| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endogenous Cushing´s syndrome (CS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| In this condition patients produce an excessive level of a steroid hormone known as cortisol |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011657 |
| E.1.2 | Term | Cushings syndrome |
| E.1.2 | System Organ Class | 100000004860 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the effect of withdrawing to placebo versus continuing treatment with levoketoconazole on the cortisol therapeutic response previously established during open-label levoketoconazole therapy. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effects of levoketoconazole with placebo on:
- cortisol status during Randomized Withdrawal and Restoration Phases;
- changes in clinical signs & symptoms of Cushing’s syndrome (CS);
- changes in biomarkers of CS comorbidities;
- To assess the safety and tolerability of levoketoconazole;
- To evaluate the population pharmacokinetics of levoketoconazole in
subjects with CS
NOTE: Secondary Objectives 4 & 5 are not subjects of hypothesis tests
Exploratory Objectives:
1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies;
2. To describe the effects & durations of levoketoconazole action with respect to cortisol status, health-related quality of life, and symptoms of depression
3. To describe the dose-response relationship of levoketoconazole with respect to safety and tolerability
4. To describe the effects of levoketoconazole on glucose tolerance among subjects with impaired fasting glucose (IFG). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Specified SONICS-Completers:
SONICS-completers, including those receiving open-label treatment after SONICS as part of an Expanded Access Program (EAP) or OLE study, whose completion of the M12 visit occurred not more than 6 months prior to the anticipated Randomization Visit (RW0), may be eligible for the study if the following two inclusion criteria are met:
1. Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical response (partial or complete) on a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to study entry (Visit RW0)
2. Able and willing to provide written informed consent prior to any study procedures being performed; eligible subjects must be able to understand the informed consent form prior to inclusion into the study
Inclusion Criteria for All Others:
The following categories of potential subjects, categorized by prior use of levoketoconazole, may be eligible if the following 11 inclusion criteria are all met:
• Naïve to levoketoconazole (defined as having never participated in SONICS);
• Completers of SONICS visit M12 more than 6 months prior to the expected RW0 visit of the current study;
• Completers of SONICS visit M12 within the 6 months prior to the expected RW0 visit who have not been receiving a stable Therapeutic Dose of levoketoconazole for at least 12 weeks prior to the start of screening.
1. Male or female and at least 18 years of age.
2. Able and willing to provide written informed consent
3. Confirmed newly diagnosed, persistent or recurrent endogenous Cushing’s syndrome of any etiology, except secondary to malignancy (including pituitary or adrenal carcinoma). Persistence will not be considered confirmed until 6 weeks or more post-surgery
4. Elevated mean 24 hour UFC levels at least 1.5X ULN of the normative range of the study’s central laboratory assay and from a minimum of three measurements from adequately collected urine; the study’s central laboratory must be used for all qualifying measurements.
5. Presence of abnormal values from at least one of these two diagnostic tests (discrepancies between test findings will not be investigated nor considered exclusionary):
• Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood cortisol at least 1.8 mcg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior with concurrent dexamethasone blood concentration greater than 5.6 nmol/liter (220 ng/dL) (results from within the 2 months prior to start of Screening or newly tested with results available by the Baseline Visit [TM0]) OR
• Elevated LNSC concentrations (at least two measurements) each greater than the ULN of the study’s central laboratory normative range; the study’s test kit and lab must be used for all qualifying measurements.
6. Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed until after study completion and agree to complete this study prior to surgery.
7. If post-surgical for CS-specific surgery, then no significant post operative sequelae remain and the risk of such sequelae is considered negligible.
8. Agree to the following minimum washout periods prior to the Baseline Visit (TM0) (as applicable):
• Ketoconazole or metyrapone: 2 weeks;
• Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks);
• Octreotide acetate LAR, lanreotide Autogel®, pasireotide LAR: 12 weeks;
• Lanreotide SR: 8 weeks;
• Octreotide acetate (immediate release) or short-acting pasireotide: 1 week;
• Mifepristone (RU 486, KORLYM®): 4 weeks;
• Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic progestins): 6 weeks.
9. Females who are either of non-child bearing potential (i.e. incapable of becoming pregnant):
• Post-menopausal, defined as age 50 or older with amenorrhea for more than 1 year or any age with serum follicle stimulating hormone (FSH) at least 23 mIU/mL and estradiol no more than 40 pg/mL (140 pmol/L) OR
• Surgically sterile—documented hysterectomy and/or bilateral oophorectomy or tubal ligation).
OR
• Females of child-bearing potential who agree to use highly effective methods of birth control while participating and for 2 weeks after participation has completed (abstinence is considered acceptable if routinely practiced).
