual - baseline (n=45,25)
    1.6
    (0.35)
    1.5
    (0.38)
    HDL Cholesterol (mmol/L) - Actual change from baseline at week 12 (n=44,24)
    -0.3
    (0.29)
    0.0
    (0.28)
    HDL Cholesterol (mmol/L) - Actual change from baseline at week 36 (n=44,25)
    -0.3
    (0.27)
    -0.2
    (0.25)
    HDL Cholesterol (mmol/L) - Actual - change from baseline at week 48 (n=42,22)
    -0.2
    (0.27)
    -0.1
    (0.29)
    18. Secondary Outcome
    Title Change in Triglyceride
    Description Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 45 25
    Triglyceride (mmol/L) - Actual - baseline (n=45,25)
    1.5
    (0.79)
    1.7
    (0.85)
    Triglyceride (mmol/L) - Actual change from baseline at week 12(n=44,24)
    0.0
    (0.53)
    -0.2
    (0.54)
    Triglyceride (mmol/L) - Actual change from baseline at week 36 (n=44,25)
    -0.1
    (0.55)
    -0.1
    (0.71)
    Triglyceride (mmol/L) - Actual change from baseline at week 48 (n=42,22)
    0.1
    (0.92)
    -0.2
    (0.62)
    19. Secondary Outcome
    Title Change in Standing Systolic Blood Pressure
    Description Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 46 25
    Standing Systolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)
    132.4
    (19.16)
    130.0
    (17.72)
    Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)
    -7.1
    (18.08)
    -0.9
    (11.77)
    Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)
    -9.3
    (19.09)
    -7.0
    (21.04)
    Standing Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)
    -9.1
    (19.45)
    -11.0
    (22.30)
    20. Secondary Outcome
    Title Change in Supine Systolic Blood Pressure
    Description Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Supine Systolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)
    131.7
    (18.33)
    127.8
    (18.69)
    Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)
    -8.0
    (17.54)
    2.3
    (15.91)
    Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)
    -9.7
    (19.88)
    -4.4
    (17.43)
    Supine Systolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=42,22)
    -7.4
    (19.38)
    -7.5
    (18.91)
    21. Secondary Outcome
    Title Change in Standing Diastolic Blood Pressure
    Description Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 46 25
    Standing Diastolic Blood Pressure (mmHg) - Actual - baseline (n=46,25)
    87.2
    (12.74)
    88.2
    (10.83)
    Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=44,24)
    -4.8
    (11.14)
    -1.4
    (9.84)
    Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=42,25)
    -6.0
    (12.09)
    -4.4
    (13.98)
    Standing Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)
    -4.4
    (11.64)
    -3.9
    (13.36)
    22. Secondary Outcome
    Title Change in Supine Diastolic Blood Pressure
    Description Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Supine Diastolic Blood Pressure (mmHg) - Actual - baseline (n=48,25)
    83.9
    (11.71)
    81.4
    (11.21)
    Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 12 (n=46,24)
    -6.3
    (11.05)
    -0.1
    (8.31)
    Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 36 (n=44,25)
    -7.7
    (11.92)
    -3.4
    (11.37)
    Supine Diastolic Blood Pressure (mmHg) - Actual change from baseline at week 48 (n=41,22)
    -5.8
    (11.60)
    -3.7
    (10.92)
    23. Secondary Outcome
    Title Change in Weight
    Description Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Weight (kg) - Actual - baseline (n=48,25)
    78.8
    (17.46)
    77.3
    (16.90)
    Weight (kg) - Actual change from baseline at week 12(n=46,24)
    -0.8
    (3.09)
    -0.1
    (2.12)
    Weight (kg) - Actual change from baseline at week 36 (n=44,25)
    -3.0
    (5.53)
    -4.8
    (5.63)
    Weight (kg) - Actual change from baseline at week 48 (n=42,22)
    -3.6
    (6.53)
    -5.5
    (6.38)
    24. Secondary Outcome
    Title Change in Waist Circumference
    Description Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
    Time Frame Baseline, weeks 12, 36, and 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Waist Circumference (cm)) - Actual - baseline (n=48,25)
