A Phase 2 interventional study of LCI699 in Cushings Disease and Cushing Disease, sponsored by Novartis Pharmaceuticals. Completed at 10 sites in 4 countries. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2021-01-22.
Sponsored by Novartis Pharmaceuticals (part of Novartis) · Phase 2, Interventional, and Treatment
This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.
In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.
A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.
The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.
The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.
Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was \< Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.
The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.
Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.
On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.
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Exclusion Criteria:
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.
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
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.
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.
HbA1c
A blood test of average blood sugar over the past two to three months, given as a percentage or in mmol/mol. 6.5% (48 mmol/mol) or more is the usual threshold for diabetes, normally confirmed by a second test.
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.
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.
Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study
Drug: LCI699
Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study
Drug: LCI699
Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study
Drug: LCI699
Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets.
Also known as: osilodrastat
Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.
Time frame: 10 weeks
Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)
Change in Deoxycorticosterone over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)
Change in Deoxycortisol over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)
Change in aldosterone \& thyroxine, free over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)
Change in Estradiol in females over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)
Change in Estradiol in males over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)
Change in FSH in females over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male)
Change in FSH in males over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin
Change in Renin, Insulin \& Thyrotropin over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Insulin-like Growth Factor-1
Change in Insulin-like Growth Factor-1 over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female)
Change in LH in females over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male)
Change in LH in males over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female)
Change in Testosterone in females over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male)
Change in Testosterone in males over time.
Time frame: baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Fasting Glucose
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Hemoglobin A1C (HbA1C) (Glycosylated Hemoglobin)
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Sitting Diastolic Blood Pressure (DBP), Sitting Systolic Blood Pressure (SBP)
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Body Mass Index (BMI)
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. QUICKI is the quantitative insulin sensitivity check index and is derived using the inverse of the sum of algorithms (base 10) of the fasting insulin and fasting glucose: 1/(log(fasting insulin mU/mL)+log(fasting glucose mg/dL)). Values typically associated with the QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. So lower numbers reflect greater insulin resistance.
Time frame: Baseline, Week 22, Week 70, Last observed value, up to Month 88
Pharmacokinetics (PK) Parameters: Area Under Curve (AUC)0-6h ss, AUC0-12h ss
Trough PK concentrations and PK profiles at steady-state were collected. The AUC from time 0 to 12 h post dose at steady state, calculated by using the predose concentration (Ctrough,ss) as the 12 h concentration, assuming steady-state has been reached.
Time frame: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
PK Parameters: Cmax ss, Ctrough ss
Trough PK concentrations and PK profiles at steady-state were collected.
Time frame: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
PK Parameters: Tmax ss,
Trough PK concentrations and PK profiles at steady-state were collected.
Time frame: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
PK Parameters: T1/2 ss,
Trough PK concentrations and PK profiles at steady-state were collected.
Time frame: pre-dose (0 hour), 1, 1.5, 2, 4 and 6 hours post AM dose for escalation dose or pre-dose (trough) for maintained dose
Percentage of Participants Who Were Responders on 24-hour Urine Free Cortisol (UFC) at Week 22
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 22 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Participants with controlled or partially controlled UFC were defined as: Controlled UFC: mean UFC level \<= upper limit of normal (ULN). Partially controlled UFC: mean UFC level \> ULN but with \>= 50% reduction from baseline.
Time frame: Week 22
Number of Participants With Escape
Escape is defined as loss of UFC control (i.e. UFC \> ULN) on at least 2 consecutive visits at the highest tolerated dose after previously attaining UFC normalization)
Time frame: approx. 7 years
31 were enrolled in the study: 12 in Part l and 19 in Part ll Core. Four of the participants in the Part II Core were previously enrolled in the Part I Core. That is, 4 participants who were included in Part 1 as well as in Part 2, re-enrolled in the study in part 2 (i.e., they completed the informed consent process again in Part 2, and were considered re-enrolled, after originally enrolling in part 1).
