A Phase 3 interventional study of osilodrostat and osilodrostat Placebo in Cushing's Disease, sponsored by Novartis Pharmaceuticals. Completed at 36 sites in 14 countries. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2021-11-01.
Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 3, Interventional, and Treatment
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.
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.
64 studies on the registry are indexed under Pituitary ACTH Hypersecretion; 16 are open to participants now.
This study's enrollment of 73 is above the median of 44 across 40 interventional studies indexed under Pituitary ACTH Hypersecretion.
Browse Pituitary ACTH Hypersecretion studies →Novartis Pharmaceuticals is the lead sponsor of 2,718 studies on the registry; 221 are open to participants now.
Of its 585 completed or terminated interventional studies of FDA-regulated products, 438 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
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):
Confirmation (based on medical history) of pituitary source of excess
ACTH as defined by any one or more of the following three criteria:
i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had prior pituitary surgery. OR ii. 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
Key exclusion criteria:
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.
D. Combination of any two of the following (a+b or a+c, or b+c):
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
ULN (upper limit of normal)
The top of the normal range for a blood test, as set by the laboratory that runs it. Each lab prints its own range next to your result.
“≤ 2.5 × ULN” means the result can be up to two and a half times that top value.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Corticosteroids (steroids)
Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.
Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg.
Also known as: LCI699
Matching Placebo in the form of filmcoated tablets for oral administration
Percentage of Randomized Participants With a Complete Response
A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
Time frame: at Week 12
Percentage of Participants With mUFC ≤ ULN at Week 36
The complete response rate in both arms combined at Week 36. A complete responder at Week 36 is defined as a participant who had mean urine free cortisol \<= upper limit of normal (mUFC \<= ULN) at Week 36. Participants with missing mUFC at Week 36 were counted as non-responders.
Time frame: At Week 36
Change From Baseline in mUFC
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
Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier.
Time frame: up to 12 weeks
Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. The median time-to-first control and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Time frame: up to 12 weeks
Time-to-first Control of mUFC - % Event Probability Estimates
To assess time-to-first control of mUFC, (in days) from randomization to the first mUFC collection that was ≤ ULN before completion/discontinuation of placebo-controlled period. Participants who did not achieve post-baseline mUFC control were censored at discontinuation or completion of placebo-controlled period, whichever was earlier. % Event probability estimate is the estimated probability that a participant will have an event prior to the specified time point. % Event probability estimates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for Confidence Interval (CI) of Kaplan-Meier (KM) estimates.
Time frame: up to 12 weeks
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants
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
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Median Time to Escape From Normal mUFC
To assess time-to-escape from the first collection of normal mUFC (≤ ULN) to the first mUFC \> 1.3 x ULN on two consecutive visits on the highest tolerated dose of osilodrostat and not related to a dose interruption or dose reduction due to safety reasons. Escape will not be assessed for participants during the first 26 weeks. The median time-to-escape and corresponding two-sided 95% Confidence Interval were calculated using Kaplan-Meier methodology of Brookmeyer and Crowley (1982).
Time frame: from week 26 to week 48
Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - % Event Probability Estimates
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
Change From Baseline in Bone Mineral Density (BMD) by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
The change from baseline in bone mineral density at the femoral neck, hip and spinal cord at Week 48 by treatment arm - QC corrected. An increase in bone mineral density is indicative of an improvement.
Time frame: Baseline, week 48
Change From Baseline in Bone Mineral Density (BMD) T-score by Dual-energy X-ray Absorptiometry (DXA) Scan at the Femoral Neck, Hip and Spinal Cord - QC Corrected
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
Patients With a Complete Response (mUFC ≤ ULN) or a Partial Response (mUFC Decrease ≥ 50% From Baseline and >ULN) at Week 12, 36 and 48
Overall response rate defined as percentage of complete responders (mUFC ≤ ULN) plus partial responders (≥ 50% reduction in mUFC from baseline and \>ULN) at week 12, 36, 48 by treatment arms for all patients.
Time frame: baseline, week 12, 36 and 48
Change in Fasting Plasma Glucose
Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Hemoglobin A1C
Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Cholesterol
Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in LDL Cholesterol
Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in HDL Cholesterol
Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Triglyceride
Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Standing Systolic Blood Pressure
Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Supine Systolic Blood Pressure
Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Standing Diastolic Blood Pressure
Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Supine Diastolic Blood Pressure
Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Weight
Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change in Waist Circumference
Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
Time frame: Baseline, weeks 12, 36, and 48
Change From Baseline to Week 12, Week 36, and Week 48 in Clinical Signs of Cushing's Disease
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
Change From Baseline in Standardized Health Related Quality of Life Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Standardized Psychosocial Issues Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
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.