    102.5
    (17.01)
    103.4
    (15.52)
    Waist Circumference (cm) - Actual change from baseline at week 12 (n=46,24)
    -1.0
    (4.43)
    -0.5
    (3.35)
    Waist Circumference (cm)) - Actual change from baseline at week 36 (n=44,25)
    -3.9
    (6.36)
    -2.1
    (8.60)
    Waist Circumference (cm) - Actual change from baseline at week 48 (n=42,22)
    -4.1
    (6.10)
    -5.3
    (5.68)
    25. Secondary Outcome
    Title Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
    Description 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
    Time Frame baseline, Week 12, Week 36 and Week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Values for improvement or no change are reported. Hirsutism applies only to females, and thus the number analyzed is lower than for other clinical signs.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 42 24
    Facial Rubor - week 12 (n=42,20)
    36
    75%
    19
    76%
    Hirsutism - week 12 (n=36,16)
    34
    70.8%
    15
    60%
    Striae - week 12 (n=41,20)
    38
    79.2%
    19
    76%
    Supraclavicular Fat Pad - week 12 (n=42,21)
    41
    85.4%
    19
    76%
    Dorsal Fat Pad - week 12 (n=41,21)
    35
    72.9%
    17
    68%
    Proximal Muscle Atrophy - week 12 (n=42,21)
    38
    79.2%
    20
    80%
    Central Obesity - week 12 (n=42,21)
    37
    77.1%
    21
    84%
    Ecchymoses - week 12 (n=42,20)
    39
    81.3%
    19
    76%
    Facial Rubor - week 36 (n=41,23)
    39
    81.3%
    22
    88%
    Hirsutism - week 36 (n=34,17)
    28
    58.3%
    16
    64%
    Striae - week 36 (n=40,23)
    38
    79.2%
    23
    92%
    Supraclavicular Fat Pad - week 36 (n=41,24)
    40
    83.3%
    24
    96%
    Dorsal Fat Pad - week 36 (n=40,24)
    36
    75%
    22
    88%
    Proximal Muscle Atrophy - week 36 (n=41,23)
    37
    77.1%
    22
    88%
    Central Obesity - week 36 (n=41,24)
    37
    77.1%
    21
    84%
    Ecchymoses - week 36 (n=41,23)
    39
    81.3%
    22
    88%
    Facial Rubor - week 48 (n=39,21)
    37
    77.1%
    21
    84%
    Hirsutism - week 48 (n=33,15)
    29
    60.4%
    15
    60%
    Striae - week 48 (n=38,21)
    38
    79.2%
    21
    84%
    Supraclavicular Fat Pad - week 48 (n=39,22)
    38
    79.2%
    22
    88%
    Dorsal Fat Pad - week 48 (n=38,22)
    36
    75%
    20
    80%
    Proximal Muscle Atrophy - week 48 (n=39,22)
    35
    72.9%
    21
    84%
    Central Obesity - week 48 (n=39,22)
    35
    72.9%
    21
    84%
    Ecchymoses - week 48 (n=39,21)
    38
    79.2%
    20
    80%
    26. Secondary Outcome
    Title Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Actual - Baseline (n=48,25)
    49.1
    (19.60)
    56.9
    (18.99)
    Actual Change from Baseline at Week 12 (n=46,24)
    6.2
    (14.85)
    8.6
    (12.06)
    Actual Change from Baseline at Week 48 (n=42,22)
    11.7
    (16.30)
    12.8
    (14.24)
    Actual Change from Week 12 at Week 36 (n=44,23)
    4.7
    (9.01)
    -0.5
    (9.99)
    Actual Change from Week 36 at Week 48 (n=42,22)
    0.1
    (8.43)
    2.5
    (7.52)
    27. Secondary Outcome
    Title Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Actual - baseline (n=48,25)
    49.9
    (20.34)
    56.7
    (21.11)
    Actual Change from Baseline at Week 12 (n=46,24)
    6.1
    (17.21)
    9.6
    (13.61)
    Actual Change from Baseline at Week 48 (n=42,22)
    11.1
    (17.84)
    13.0
    (16.30)
    Actual Change from Week 12 at Week 36 (n=44,23)
    4.1
    (9.94)
    -1.3
    (12.36)
    Actual Change from Week 36 at Week 48 (n=42,22)
    0.1
    (9.60)
    2.4
    (8.96)
    28. Secondary Outcome
    Title Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Actual - baseline (n=48,25)
    46.9
    (22.32)
    57.7
    (21.91)
    Actual Change from Baseline at Week 12 (n=46,24)
    6.3
    (13.29)
    5.6
    (13.38)
    Actual Change from Baseline at Week 48 (n=42,22)
    13.3
    (19.83)
    12.1
    (15.59)
    Actual Change from Week 12 at Week 36 (n=44,23)
    6.6
    (12.40)
    2.2
    (12.11)
    Actual Change from Week 36 at Week 48 (n=42,22)
    23.59
    (11.27)
