Safety and Efficacy of LCI699 in Cushing's Disease Patients

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01331239

Enrollment

Registered

2011-04-08

Start date

2011-03-23

Completion date

2019-10-22

Last updated

2021-01-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cushing Disease, Cushings Disease

Keywords

Cushing Disease, osilodrostat, LCI699, Pituitary Gland, Adrenocorticotropic Hormone

Brief summary

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

Detailed description

The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease. The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study. Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was \< Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted. The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period. Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit. On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.

Interventions

DRUGLCI699

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

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

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

Exclusion criteria

* Patients treated with mitotane 6 months prior to Visit 1 * Patients with compression of the optic chiasm * Patients with a known inherited syndrome as the cause for hormone over secretion * Patients with Cushing's syndrome due to ectopic ACTH secretion or adrenal Cushing's syndrome * Patients with pseudo-Cushing's syndrome * Patients who are not biochemically euthyroid * Diabetic patients with poorly controlled diabetes (HbA1c \>9%) * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after completion of dosing. * Patients who have received pituitary irradiation within five years prior to Visit 1. * Patients with risk factors for QTc prolongation or Torsade de Pointes.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Responders to LCI699 Based on the Change in Mean Urinary Free Cortisol (UFC) From Baseline to Week 10	10 weeks	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.

Secondary

Measure	Time frame	Description
Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Deoxycorticosterone over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Deoxycortisol over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in aldosterone & thyroxine, free over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Estradiol in females over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Estradiol in males over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in FSH in females over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in FSH in males over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Renin, Insulin & Thyrotropin over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in LH in females over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in LH in males over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Testosterone in females over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male)	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Testosterone in males over time.
Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Insulin-like Growth Factor-1	baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88	Change in Insulin-like Growth Factor-1 over time.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Hemoglobin A1C (HbA1C) (Glycosylated Hemoglobin)	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Sitting Diastolic Blood Pressure (DBP), Sitting Systolic Blood Pressure (SBP)	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Body Mass Index (BMI)	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Quantitative Insulin Sensitivity Check Index (QUICKI)	Baseline, Week 22, Week 70, Last observed value, up to Month 88	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.
Pharmacokinetics (PK) Parameters: Area Under Curve (AUC)0-6h ss, AUC0-12h ss	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	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.
PK Parameters: Cmax ss, Ctrough ss	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	Trough PK concentrations and PK profiles at steady-state were collected.
PK Parameters: Tmax ss,	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	Trough PK concentrations and PK profiles at steady-state were collected.
PK Parameters: T1/2 ss,	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	Trough PK concentrations and PK profiles at steady-state were collected.
Percentage of Participants Who Were Responders on 24-hour Urine Free Cortisol (UFC) at Week 22	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.
Number of Participants With Escape	approx. 7 years	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)
Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Fasting Glucose	Baseline, Week 22, Week 70, Last observed value, up to Month 88	Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline.

Countries

France, Italy, Japan, United States

Participant flow

Recruitment details

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).

Pre-assignment details

For overall study: 27 patients were planned; For Part l of the study, 12 - 15 patients were planned to be enrolled. For Part ll Core 19 patients were planned to be enrolled.

Participants by arm

Arm	Count
Part l: Core Cohort Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part l of this study. 4 patients in this cohort moved to Part II of the study	12
Part II Core: Expansion Cohort Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part ll Core Expansion of this study. These patients were all newly enrolled into the phase ll part of the study.	15
Total	27

Withdrawals & dropouts

Period	Reason	FG001	FG002
Part II: Core Study	Administrative problems	1	0
Part II: Core Study	Adverse Event	3	0
Part II: Core Study	Subj's cond. no longer require treatment	2	1
Part II: Core Study	Withdrawal by Subject	2	0

Baseline characteristics

Characteristic	Part l: Core Cohort	Part II Core: Expansion Cohort	Total
Age, Customized <65 years	12 Participants	15 Participants	27 Participants
Race/Ethnicity, Customized Asian	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Black or African American	0 Participants	3 Participants	3 Participants
Race/Ethnicity, Customized White	12 Participants	11 Participants	23 Participants
Sex: Female, Male Female	8 Participants	11 Participants	19 Participants
Sex: Female, Male Male	4 Participants	4 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 12	0 / 15	0 / 4
other Total, other adverse events	12 / 12	15 / 15	4 / 4
serious Total, serious adverse events	1 / 12	5 / 15	1 / 4

Outcome results

Primary

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

Population: Primary Analysis Set: All patients with evaluable UFC data (at least two 24 hour measurements for both baseline and Week 10) were included in the primary efficacy analysis set. Of the 12 patients enrolled to this arm, 9 of the 12 patients met this criteria.

Arm	Measure	Value (NUMBER)
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 Percentage of participants

Secondary