Change From Baseline in Standardized Physical Problems Score, Using Cushing Disease-specific Quality of Life Patient Reported Outcome (PRO) Assessment
The CushingQoL is a valid and reliable disease-specific QoL questionnaire which assesses health-related quality of life (HRQoL) in patients with Cushing's syndrome and has been validated in patients with Cushing's disease. The CushingQoL consists of questions reflecting dimensions of HRQoL related to physical aspects (e.g. 'I bruise easily'), psychological aspects (e.g. 'I am more irritable, I have sudden mood swings and angry outbursts'), and social aspects (e.g. 'I have had to give up my social or leisure activities due to my illness'). The questionnaire consists of 12 items measured on a five point Likert-type scale assessing how often or how much each item has been related to the patient's Cushing's disease in the previous week. The raw score is calculated by summing the individual item scores prior to being standardized so that the total score ranges from 0 to 100. Increases from baseline are indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in EQ-5D-5L Utility Index
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.
Change From Baseline in EQ-5D VAS
The EQ-5D-5L also includes a 20 cm vertical, VAS (visual analogue scale) with a scale of 0-100, with endpoints labeled 100='the best health you can imagine' and 0='the worst health you can imagine'. A single index value is analyzed for the EQ-5D-5L VAS score. An increase from baseline in the EQ-ED-5L VAS is indicative of an improvement.
Time frame: Baseline to Week 12 and 48, Week 12 to Week 36, Week 36 to Week 48.
Change From Baseline in Beck Depression Inventory-II - Total Score Derived
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.
Change From Baseline in Serum Cortisol
Change from baseline in serum cortisol
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Late Night Saliva Cortisol
Change from baseline in late night saliva cortisol (nmol/L)
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Morning Saliva Cortisol
Change from baseline in morning saliva cortisol (nmol/L)
Time frame: Baseline, Week 12, Week 36, Week 48
Change From Baseline in Hair Cortisol Levels
Change from baseline in hair cortisol levels
Time frame: Baseline, Week 26, Week 48
Plasma Osilodrostat Concentrations (ng/mL)
Plasma osilodrostat concentrations (ng/mL)
Time frame: pre-dose and 1-2hrs post dose at weeks 1, 2, 5, 8, 12, 14, 20, 26
| Milestone | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Started | 48 | 25 |
| Completed | 42 | 23 |
| Not completed | 6 | 2 |
| Withdrew: Withdrawal by subject | 4 | 0 |
| Withdrew: Adverse event | 1 | 2 |
| Withdrew: Physician decision | 1 | 0 |
| Milestone | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Started | 38 | 22 |
| Completed | 33 | 20 |
| Not completed | 5 | 2 |
| Withdrew: Adverse event | 5 | 1 |
| Withdrew: Physician decision | 0 | 1 |
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.
| Participants | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Percentage of Randomized Participants With a Complete Response | 37 | 2 |
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.
| Percentage of participants | All Participants Combined |
|---|---|
| Percentage of Participants With mUFC ≤ ULN at Week 36 | 80.8 (69.9 to 89.1) |
To assess the change in mean urinary free cortisol (mUFC) from baseline by treatment arm.
| nmol/24hr | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Participants | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Time-to-first Control of mUFC - Number (%) of Participants With mUFC <=ULN | 45 | 8 |
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).
| Days | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Time-to-first Control of mUFC - Median Time to First Controlled mUFC Response | 35 (34.0 to 52.0) | NA (87.0 to NA) |
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.
| Percent (event probability estimates) | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 2 Weeks | 25.0 (15.0 to 39.8) | 16.0 (6.3 to 37.2) |
| 5 Weeks | 60.4 (47.0 to 74.1) | 20.0 (8.9 to 41.6) |
| 8 Weeks | 79.4 (67.0 to 89.4) | 28.0 (14.5 to 49.9) |
| 12 Weeks | NA (NA to NA) | 28.0 (14.5 to 49.9) |
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.
| Participants | Osilodrostat Group | Osilodrostat Placebo Group | All Participants |
|---|---|---|---|
| Time-to-escape During Osilodrostat Treatment From Collection of Normal mUFC (≤ ULN) to the First mUFC > 1.3 x ULN - Number (%) of Participants | 0 | 2 | 2 |
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).