    2.7
    (12.17)
    29. Secondary Outcome
    Title Change From Baseline in EQ-5D-5L Utility Index
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 24
    Actual - baseline (n=48,24)
    0.825
    (0.1486)
    0.903
    (0.1125)
    Actual Change from Baseline at Week 12 (n=46,24)
    -0.000
    (0.1402)
    0.021
    (0.0771)
    Actual Change from Baseline at Week 48 (n=42,22)
    0.044
    (0.1393)
    0.033
    (0.0826)
    Actual Change from Week 12 at Week 36 (n=44,23)
    0.025
    (0.1283)
    0.010
    (0.0487)
    Actual Change from Week 36 at Week 48 (n=42,22)
    0.023
    (0.0762)
    -0.008
    (0.0367)
    30. Secondary Outcome
    Title Change From Baseline in EQ-5D VAS
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 24
    Actual - baseline (n=48,23)
    70.3
    (17.26)
    76.7
    (17.88)
    Actual Change from Baseline at week 12 (n=46,24)
    0.5
    (13.57)
    -0.3
    (10.52)
    Actual Change from Baseline at week 48 (n=42,22)
    9.4
    (13.13)
    5.8
    (9.45)
    Actual Change from Week 12 at Week 36 (n=44,23)
    6.0
    (11.08)
    3.7
    (9.29)
    Actual Change from Week 36 at Week 48 (n=42,22)
    3.2
    (8.40)
    -0.8
    (4.44)
    31. Secondary Outcome
    Title Change From Baseline in Beck Depression Inventory-II - Total Score Derived
    Description 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.
    Time Frame Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Actual - baseline (n=48,25)
    12.2
    (10.22)
    8.4
    (7.82)
    Actual Change from Baseline at Week 12 (n=46,24)
    -1.4
    (7.99)
    -3.9
    (5.42)
    Actual Change from Baseline at Week 48 (n=42,22)
    -4.3
    (7.52)
    -4.0
    (7.70)
    Actual Change from Week 12 at Week 36 (n=44,23)
    -2.0
    (4.70)
    0.6
    (6.29)
    Actual Change from Week 36 at Week 48 (n=42,22)
    -1.1
    (4.83)
    -0.4
    (3.39)
    32. Secondary Outcome
    Title Change From Baseline in Serum Cortisol
    Description Change from baseline in serum cortisol
    Time Frame Baseline, Week 12, Week 36, Week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 47 25
    Baseline - actual (n=47,25)
    565.8
    (169.01)
    486.1
    (198.12)
    Actual Change from Baseline at Week 12 (n=44,24)
    -276.0
    (178.43)
    73.0
    (185.29)
    Actual Change from Baseline at Week 36 (n=42,25)
    -267.0
    (174.18)
    -157.8
    (225.56)
    Actual Change from Baseline at Week 48 (n=41,22)
    -210.7
    (161.07)
    -131.0
    (236.88)
    33. Secondary Outcome
    Title Change From Baseline in Late Night Saliva Cortisol
    Description Change from baseline in late night saliva cortisol (nmol/L)
    Time Frame Baseline, Week 12, Week 36, Week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Baseline - actual (n=48,25)
    11.7
    (28.68)
    9.0
    (6.74)
    Actual Change from Baseline at Week 12 (n=46,24)
    -8.5
    (29.60)
    1.3
    (8.87)
    Actual Change from Baseline at Week 36 (n=42,25)
    -9.6
    (30.82)
    -5.8
    (6.84)
    Actual Change from Baseline at Week 48 (n=41,22)
    -9.3
    (29.05)
    -5.0
    (5.75)
    34. Secondary Outcome
    Title Change From Baseline in Morning Saliva Cortisol
    Description Change from baseline in morning saliva cortisol (nmol/L)
    Time Frame Baseline, Week 12, Week 36, Week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 48 25
    Baseline - actual (n=48,25)
    17.2
    (30.00)
    14.1
    (12.29)
    Actual Change from Baseline at Week 12 (n=46,24)
    -11.6
    (30.05)
    -0.3
    (11.21)
    Actual Change from Baseline at Week 36 (n=40,25)
    -11.8
    (30.74)
    -9.3
    (11.82)
    Actual Change from Baseline at Week 48 (n=41,22)
    -11.8
    (31.74)
    -6.0
    (10.97)
    35. Secondary Outcome
    Title Change From Baseline in Hair Cortisol Levels
    Description Change from baseline in hair cortisol levels
    Time Frame Baseline, Week 26, Week 48

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set: comprises all randomized participants who received at least one dose of study drug (osilodrostat or placebo). The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase.
