Clinical Trials Register

Summary
EudraCT Number:	2013-002133-37
Sponsor's Protocol Code Number:	COR-2012-01
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-03-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2013-002133-37

A.3

Full title of the trial

An Open Label Study to Assess the Safety and Efficacy of COR—003 (2S, 4R-Ketoconazole) in the Treatment of Endogenous Cushing’s Syndrome

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A clinical study to find out whether a new drug known as COR-003 is safe and effective in people who have Cushing’s Syndrome or Cushing's Disease

A.4.1

Sponsor's protocol code number

COR-2012-01

A.5.4

Other Identifiers

Name:

IND No.

Number:

115968

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Cortendo AB
B.1.3.4	Country
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Cortendo AB
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cortendo AB
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	c/o TMF Sweden AB. Sergels Torg 12
B.5.3.2	Town/ city	Stockholm
B.5.3.3	Post code	11157
B.5.6	E-mail	info@cortendo.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	3/12/1012
D.3 Description of the IMP
D.3.1	Product name	COR-003
D.3.2	Product code	COR-003
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	65277-42-I
D.3.9.2	Current sponsor code	COR-003
D.3.9.3	Other descriptive name	2S,4R-(-)-ketoconazole, levoketoconazole
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Endogenous Cushing's syndrome (CS) or Cushing's disease

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 evaluate the clinical responder rate defined as the proportion of subjects with normal UFC after 6 months of treatment with COR-003 in the Maintenance Phase without dose increase, and to evaluate the range of effective doses in subjects with various levels of hypercortisolism.

E.2.2

Secondary objectives of the trial

• To identify the proportion of subjects with clinical response, defined as reduction in mean 24-hour UFC levels to below or equal to the upper
limit of normal (≤ ULN) after each month of treatment with COR-003 without a dose increase during the Maintenance Phase;
• To identify the proportion of subjects with complete or partial response, defined as ≥50% reduction of 24-hour UFC levels from
Baseline after each of the 6 months of treatment with COR-003 without a dose increase during the Maintenance Phase;
• To characterize changes in 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases;
• To characterize shifts in normality for 24-hour UFC levels from Baseline during the 6 months of treatment with COR-003 in the Maintenance Phase regardless of dose increases;