| days | Osilodrostat Group | Osilodrostat Placebo Group | All Participants |
|---|---|---|---|
| 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 | NA (NA to NA) | NA (116.0 to NA) | NA (NA to NA) |
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.
| Percent (event probability estimates) | Osilodrostat Group | Osilodrostat Placebo Group | All Participants |
|---|---|---|---|
| % Event probability estimates (95% CI) at 26 Weeks | 0 (NA to NA) | 21.3 (5.7 to 61.9) | 15.6 (4.1 to 49.6) |
| % Event probability estimates (95% CI) at 36 Weeks | 0 (NA to NA) | NA (NA to NA) | 15.6 (4.1 to 49.6) |
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.
| g/cm2 | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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"
| scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Participants | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| week 12 Complete responders | 37 | 2 |
| week 12 Partial responders | 2 | 2 |
| week 12 Overall responders (complete or partial responders) | 39 | 4 |
| week 12 Non-responders | 9 | 21 |
| week 36 Complete responders | 38 | 21 |
| week 36 Partial responders | 2 | 3 |
| week 36 Overall responders (complete or partial responders) | 40 | 24 |
| week 36 Non-responders | 8 | 1 |
| week 48 Complete responders | 34 | 16 |
| week 48 Partial responders | 5 | 3 |
| week 48 Overall responders (complete or partial responders) | 39 | 19 |
| week 48 Non-responders | 9 | 6 |
Change from baseline in fasting plasma glucose at Week 12, Week 36, and Week 48 by treatment arm
| mg/dL | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Hemoglobin A1C (%) at Week 12, Week 36, and Week 48 by treatment arm
| percentage of Hemoglobin A1C | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
| mmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in LDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
| mmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in HDL Cholesterol (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
| mmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Triglyceride (mmol/L) at Week 12, Week 36, and Week 48 by treatment arm
| mmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Standing Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
| mmHg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Supine Systolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
| mmHg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Standing Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
| mmHg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Supine Diastolic Blood Pressure (mmHg) at Week 12, Week 36, and Week 48 by treatment arm
| mmHg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Weight (kg) at Week 12, Week 36, and Week 48 by treatment arm
| kg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in Waist Circumference (cm) at Week 12, Week 36, and Week 48 by treatment arm
| cm | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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
| Participants | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| Facial Rubor - week 12 (n=42,20) | 36 | 19 |
| Hirsutism - week 12 (n=36,16) | 34 | 15 |
| Striae - week 12 (n=41,20) | 38 | 19 |
| Supraclavicular Fat Pad - week 12 (n=42,21) | 41 | 19 |
| Dorsal Fat Pad - week 12 (n=41,21) | 35 | 17 |
| Proximal Muscle Atrophy - week 12 (n=42,21) | 38 | 20 |
| Central Obesity - week 12 (n=42,21) | 37 | 21 |
| Ecchymoses - week 12 (n=42,20) | 39 | 19 |
| Facial Rubor - week 36 (n=41,23) | 39 | 22 |
| Hirsutism - week 36 (n=34,17) | 28 | 16 |
| Striae - week 36 (n=40,23) | 38 | 23 |
| Supraclavicular Fat Pad - week 36 (n=41,24) | 40 | 24 |
| Dorsal Fat Pad - week 36 (n=40,24) | 36 | 22 |
| Proximal Muscle Atrophy - week 36 (n=41,23) | 37 | 22 |
| Central Obesity - week 36 (n=41,24) | 37 | 21 |
| Ecchymoses - week 36 (n=41,23) | 39 | 22 |
| Facial Rubor - week 48 (n=39,21) | 37 | 21 |
| Hirsutism - week 48 (n=33,15) | 29 | 15 |
| Striae - week 48 (n=38,21) | 38 | 21 |
| Supraclavicular Fat Pad - week 48 (n=39,22) | 38 | 22 |
| Dorsal Fat Pad - week 48 (n=38,22) | 36 | 20 |
| Proximal Muscle Atrophy - week 48 (n=39,22) | 35 | 21 |
| Central Obesity - week 48 (n=39,22) | 35 | 21 |
| Ecchymoses - week 48 (n=39,21) | 38 | 20 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
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.