    Arm/Group Title Osilodrostat Group Osilodrostat Placebo Group
    Arm/Group Description 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). 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).
    Measure Participants 19 9
    Baseline - actual (n=19,9)
    38.9
    (37.48)
    10.5
    (10.47)
    Actual Change from Baseline at Week 26 (n=16,7)
    -15.8
    (32.83)
    -1.1
    (12.72)
    Actual Change from Baseline at Week 48 (n=14,6)
    -17.8
    (26.66)
    -9.7
    (8.90)
    36. Secondary Outcome
    Title Plasma Osilodrostat Concentrations (ng/mL)
    Description Plasma osilodrostat concentrations (ng/mL)
    Time Frame pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic Analysis Set (PAS): comprises all participants who received at least one dose of osilodrostat and have at least one evaluable pharmacokinetic concentration (post-first-dose) at any visit. The number analyzed varied from one visit to another because of missed visits, missed assessments, early discontinuation from the study, and completion of the extension phase. Note that participants took several different doses of study medication in this dose titration study.
    Arm/Group Title Osilodrostat Incident Dose 1mg Osilodrostat Incident Dose 2mg Osilodrostat Incident Dose 5mg
    Arm/Group Description Participants received 1mg of osilodrostat. Participants received 2mg of osilodrostat. Participants received 5mg of osilodrostat.
    Measure Participants 16 55 29
    week 1 1-2 hrs post dose (n=1,43,0)
    3.85
    (NA)
    7.29
    (101.0)
    week 2 0 hrs pre dose (n=0,41,0)
    2.19
    (107.5)
    week 2 1-2 hrs post dose (n=0,42,0)
    9.76
    (53.4)
    week 5 pre dose (n=2,18,17)
    0.576
    (141.9)
    2.07
    (82.1)
    5.06
    (109.6)
    week 5 1-2 hrs post dose (n=2,9,29)
    3.64
    (60.5)
    11.1
    (31.5)
    25.8
    (84.4)
    week 8 0 hrs pre dose (n=2,4,13)
    0.971
    (76.7)
    2.64
    (53.7)
    4.99
    (55.6)
    week 8 1-2 hrs post dose (n=3,6,14)
    3.70
    (47.6)
    8.31
    (45.6)
    23.3
    (68.1)
    week 12 0 hrs pre dose (n=2,8,11)
    1.55
    (3.7)
    2.45
    (39.2)
    5.03
    (74.6)
    week 12 1-2 hrs post dose (n=4,34,0)
    4.93
    (32.0)
    11.7
    (78.9)
    week 14 0 hrs pre dose (n=4,55,0)
    0.974
    (129.7)
    1.96
    (74.9)
    week 14 1-2 hrs post dose (n=6,49,6)
    3.74
    (161.4)
    9.69
    (35.8)
    22.6
    (37.8)
    week 20 0 hrs pre dose (n=10,19,15)
    1.63
    (71.1)
    1.95
    (68.1)
    6.21
    (74.3)
    week 20 1-2 hrs post dose (n=13,18,12)
    6.09
    (27.3)
    8.66
    (94.0)
    26.0
    (99.3)
    week 26 0 hrs pre dose (n=12,13,10)
    1.77
    (86.4)
    2.12
    (77.8)
    6.89
    (85.1)
    week 26 1-2 hrs post dose (n=16,14,10)
    5.28
    (31.5)
    8.04
    (50.7)
    33.1
    (31.4)

    Adverse Events

    Time Frame Adverse events are reported from first dose of study treatment until end of study treatment plus 8 weeks post treatment, up to maximum duration of 116.7 weeks.