10. Men who, if fertile, agree to use an acceptable form of birth control, including abstinence if routinely practiced, while enrolled and for 2 weeks after participation has completed.
11. Able to comprehend and comply with all procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if ANY of the following criteria are met (NOTE: exclusion criteria apply to and must be assessed in both cohorts):
1. Enrolled in SONICS but have not completed SONICS through Visit M12
2. Pseudo-Cushing’s syndrome based on assessment of the Investigator
3. Cyclic Cushing’s syndrome with multi-week periods of apparent spontaneous CS remission
4. Non-endogenous source of hypercortisolism, including pharmacological
corticosteroids or ACTH
5. Radiotherapy of any modality directed against the source of hypercortisolism within the last 5 years
6. Treatment with mitotane within 6 months of enrollment
7. History of malignancy, including adrenal or pituitary carcinomas (other than low risk, well-differentiated carcinomas of thyroid, breast or prostate that are very unlikely to require further treatment in the opinion of the treating physician, or squamous cell or basal cell carcinoma of the skin)
8. Clinical or radiological signs of compression of the optic chiasm
9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary surgery)
10. Clinically significant abnormality in 12-lead ECG during the Screening Phase requiring medical intervention
11. QTc interval above 470 msec during the Screening Phase
12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation, history of prolonged QT syndrome
13. Use of medications associated with possible, probable, or definite QT/QTc prolongation
14. Pre-existing hepatic disease
15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive
16. Human immunodeficiency virus (HIV)-positive.
17. History of symptomatic cholelithiasis with intact gallbladder
18. History of pancreatitis
19. Liver safety tests during the Screening Phase as follows:
- ALT and/or AST above 3X ULN
- Alkaline phosphatase or TBN above 2X ULN
Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert’s syndrome and may be enrolled if all other liver safety tests are within normal levels
20. History of documented or suspected drug-induced liver injury to ketoconazole or any other azole drug
21. Serum potassium below 3.0 mEq/L
22 Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at least 4 weeks. Subjects with thyroid-stimulating hormone (TSH) less than the lower limit of normal (LLN) and normal FT4 are potentially eligible without intervention
23. History of persistent uncontrolled hypertension
24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and unwilling or unable to change to alternative therapy with: pravastatin, fluvastatin, pitavastatin or rosuvastatin (must switch statin at least 2 weeks prior to dosing) or another allowed therapy.
25. More than one hospitalization for hyperglycemia or complication of diabetes during the last 12 months
26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD equation for eGFR
27. Pregnant or lactating
28. Body habitus preventing repeated venipuncture as required by protocol
29. Any other clinically significant medical condition, as determined by the
Investigator that precludes enrollment and participation in the study through completion, including conditions that would preclude the subject from being able to follow instructions or perform necessary procedures
30. History of alcohol or drug abuse in the 6-month period prior to Screening
31. Currently participating in another study or has received any investigational treatment (drug, biological agent or device) other than levoketoconazole, within prior 30 days or five half-lives of treatment, whichever is longer
33. Current use of any prohibited concomitant medication that cannot be discontinued safely and washed out completely prior to the Baseline Visit (TM0 or RW0, for the levoketoconazole-naïve and SONICS-completers cohorts, respectively), including but not limited to the following:
- Weight loss medications;
- Acetaminophen (paracetamol) above 2 g total daily dose;
- Strong inducers or inhibitors of CYP3A4 enzyme system that cannot be discontinued prior to first dose;
- Herbal preparations: St John’s Wort, echinacea, gingko, goldenseal, yohimbe, red rice yeast, danshen, silybum marianum, Asian ginseng, schissandra sphenanther, shankhapushi, and Asian herb mixture (Xiao chai hu tang and Salboku-to);
- Topical or inhaled corticosteroids;
- Carbamazepine, fenofibrate, carbenoxolone;
- Drugs that pose unacceptable risk due to overlapping or exaggerated toxicities or pharmacological action due to presumed PK or PD interactions with levoketoconazole;
- Genuine licorice
Additional exclusion criteria for Hungary:
Subjects who are on well-tolerated current treatment for Cushing's disease or Cushing's syndrome |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects with loss of therapeutic response to levoketoconazole upon withdrawing to placebo compared with the proportion of subjects with loss of therapeutic response upon continuing treatment with levoketoconazole. Loss of therapeutic response (i.e. relapse) is inferred based on mUFC from of three 24-hour urinary free cortisol (UFC) measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when:
(1) mUFC is above 1.5X the ULN of the central laboratory’s reference range, OR
(2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is at or above the ULN (i.e. ≥1.0X ULN) , OR
(3) an early rescue criterion is met, necessitating open-label therapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Loss of therapeutic response is inferred based on the mean of three 24-hour UFC measurements (mUFC) obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) |
|
| E.5.2 | Secondary end point(s) |
1. Changes from Baseline (RW0) in mUFC and LNSC at all post-Baseline visits
with these assessments through the final study visit (RES2)—applies to
Secondary Objective 1;
2. Proportion of subjects with normalization of mUFC at RES2—applies to
Secondary Objective 1;
3. Changes from Baseline (RW0) in clinical signs and symptoms of CS at all post Baseline visits with these assessments through the final study visit (RES2)—applies to Secondary Objective 2;
4. Changes from Baseline (RW0) in biomarkers of CS comorbidities (fasting
glucose, fasting insulin, homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c (HbA1c), blood pressure, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density
lipoprotein-cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP) at all post-Baseline visits with these measurements through the final study visit (RES2)—applies to Secondary Objective 3;
5. Incidence and severity of adverse events (AEs), particularly adverse events of special interest (AESI) during
levoketoconazole open-label therapy in the Dose Titration and Maintenance Phase (levoketoconazole-naïve cohort) and during blinded therapy in the Randomized Withdrawal and Restoration Phases (both cohorts)—applies to Secondary Objective 4.