| Milestone | Part l: Core Cohort | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|---|
| Started | 12 | 0 | 0 |
| Completed | 12 | 0 | 0 |
| Not completed | 0 | 0 | 0 |
| Milestone | Part l: Core Cohort | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|---|
| Started | 0 | 15 | 4 |
| Completed | 0 | 7 | 3 |
| Not completed | 0 | 8 | 1 |
| Withdrew: Adverse event | 0 | 3 | 0 |
| Withdrew: Subj's cond. no longer require treatment | 0 | 2 | 1 |
| Withdrew: Withdrawal by subject | 0 | 2 | 0 |
| Withdrew: Administrative problems | 0 | 1 | 0 |
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.
| Percentage of participants | Part l: Core Cohort |
|---|---|
| Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10 | 100.0 |
Change in Deoxycorticosterone over time.
| pmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: 11-Deoxycorticosterone | 292.8 ± 371.54 | 188.0 ± 105.21 |
| WK 22: 11-Deoxycorticosterone | 6957.8 ± 9627.77 | 3670.0 ± 2734.34 |
| WK 70: 11-Deoxycorticosterone | 2523.1 ± 1597.39 | 1743.0 ± 1048.22 |
| LOV: 11-Deoxycorticosterone | 1640.8 ± 2097.16 | 1822.3 ± 1452.72 |
Change in Deoxycortisol over time.
| nmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: 11-Deoxycortisol | 4.21 ± 4.648 | 5.48 ± 6.549 |
| WK 22: 11-Deoxycortisol | 45.48 ± 44.880 | 54.75 ± 60.676 |
| WK 70: 11-Deoxycortisol | 15.32 ± 13.463 | 9.03 ± 7.934 |
| LOV: 11-Deoxycortisol | 8.60 ± 18.910 | 11.83 ± 19.101 |
Change in aldosterone \& thyroxine, free over time.
| pmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Aldosterone | 165.5 ± 255.07 | 127.0 ± 177.04 |
| WK 22: Aldosterone | -151.1 ± 290.53 | -64.5 ± 247.93 |
| WK 70: Aldosterone | -101.9 ± 153.82 | -120.0 ± 182.11 |
| LOV: Aldosterone | -135.1 ± 258.36 | -99.5 ± 149.06 |
| BL: Thyroxine, free | 14.02 ± 3.233 | 18.40 ± 8.050 |
| WK 22: Thyroxine, free | -1.17 ± 3.254 | -3.63 ± 3.247 |
| WK 70: Thyroxine, free | 0.46 ± 2.355 | -3.78 ± 7.951 |
| LOV: Thyroxine, free | 1.69 ± 3.281 | -2.33 ± 5.324 |
Change in Estradiol in females over time.
| pmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Female Estradiol | 209.60 ± 282.423 | 307.23 ± 263.028 |
| WK 22: Female Estradiol | -42.19 ± 223.444 | -24.63 ± 234.288 |
| WK 70: Female Estradiol | 10.55 ± 187.443 | -141.00 ± 376.080 |
| LOV: Female Estradiol | -114.24 ± 305.334 | 666.93 ± 1108.794 |
Change in Estradiol in males over time.
| pmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Male Estradiol | 55.00 ± 25.755 | 77.10 ± NA |
| WK 22: Male Estradiol | 35.00 ± 68.005 | 18.30 ± NA |
| WK 70: Male Estradiol | -1.00 ± 16.523 | 110.10 ± NA |
| LOV: Male Estradiol | 2.50 ± 55.729 | -33.10 ± NA |
Change in FSH in females over time.
| U/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Female FSH | 9.09 ± 13.277 | 2.43 ± 0.929 |
| WK 22: Female FSH | 14.89 ± 28.673 | 2.90 ± 2.476 |
| WK 70: Female FSH | 3.58 ± 14.021 | 3.20 ± 2.081 |
| LOV: Female FSH | 15.41 ± 23.613 | 3.70 ± 2.524 |
Change in FSH in males over time.