    Adverse Event Reporting Description
    Arm/Group Title Placebo Controlled Period - Osilodrostat Arm. Placebo Controlled Period - Placebo Arm. Overall Study Period - Osilodrostat Arm. Overall Study Period - Placebo Arm. Overall Study Period - All Participants.
    Arm/Group Description All data while on osilodrostat treatment up to week 12 in participants initially randomized to osilodrostat. All data while on placebo treatment up to week 12 in participants initially randomized to placebo. All data while on osilodrostat treatment from randomization up to end-of-study in participants initially randomized to osilodrostat. All data while on osilodrostat treatment from Week 12 up to end-of-study in participants initially randomized to placebo. All data while on osilodrostat treatment up to end-of-study in all randomized participants, excluding data while on placebo from participants initially randomized to placebo.
    All Cause Mortality
    Placebo Controlled Period - Osilodrostat Arm. Placebo Controlled Period - Placebo Arm. Overall Study Period - Osilodrostat Arm. Overall Study Period - Placebo Arm. Overall Study Period - All Participants.
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/48 (0%) 0/25 (0%) 0/48 (0%) 0/25 (0%) 0/73 (0%)
    Serious Adverse Events
    Placebo Controlled Period - Osilodrostat Arm. Placebo Controlled Period - Placebo Arm. Overall Study Period - Osilodrostat Arm. Overall Study Period - Placebo Arm. Overall Study Period - All Participants.
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/48 (4.2%) 1/25 (4%) 10/48 (20.8%) 0/25 (0%) 10/73 (13.7%)
    Endocrine disorders
    Adrenal insufficiency 0/48 (0%) 0/25 (0%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Gastrointestinal disorders
    Abdominal pain 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Erosive duodenitis 1/48 (2.1%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Nausea 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Infections and infestations
    Anal abscess 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Dengue fever 1/48 (2.1%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Pneumonia 0/48 (0%) 1/25 (4%) 0/48 (0%) 0/25 (0%) 0/73 (0%)
    Pyelonephritis 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Injury, poisoning and procedural complications
    Conjunctival laceration 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Eye injury 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Retinal injury 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Wrist fracture 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Investigations
    Electrocardiogram QT prolonged 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Electrocardiogram T wave inversion 1/48 (2.1%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Musculoskeletal and connective tissue disorders
    Myalgia 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Periarthritis 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Nervous system disorders
    Cerebral vascular occlusion 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Hemiparesis 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Obstructive airways disorder 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Vascular disorders
    Hypertension 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Hypotension 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Orthostatic hypotension 0/48 (0%) 0/25 (0%) 1/48 (2.1%) 0/25 (0%) 1/73 (1.4%)
    Other (Not Including Serious) Adverse Events
    Placebo Controlled Period - Osilodrostat Arm. Placebo Controlled Period - Placebo Arm. Overall Study Period - Osilodrostat Arm. Overall Study Period - Placebo Arm. Overall Study Period - All Participants.