| Scores on a scale | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in serum cortisol
| nmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in late night saliva cortisol (nmol/L)
| nmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in morning saliva cortisol (nmol/L)
| nmol/L | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Change from baseline in hair cortisol levels
| pg/mg | Osilodrostat Group | Osilodrostat Placebo Group |
|---|---|---|
| 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 |
Plasma osilodrostat concentrations (ng/mL)
| ng/mL | Osilodrostat Incident Dose 1mg | Osilodrostat Incident Dose 2mg | Osilodrostat Incident Dose 5mg |
|---|---|---|---|
| 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 |
Collected over 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.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Placebo Controlled Period - Osilodrostat Arm. | 0/48 (0%) | 2/48 (4.2%) | 45/48 (93.8%) |
| Placebo Controlled Period - Placebo Arm. | 0/25 (0%) | 1/25 (4%) | 21/25 (84%) |
| Overall Study Period - Osilodrostat Arm. | 0/48 (0%) | 10/48 (20.8%) | 47/48 (97.9%) |
| Overall Study Period - Placebo Arm. | 0/25 (0%) | 0/25 (0%) | 24/25 (96%) |
| Overall Study Period - All Participants. | 0/73 (0%) | 10/73 (13.7%) | 71/73 (97.3%) |
| Event | 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. |
|---|---|---|---|---|---|
| Adrenal insufficiencyEndocrine disorders | 0/48 | 0/25 | 3/48 | 0/25 | 3/73 |
| PneumoniaInfections and infestations | 0/48 | 1/25 | 0/48 | 0/25 | 0/73 |
| Abdominal painGastrointestinal disorders | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Erosive duodenitisGastrointestinal disorders | 1/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| NauseaGastrointestinal disorders | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Anal abscessInfections and infestations | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Dengue feverInfections and infestations | 1/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| PyelonephritisInfections and infestations | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Conjunctival lacerationInjury, poisoning and procedural complications | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Eye injuryInjury, poisoning and procedural complications | 0/48 | 0/25 | 1/48 | 0/25 | 1/73 |
| Event | 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. |
|---|---|---|---|---|---|
| ArthralgiaMusculoskeletal and connective tissue disorders | 17/48 | 3/25 | 26/48 | 7/25 | 33/73 |
| Decreased appetiteMetabolism and nutrition disorders | 18/48 | 4/25 | 24/48 | 10/25 | 34/73 |
| FatigueGeneral disorders | 12/48 | 4/25 | 23/48 | 6/25 | 29/73 |
| NauseaGastrointestinal disorders | 15/48 | 3/25 | 22/48 | 5/25 | 27/73 |
| DizzinessNervous system disorders | 9/48 | 4/25 | 19/48 | 3/25 | 22/73 |
| HeadacheNervous system disorders | 7/48 | 6/25 | 17/48 | 8/25 | 25/73 |
| AstheniaGeneral disorders | 11/48 | 0/25 | 15/48 | 2/25 | 17/73 |
| MyalgiaMusculoskeletal and connective tissue disorders | 10/48 | 1/25 | 15/48 | 3/25 | 18/73 |
| DiarrhoeaGastrointestinal disorders | 10/48 | 0/25 | 14/48 | 3/25 | 17/73 |
| HypertensionVascular disorders | 7/48 | 7/25 | 12/48 | 4/25 | 16/73 |
| Age, Categorical(Participants) | Osilodrostat Group | Osilodrostat Placebo Group | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 46 | 25 | 71 |
| >=65 years | 2 | 0 | 2 |
| Age, Continuous(Years) | Osilodrostat Group | Osilodrostat Placebo Group | Total |
|---|---|---|---|
| Mean | 42.3 ± 13.82 | 38.9 ± 12.33 | 41.2 ± 13.35 |
| Sex: Female, Male(Participants) | Osilodrostat Group | Osilodrostat Placebo Group | Total |
|---|---|---|---|
| Female | 43 | 18 | 61 |
| Male | 5 | 7 | 12 |
| Race (NIH/OMB)(Participants) | Osilodrostat Group | Osilodrostat Placebo Group | Total |
|---|---|---|---|
| American Indian or Alaska Native | 1 | 0 | 1 |
| Asian | 9 | 8 | 17 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 2 | 0 | 2 |
| White | 34 | 15 | 49 |
| More than one race | 0 | 1 | 1 |
| Unknown or Not Reported | 2 | 1 | 3 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: Yes — Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Data sharing details ↗ · www.clinicalstudydatarequest.com
Ran from Oct 2016 to primary completion in Jun 2019, 32 months.
Results were first posted in Oct 2021, 2 years 4 months after primary completion. A results delay was requested in Aug 2019.
How these figures are worked out, and which studies are left out of them.
This study is completed, as verified in Oct 2021. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
Studies of the drug tested here: Osilodrostat
Pituitary ACTH Hypersecretion →