| U/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Male FSH | 5.88 ± 3.241 | 5.80 ± NA |
| WK 22: Male FSH | -1.20 ± 1.560 | -5.20 ± NA |
| WK 70: Male FSH | -1.80 ± 1.735 | -5.80 ± NA |
| LOV: Male FSH | -1.38 ± 5.660 | -2.90 ± NA |
Change in Renin, Insulin \& Thyrotropin over time.
| mU/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Renin | 23.706 ± 18.0642 | 73.973 ± 102.338 |
| WK 22: Renin | 45.899 ± 144.9575 | -16.838 ± 145.6609 |
| WK 70: Renin | 70.051 ± 117.9931 | -55.638 ± 88.9155 |
| LOV: Renin | 24.209 ± 52.0438 | -43.718 ± 70.5958 |
| BL: Insulin | 25.61 ± 27.166 | 22.38 ± 7.071 |
| WK 22: Insulin | -10.63 ± 20.247 | -8.58 ± 4.456 |
| WK 70: Insulin | -8.69 ± 24.132 | -12.53 ± 8.772 |
| LOV: Insulin | -8.11 ± 23.169 | -5.78 ± 11.771 |
| BL: Thyrotropin | 0.659 ± 0.6827 | 0.815 ± 0.8364 |
| WK 22: Thyrotropin | 1.445 ± 2.3295 | 0.280 ± 0.3118 |
| WK 70: Thyrotropin | 2.387 ± 4.0991 | 0.395 ± 0.4674 |
| LOV: Thyrotropin | 1.244 ± 3.4627 | 0.885 ± 0.5994 |
Change in Insulin-like Growth Factor-1 over time.
| ug/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Insulin-like Growth Factor-1 | 157.56 ± 109.044 | 235.30 ± 110.249 |
| WK 22: Insulin-like Growth Factor-1 | -9.78 ± 67.387 | -35.20 ± 153.817 |
| WK 70: Insulin-like Growth Factor-1 | -41.23 ± 76.969 | -113.43 ± 86.529 |
| LOV: Insulin-like Growth Factor-1 | -56.76 ± 105.936 | -46.07 ± 62.155 |
Change in LH in females over time.
| U/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Female LH | 2.78 ± 2.220 | 1.00 ± 1.000 |
| WK 22: Female LH | 7.45 ± 17.051 | 4.40 ± 0.990 |
| WK 70: Female LH | 7.47 ± 15.267 | 2.63 ± 3.235 |
| LOV: Female LH | 7.30 ± 10.885 | 3.37 ± 2.060 |
Change in LH in males over time.
| U/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Male LH | 2.48 ± 1.328 | 5.90 ± NA |
| WK 22: Male LH | 0.48 ± 1.081 | -5.70 ± NA |
| WK 70: Male LH | -0.53 ± 1.021 | -5.90 ± NA |
| LOV: Male LH | -0.05 ± 2.610 | -2.70 ± NA |
Change in Testosterone in females over time.
| nmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Female Testosterone | 1.18 ± 0.820 | 1.43 ± 0.404 |
| WK 22: Female Testosterone | 1.85 ± 1.790 | 5.27 ± 5.353 |
| WK 70: Female Testosterone | 0.53 ± 1.409 | 0.50 ± 1.400 |
| LOV: Female Testosterone | 0.25 ± 1.532 | 0.17 ± 1.266 |
Change in Testosterone in males over time.