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 45/48 (93.8%) 21/25 (84%) 47/48 (97.9%) 24/25 (96%) 71/73 (97.3%)
    Blood and lymphatic system disorders
    Anaemia 2/48 (4.2%) 2/25 (8%) 2/48 (4.2%) 1/25 (4%) 3/73 (4.1%)
    Cardiac disorders
    Palpitations 0/48 (0%) 2/25 (8%) 2/48 (4.2%) 0/25 (0%) 2/73 (2.7%)
    Tachycardia 6/48 (12.5%) 0/25 (0%) 8/48 (16.7%) 1/25 (4%) 9/73 (12.3%)
    Endocrine disorders
    Adrenal insufficiency 7/48 (14.6%) 0/25 (0%) 12/48 (25%) 6/25 (24%) 18/73 (24.7%)
    Gastrointestinal disorders
    Abdominal distension 3/48 (6.3%) 1/25 (4%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Abdominal pain 4/48 (8.3%) 0/25 (0%) 10/48 (20.8%) 2/25 (8%) 12/73 (16.4%)
    Abdominal pain upper 1/48 (2.1%) 1/25 (4%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Diarrhoea 10/48 (20.8%) 0/25 (0%) 14/48 (29.2%) 3/25 (12%) 17/73 (23.3%)
    Nausea 15/48 (31.3%) 3/25 (12%) 22/48 (45.8%) 5/25 (20%) 27/73 (37%)
    Vomiting 5/48 (10.4%) 0/25 (0%) 9/48 (18.8%) 0/25 (0%) 9/73 (12.3%)
    General disorders
    Asthenia 11/48 (22.9%) 0/25 (0%) 15/48 (31.3%) 2/25 (8%) 17/73 (23.3%)
    Fatigue 12/48 (25%) 4/25 (16%) 23/48 (47.9%) 6/25 (24%) 29/73 (39.7%)
    Oedema peripheral 5/48 (10.4%) 0/25 (0%) 12/48 (25%) 0/25 (0%) 12/73 (16.4%)
    Pyrexia 2/48 (4.2%) 0/25 (0%) 5/48 (10.4%) 0/25 (0%) 5/73 (6.8%)
    Infections and infestations
    Gastroenteritis 1/48 (2.1%) 0/25 (0%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Influenza 2/48 (4.2%) 0/25 (0%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Laryngitis 0/48 (0%) 0/25 (0%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Nasopharyngitis 1/48 (2.1%) 1/25 (4%) 2/48 (4.2%) 2/25 (8%) 4/73 (5.5%)
    Oral herpes 1/48 (2.1%) 0/25 (0%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Pharyngitis 1/48 (2.1%) 0/25 (0%) 5/48 (10.4%) 1/25 (4%) 6/73 (8.2%)
    Upper respiratory tract infection 5/48 (10.4%) 0/25 (0%) 12/48 (25%) 4/25 (16%) 16/73 (21.9%)
    Urinary tract infection 4/48 (8.3%) 0/25 (0%) 8/48 (16.7%) 4/25 (16%) 12/73 (16.4%)
    Injury, poisoning and procedural complications
    Fall 2/48 (4.2%) 0/25 (0%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Investigations
    Alanine aminotransferase increased 2/48 (4.2%) 2/25 (8%) 3/48 (6.3%) 3/25 (12%) 6/73 (8.2%)
    Aspartate aminotransferase increased 1/48 (2.1%) 0/25 (0%) 2/48 (4.2%) 3/25 (12%) 5/73 (6.8%)
    Blood cholesterol increased 2/48 (4.2%) 1/25 (4%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Blood potassium decreased 1/48 (2.1%) 1/25 (4%) 2/48 (4.2%) 2/25 (8%) 4/73 (5.5%)
    Blood pressure increased 1/48 (2.1%) 1/25 (4%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Blood testosterone increased 5/48 (10.4%) 0/25 (0%) 13/48 (27.1%) 5/25 (20%) 18/73 (24.7%)
    Electrocardiogram T wave inversion 0/48 (0%) 1/25 (4%) 0/48 (0%) 2/25 (8%) 2/73 (2.7%)