Pharmacokinetic Endpoints and Pharmacokinetic/Pharmacodynamic modeling:
6. Estimates of the following PK parameters: clearance (CL/F), volume of
distribution (V/F), absorption rate constant (Ka), with associated between subject variability where feasible. These parameters will be used to calculate half-life (t½), area under the concentration time curve (AUC) and peak concentration (Cmax), if feasible—applies to Secondary Objective 5;
7. Estimates of the following pharmacodynamic (PD) parameters: levoketoconazole concentration producing half maximal UFC suppression (IC50), maximal suppression of UFC (Imax) and associated estimates of between-subject variability, if feasible. UFC concentrations in relation to dose and plasma exposure will be explored—applies to Secondary Objective 5.
Exploratory Endpoints:
8. Frequency of usage and changes from Baseline (RW0) in frequency of usage of anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies at all post-Baseline visits; changes in corresponding biomarkers accounting for changes in medication usage will also be explored—applies to Exploratory Objective 1;
9. Time from RW0 to first time of loss of response —applies to Exploratory Objective 2;
10. Time to first normalization of mUFC beginning from RES1 (subset with mUFC above 1.5X ULN at RES1)—applies to Exploratory Objective 2;
11. Time to first normalization of LNSC beginning from RES1 (subset with LNSC above ULN at RES1)—applies to Exploratory Objective 2;
12. Proportion of subjects with normalization of LNSC at RES2—applies to Exploratory Objective 2;
13. Changes from Baseline (RW0) in health-related QoL, and symptoms of depression at all post-Baseline visits with these assessments through the final study visit (RES2)—applies to Exploratory Objective 2;
14. Changes from Baseline (RW0) in serum cortisol and adrenocorticotrophic hormone (ACTH) at all post-Baseline visits with these assessments through the final study visit (RES2)—applies to Exploratory Objective 2;
15. Frequency and severity of common AEs and laboratory abnormalities in relation to dose of study drug administered at the time of the reported AE or laboratory abnormality—applies to Exploratory Objective 3;
16. Shifts from normality and concentration changes from Baseline (RW0) in serum transaminases, alkaline phosphatase, and total bilirubin at all post-Baseline visits in relation to dose of study drug administered at the time of the shift or change—applies to Exploratory Objective 3;
17. Durations and changes in durations from Baseline (RW0) of the QT interval corrected for heart rate (QTc) in relation to dose of study drug administered proximal to the measurement—applies to Exploratory Objective 3.
18. Change from Baseline in observed and derived glucose and insulin parameters during oral glucose tolerance test (OGTT) in the subset of subjects with IFG—applies to Exploratory Objective 4. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: at all post-Baseline visits through the final study visit (RES2)
2: at RES2
3: at all post-Baseline visits through the final study visit (RES2)
4: at all post-Baseline visits through the final study visit (RES2)
5, 6 and 7: along the study
8: all post-Baseline visits
9: from baseline till first time of loss of response
10: from RES1 till first normalization of mUFC
11: from RES1 till first normalization of LNSC
12: at RES2
13: at all post-Baseline visits through the final study visit (RES2)
14: at all post-Baseline visits through the final study visit (RES2)
15: along the study
16: at all post-Baseline visits through the final study visit (RES2)
17: along the study
18 along the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Denmark |
| France |
| Greece |
| Hungary |
| Israel |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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