| nmol/L | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL: Male Testosterone | 7.53 ± 4.076 | 7.10 ± NA |
| WK 22: Male Testosterone | 6.55 ± 4.751 | 2.40 ± NA |
| WK 70: Male Testosterone | 5.17 ± 1.504 | 32.60 ± NA |
| LOV: Male Testosterone | 8.15 ± 7.859 | 0.00 ± NA |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| mg/dL | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL | 108.1 ± 55.12 | 96.3 ± 14.43 |
| WK 22 | -14.5 ± 32.45 | -16.3 ± 14.93 |
| WK 70 | -22.5 ± 36.87 | -20.8 ± 24.62 |
| LOV | -17.9 ± 35.99 | -13.8 ± 22.88 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| Percentage | Part II Core: Expansion Cohort | Part II Core: Follow-up Cohort |
|---|---|---|
| BL | 5.7 ± 0.77 | 6.0 ± 0.61 |
| WK 22 | -0.1 ± 0.27 | -0.3 ± 0.28 |
| WK 70 | -0.1 ± 0.43 | -0.6 ± 0.74 |
| LOV | -0.1 ± 0.56 | -0.4 ± 0.49 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| mmo1/L | Part ll Core: Expansion Cohort | Part II Core: Follow-up Cohort |
|---|---|---|
| BL Cholesterol | 5.2 ± 1.36 | 5.7 ± 1.44 |
| WK 22 Cholesterol | -0.7 ± 1.58 | -0.5 ± 0.56 |
| WK 70 Cholesterol | -0.1 ± 1.35 | -1.2 ± 1.74 |
| LOV Cholesterol | 0.5 ± 2.39 | 1.5 ± 5.22 |
| BL LDL Cholesterol | 3.0 ± 1.32 | 4.8 ± 2.31 |
| WK 22 LDL Cholesterol | -0.3 ± 1.35 | -1.5 ± 1.98 |
| WK 70 LDL Cholesterol | 0.0 ± 1.17 | -2.2 ± 2.11 |
| LOV LDL Cholesterol | 0.3 ± 1.58 | -0.7 ± 1.83 |
| BL HDL Cholesterol | 1.6 ± 0.39 | 2.1 ± 1.85 |
| WK 22 HDL Cholesterol | -0.3 ± 0.32 | -0.9 ± 1.58 |
| WK 70 HDL Cholesterol | -0.3 ± 0.42 | -0.9 ± 1.60 |
| LOV HDL Cholesterol | 0.1 ± 0.66 | -0.0 ± 0.49 |
| BL Triglycerides | 1.5 ± 0.70 | 1.4 ± 0.32 |
| WK 22 Triglycerides | -0.1 ± 0.42 | 0.1 ± 0.49 |
| WK 70 Triglycerides | 0.3 ± 0.76 | -0.2 ± 0.25 |
| LOV Triglycerides | 0.1 ± 0.64 | -0.1 ± 0.54 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| mmHG | Part ll Core: Expansion Cohort | Part II Core: Follow-up Cohort |
|---|---|---|
| BL DBP | 84.5 ± 7.01 | 87.3 ± 4.21 |
| WK 22 DPB | 0.8 ± 9.59 | 2.6 ± 11.36 |
| WK 70 DPB | -3.4 ± 11.65 | -5.8 ± 12.14 |
| LOV DPB | -1.3 ± 9.23 | -3.2 ± 7.07 |
| BL SBP | 133.2 ± 12.51 | 130.3 ± 7.75 |
| WK 22 SPB | -4.0 ± 12.46 | 8.8 ± 24.74 |
| WK 70 SPB | -9.5 ± 15.78 | -4.7 ± 26.09 |
| LOV SPB | -6.2 ± 16.50 | 0.3 ± 20.60 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| Kg | Part ll Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| BL | 85.4 ± 23.52 | 84.0 ± 23.32 |
| WK 22 | -2.1 ± 4.02 | 0.6 ± 2.64 |
| WK 70 | -5.2 ± 4.56 | -3.2 ± 5.61 |
| LOV | -4.5 ± 6.68 | -4.4 ± 7.00 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
| Kg/m^2 | Part ll Core: Expansion Cohort | Part II Core: Follow-up Cohort |
|---|---|---|
| BL | 30.6 ± 7.46 | 31.3 ± 5.49 |
| WK 22 | -0.7 ± 1.42 | 0.2 ± 1.09 |
| WK 70 | -1.9 ± 1.93 | -1.4 ± 2.25 |
| LOV | -1.6 ± 2.73 | -2.0 ± 2.73 |
Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. QUICKI is the quantitative insulin sensitivity check index and is derived using the inverse of the sum of algorithms (base 10) of the fasting insulin and fasting glucose: 1/(log(fasting insulin mU/mL)+log(fasting glucose mg/dL)). Values typically associated with the QUICKI calculation for insulin resistance in humans fall broadly within a range between 0.45 for unusually healthy individuals and 0.30 in diabetics. So lower numbers reflect greater insulin resistance.