    Renin increased 1/48 (2.1%) 0/25 (0%) 1/48 (2.1%) 4/25 (16%) 5/73 (6.8%)
    Weight decreased 2/48 (4.2%) 0/25 (0%) 3/48 (6.3%) 1/25 (4%) 4/73 (5.5%)
    Metabolism and nutrition disorders
    Decreased appetite 18/48 (37.5%) 4/25 (16%) 24/48 (50%) 10/25 (40%) 34/73 (46.6%)
    Hypercholesterolaemia 3/48 (6.3%) 1/25 (4%) 6/48 (12.5%) 0/25 (0%) 6/73 (8.2%)
    Hypoglycaemia 1/48 (2.1%) 0/25 (0%) 3/48 (6.3%) 1/25 (4%) 4/73 (5.5%)
    Hypokalaemia 1/48 (2.1%) 0/25 (0%) 6/48 (12.5%) 2/25 (8%) 8/73 (11%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 17/48 (35.4%) 3/25 (12%) 26/48 (54.2%) 7/25 (28%) 33/73 (45.2%)
    Back pain 2/48 (4.2%) 0/25 (0%) 8/48 (16.7%) 2/25 (8%) 10/73 (13.7%)
    Muscle spasms 2/48 (4.2%) 0/25 (0%) 3/48 (6.3%) 1/25 (4%) 4/73 (5.5%)
    Muscular weakness 2/48 (4.2%) 0/25 (0%) 4/48 (8.3%) 2/25 (8%) 6/73 (8.2%)
    Myalgia 10/48 (20.8%) 1/25 (4%) 15/48 (31.3%) 3/25 (12%) 18/73 (24.7%)
    Pain in extremity 2/48 (4.2%) 0/25 (0%) 3/48 (6.3%) 2/25 (8%) 5/73 (6.8%)
    Nervous system disorders
    Dizziness 9/48 (18.8%) 4/25 (16%) 19/48 (39.6%) 3/25 (12%) 22/73 (30.1%)
    Headache 7/48 (14.6%) 6/25 (24%) 17/48 (35.4%) 8/25 (32%) 25/73 (34.2%)
    Paraesthesia 0/48 (0%) 0/25 (0%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Psychiatric disorders
    Anxiety 0/48 (0%) 0/25 (0%) 2/48 (4.2%) 2/25 (8%) 4/73 (5.5%)
    Renal and urinary disorders
    Renal colic 0/48 (0%) 1/25 (4%) 0/48 (0%) 2/25 (8%) 2/73 (2.7%)
    Respiratory, thoracic and mediastinal disorders
    Cough 0/48 (0%) 0/25 (0%) 4/48 (8.3%) 0/25 (0%) 4/73 (5.5%)
    Dyspnoea 1/48 (2.1%) 0/25 (0%) 2/48 (4.2%) 2/25 (8%) 4/73 (5.5%)
    Epistaxis 0/48 (0%) 0/25 (0%) 0/48 (0%) 2/25 (8%) 2/73 (2.7%)
    Nasal congestion 1/48 (2.1%) 0/25 (0%) 3/48 (6.3%) 0/25 (0%) 3/73 (4.1%)
    Skin and subcutaneous tissue disorders
    Acne 2/48 (4.2%) 0/25 (0%) 9/48 (18.8%) 1/25 (4%) 10/73 (13.7%)
    Alopecia 1/48 (2.1%) 1/25 (4%) 4/48 (8.3%) 1/25 (4%) 5/73 (6.8%)
    Dry skin 3/48 (6.3%) 0/25 (0%) 3/48 (6.3%) 1/25 (4%) 4/73 (5.5%)
    Eczema 0/48 (0%) 0/25 (0%) 2/48 (4.2%) 2/25 (8%) 4/73 (5.5%)
    Hirsutism 0/48 (0%) 1/25 (4%) 6/48 (12.5%) 1/25 (4%) 7/73 (9.6%)
    Pruritus 6/48 (12.5%) 0/25 (0%) 7/48 (14.6%) 2/25 (8%) 9/73 (12.3%)
    Skin hyperpigmentation 2/48 (4.2%) 0/25 (0%) 3/48 (6.3%) 1/25 (4%) 4/73 (5.5%)
    Vascular disorders
    Hypertension 7/48 (14.6%) 7/25 (28%) 12/48 (25%) 4/25 (16%) 16/73 (21.9%)
    Hypotension 5/48 (10.4%) 0/25 (0%) 9/48 (18.8%) 3/25 (12%) 12/73 (16.4%)
    Orthostatic hypotension 4/48 (8.3%) 0/25 (0%) 7/48 (14.6%) 1/25 (4%) 8/73 (11%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone + 1 862 778 8300
    Email Novartis.email@Novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT02697734
    Other Study ID Numbers:
    • CLCI699C2302
    First Posted:
    Mar 3, 2016
    Last Update Posted:
    Nov 1, 2021
    Last Verified:
    Oct 1, 2021