Cushing Disease Clinical Trial
Official title:
A Proof of Concept, Open-label, Forced Titration, Multi-center Study to Assess the Safety/Tolerability and Efficacy of 10-weeks Treatment of LCI699 in Patients With Cushing's Disease
Verified date | January 2021 |
Source | Novartis |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 31 |
Est. completion date | October 22, 2019 |
Est. primary completion date | October 22, 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 75 Years |
Eligibility | 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. |
Country | Name | City | State |
---|---|---|---|
France | Novartis Investigative Site | Le Kremlin Bicetre | |
France | Novartis Investigative Site | Paris | |
Italy | Novartis Investigative Site | Ancona | |
Italy | Novartis Investigative Site | Napoli | |
Japan | Novartis Investigative Site | Chiba | |
Japan | Novartis Investigative Site | Sapporo city | Hokkaido |
United States | Massachusetts General Hospital Neuroendocrine Unit | Boston | Massachusetts |
United States | Northwestern University Endo, Metabolism and Molecular | Chicago | Illinois |
United States | Cleveland Clinic Foundation | Cleveland | Ohio |
United States | Oregon Health and Science University SC | Portland | Oregon |
Lead Sponsor | Collaborator |
---|---|
Novartis Pharmaceuticals |
United States, France, Italy, Japan,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
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. | 10 weeks | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of Hypothalamic-Pituitary-Adrenal (HPA)-Axis: 11- Deoxycorticosterone (Overall) | Change in Deoxycorticosterone over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: 11-Deoxycortisol (Overall) | Change in Deoxycortisol over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Aldosterone, Thyroxine, Free (T4) | Change in aldosterone & thyroxine, free over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Female) | Change in Estradiol in females over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Estradiol (Male) | Change in Estradiol in males over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (FSH) (Female) | Change in FSH in females over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Follicle Stimulation Hormone (Male) | Change in FSH in males over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Renin, Insulin, Thyrotropin | Change in Renin, Insulin & Thyrotropin over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | 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. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Luteinising Hormone (LH) (Female) | Change in LH in females over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: LH (Male) | Change in LH in males over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Female) | Change in Testosterone in females over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | Actual Change From Baseline (BL) in Steroid Hormones of HPA-axis: Testosterone (Male) | Change in Testosterone in males over time. | baseline, Week 22, Week 70, Last observed value (LOV), up to Month 88 | |
Secondary | 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. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | Actual Change From BL in Cardiovascular and Other Metabolic Parameters: Weight | Improving metabolic abnormalities was assessed by descriptive statistics on the change from baseline. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. | Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. |
Baseline, Week 22, Week 70, Last observed value, up to Month 88 | |
Secondary | 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. | 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 | |
Secondary | PK Parameters: Cmax ss, Ctrough ss | Trough PK concentrations and PK profiles at steady-state were collected. | 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 | |
Secondary | PK Parameters: Tmax ss, | Trough PK concentrations and PK profiles at steady-state were collected. | 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 | |
Secondary | PK Parameters: T1/2 ss, | Trough PK concentrations and PK profiles at steady-state were collected. | 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 | |
Secondary | 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. |
Week 22 | |
Secondary | 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) | approx. 7 years |
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