| unitless | Part ll Core: Expansion Cohort | Part II Core: Follow-up Cohort |
|---|---|---|
| BL | 0.3 ± 0.03 | 0.3 ± 0.02 |
| WK 22 | 0.0 ± 0.02 | 0.0 ± 0.01 |
| WK 70 | 0.0 ± 0.03 | 0.0 ± 0.06 |
| LOV | 0.0 ± 0.04 | 0.0 ± 0.04 |
Trough PK concentrations and PK profiles at steady-state were collected. The AUC from time 0 to 12 h post dose at steady state, calculated by using the predose concentration (Ctrough,ss) as the 12 h concentration, assuming steady-state has been reached.
| hr•ng/mL | 2mg Bid | 5mg Bid | 10mg Bid | 20mg Bid | 30mg Bid |
|---|---|---|---|---|---|
| AUC0-6h,ss | 37.79 ± 42.7 | 94.21 ± 37.0 | 236.83 ± 29.9 | NA ± NA | NA ± NA |
| AUC0-12h,ss | 69.96 ± 32.6 | 140.65 ± 43.9 | 339.62 ± 37.6 | NA ± NA | NA ± NA |
Trough PK concentrations and PK profiles at steady-state were collected.
| ng/mL | 2mg Bid | 5mg Bid | 10mg Bid | 20mg Bid | 30mg Bid |
|---|---|---|---|---|---|
| Cmax,ss | 8.76 ± 46.1 | 23.09 ± 31.5 | 59.17 ± 25.5 | NA ± NA | NA ± NA |
| Ctrough, ss | 2.73 ± 49.1 | 4.30 ± 112.9 | 10.60 ± 104.8 | 19.69 ± 53.6 | NA ± NA |
Trough PK concentrations and PK profiles at steady-state were collected.
| hour (hr) | 2mg Bid | 5mg Bid | 10mg Bid | 20mg Bid | 30mg Bid |
|---|---|---|---|---|---|
| PK Parameters: Tmax ss, | 1.50 (1.0 to 4.1) | 1.50 (1.0 to 4.0) | 1.26 (1.0 to 2.0) | NA (NA to NA) | NA (NA to NA) |
Trough PK concentrations and PK profiles at steady-state were collected.
| hour (hr) | 2mg Bid | 5mg Bid | 10mg Bid | 20mg Bid | 30mg Bid |
|---|---|---|---|---|---|
| PK Parameters: T1/2 ss, | 6.39 ± 13.8 | 3.54 ± 49.8 | 4.32 ± 47.8 | NA | NA |
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 22 was ≤ ULN (as defined by the local laboratories) or represented a ≥50% decrease from baseline. Participants with controlled or partially controlled UFC were defined as: Controlled UFC: mean UFC level \<= upper limit of normal (ULN). Partially controlled UFC: mean UFC level \> ULN but with \>= 50% reduction from baseline.
| Percentage pf participants | Part II Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|
| Responders | 80.0 (51.91 to 95.67) | 75.0 (19.41 to 99.37) |
| Controlled UFC responders | 80.0 (51.91 to 95.67) | 75.0 (19.41 to 99.37) |
| Partially controlled UFC responders | 0 (0.00 to 21.80) | 0 (0.00 to 60.24) |
Escape is defined as loss of UFC control (i.e. UFC \> ULN) on at least 2 consecutive visits at the highest tolerated dose after previously attaining UFC normalization)
| Participants | Part l: Core Cohort | Part II Core: Expansion Cohort |
|---|---|---|
| Number of Participants With Escape | 2 | 0 |
Collected over Adverse Event (AE) timeframe: Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration of 350.6 weeks.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part l: Core Cohort | 0/12 (0%) | 1/12 (8.3%) | 12/12 (100%) |
| Part ll Core: Expansion Cohort | 0/15 (0%) | 5/15 (33.3%) | 15/15 (100%) |
| Part ll Core: Follow-up Cohort | 0/4 (0%) | 1/4 (25%) | 4/4 (100%) |
| Event | Part l: Core Cohort | Part ll Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|---|
| Supraventricular extrasystolesCardiac disorders | 0/12 | 0/15 | 1/4 |
| Ventricular extrasystolesCardiac disorders | 0/12 | 0/15 | 1/4 |
| Adrenal insufficiencyEndocrine disorders | 0/12 | 1/15 | 1/4 |
| Abdominal painGastrointestinal disorders | 0/12 | 0/15 | 1/4 |
| PyelonephritisInfections and infestations | 0/12 | 0/15 | 1/4 |
| Pituitary-dependent Cushing's syndromeEndocrine disorders | 0/12 | 2/15 | 0/4 |
| PalpitationsCardiac disorders | 1/12 | 0/15 | 0/4 |
| TachycardiaCardiac disorders | 1/12 | 0/15 | 0/4 |
| Non-cardiac chest painGeneral disorders | 1/12 | 1/15 | 0/4 |
| Haemoglobin decreasedInvestigations | 1/12 | 0/15 | 0/4 |
| Event | Part l: Core Cohort | Part ll Core: Expansion Cohort | Part ll Core: Follow-up Cohort |
|---|---|---|---|
| Blood testosterone increasedInvestigations | 0/12 | 2/15 | 4/4 |
| Abdominal painGastrointestinal disorders | 2/12 | 2/15 | 3/4 |
| DiarrhoeaGastrointestinal disorders | 3/12 | 4/15 | 3/4 |
| FatigueGeneral disorders | 7/12 | 3/15 | 3/4 |
| Urinary tract infectionInfections and infestations | 1/12 | 3/15 | 3/4 |
| Blood corticotrophin increasedInvestigations | 0/12 | 5/15 | 3/4 |
| Hormone level abnormalInvestigations | 0/12 | 4/15 | 3/4 |
| NauseaGastrointestinal disorders | 5/12 | 8/15 | 2/4 |
| VertigoEar and labyrinth disorders | 0/12 | 1/15 | 2/4 |
| Adrenal insufficiencyEndocrine disorders | 0/12 | 6/15 | 2/4 |
Part l: Core cohort: safety analysis set (SAS): All subjects that received at least one dose of study drug. Part 2: Expansion cohort: Full Analysis Set (FAS): All patients in Follow-up cohort.
| Age, Customized(Participants) | Part l: Core Cohort | Part II Core: Expansion Cohort | Total |
|---|---|---|---|
| <65 years | 12 | 15 | 27 |
| Sex: Female, Male(Participants) | Part l: Core Cohort | Part II Core: Expansion Cohort | Total |
|---|---|---|---|
| Female | 8 | 11 | 19 |
| Male | 4 | 4 | 8 |
| Race/Ethnicity, Customized(Participants) | Part l: Core Cohort | Part II Core: Expansion Cohort | Total |
|---|---|---|---|
| White | 12 | 11 | 23 |
| Black or African American | 0 | 3 | 3 |
| Asian | 0 | 1 | 1 |
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
Ran from Mar 2011 to primary completion in Oct 2019, 102 months.
Results were first posted in Jan 2021, 1 year 3 months after primary completion.
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Studies of the drug tested here: Osilodrostat
Adrenocortical Hyperfunction →