For all other secondary objectives, please refer to the protocol.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female ≥18 years of age
2. Able 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.
3. Confirmed diagnosis of newly diagnosed, persistent or recurrent CD or endogenous CS of other etiology if subjects are not candidates for surgery or radiotherapy within the 18 months after enrollment.
Previous medical records will be collected and used to support the diagnosis of CD or endogenous CS of other etiology, including the following etiologies:
• Ectopic ACTH secretion, i.e. ACTH not of pituitary origin
• Ectopic corticotropin-releasing hormone (CRH) secretion
• Adrenal-dependent CS (i.e. adrenal adenoma (NOT carcinoma), adrenal hyperplasia, etc.)
• Etiology unknown
In the absence of pathological or post-surgical confirmation of the diagnosis of CD (i.e. documented adrenal insufficiency post- adenomectomy or hypophysectomy, which will be considered diagnostic). The following historical evidence will be considered satisfactory to establish the diagnosis of CD:
• Plasma corticotropin (ACTH) level >20 pg/mL (4.5 pmol/L) or greater (Note: ACTH ≥5 pg/mL (1.1 pmol/L) and ≤20 pg/mL will generally suffice only if accompanied by either a positive CRH stimulation test or DST or combined CRH-DST) PLUS one of the diagnostic strategies described below based on pituitary MRI/computed tomography (CT) findings (Note: pituitary imaging preceding the original diagnosis is a requirement for eligibility):
• For tumors ≥6 mm by imaging:
− Inferior petrosal sinus sampled (IPSS) ACTH central:plasma gradient
≥2 before CRH or ≥3 after CRH, OR if IPSS was not done then:
− Positive ACTH and/or cortisol response to CRH/desmopressin or combined CRH-desmopressin stimulation plus high-dose (8 mg) dexamethasone suppression of plasma cortisol, ideally on more than one occasion, performed and interpreted according to internationally recognized standards of diagnosis
− In the absence of IPPS and the combination of tests described, an individual might be eligible if CD was otherwise confirmed via adequate testing. Such cases must be discussed with and explicitly approved by the Medical Monitor, and the specific diagnostic criteria used to establish the diagnosis of CD must be documented.
• For tumors <6 mm or not visible by MRI:
− IPSS with ACTH central:plasma gradient ≥2 before CRH or ≥3 after
CRH
− In the absence of IPSS, an individual might be eligible if CD was otherwise confirmed via adequate testing. Such cases must be discussed with and explicitly approved by the Medical Monitor, and the specific diagnostic criteria used to establish the diagnosis of CD must be documented.
4. Regardless of the etiology of endogenous CS, subjects MUST have elevated mean 24-hour UFC levels ≥1.5X ULN based on the normative range of the central lab assay and on a minimum of four measurements from adequately collected urine. Urine will ideally be collected on sequential days.
5. In addition to elevated mean UFC, presence of abnormal values from one of the following tests:
• Abnormal DST: Elevated 8 AM serum cortisol ≥1.8 μg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior (if not conducted already in the diagnostic workup of the subject within the previous 2 months before start of Screening Phase; in that case previous test results and details of conduct will need to be available by the Baseline Visit)
• Elevated late night salivary cortisol concentrations (at least two measurements) >ULN
NOTE: For subjects with estimated glomerular filtration rate (eGFR as determined by Modified Diet in Renal Disease MDRD equation) >40 and
<60 mL/min/1.73 m2 in addition to meeting the UFC criteria, late night salivary cortisol test results (≥2 measurements) MUST also demonstrate evidence of CS.
6. Previously irradiated subjects with CD or endogenous CS of other etiology will be allowed as long as the radiation treatment occurred >4 years ago and subjects have not exhibited evidence for improvement in their underlying CD for 6 months prior to the Screening visit. The total number of previously irradiated subjects enrolled in this study will not exceed 10.
7. Subjects with CD or CS of other etiology who are not candidates for surgery, refuse surgery, or in whom surgery will be delayed for at least
18 months following enrollment. Subjects may be allowed to participate in the trial while awaiting surgery, but must agree to complete this study prior to surgery. For subjects who have already
undergone surgery, a minimum of 6 weeks should have elapsed before the subject can be deemed a surgical failure. Subjects who have undergone surgery should be stable post-surgery (i.e., no significant post-operative sequelae remain and the risk of such sequelae is considered negligible).

For all other inclusion criteria, please refer to the protocol.

E.4

Principal exclusion criteria

1. Subjects with Pseudo-CS based on assessment of the Investigator
2. Subjects with cyclic CS based on assessment of the investigator
3. Subjects with a non-endogenous source of hypercortisolism such as exogenous source of glucocorticoids or therapeutic use of ACTH.
4. Known inherited syndrome as the cause of hypercortisolism, including but not limited to multiple endocrine neoplasia Type 1, McCune Albright Syndrome and Carney Complex
5. Subjects with adrenal carcinoma
6. History of malignancy, other than thyroid, early stage prostate, squamous cell and basal cell carcinoma, within 3 years prior to the Screening Phase. Subjects with history of such allowed carcinoma must have a life expectancy of >18 months and must be considered medically stable. Subjects with early stage prostate cancer undergoing no treatment due to low grade potential may be enrolled
7. Clinical or radiological signs of compression of the optic chiasm
8. Major surgery within 1 month prior to enrollment
9. Subjects with clinically significant abnormality in 12-lead ECGs during the Screening Phase needing medical intervention
10. Subjects with QTc interval of >470 msec during the Screening Phase
11. Subjects with a history of Torsades des Pointes, or ventricular tachycardia, or ventricular fibrillation, or history of prolonged QT syndrome (including family history), or use of medications resulting in QT/QTc prolongation, or hypokalemia <3.0 meq/L.
12.Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed)
13. Positive for HbsAg or positive HBC test.
14. History or symptoms of recurrent symptomatic cholelithiasis or pancreatitis
15. LFT must not be above the following cut-offs during the Screening
Phase:
• ALT and/or AST >3 X ULN
• Total bilirubin (TBN) >2 X ULN
If all LFTs are within normal limits and TBN is elevated, examination of direct and indirect bilirubin may be conducted. Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert's syndrome and may be enrolled if all other LFTs are within normal levels
16. History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals
17. Pregnant or lactating women
18. HIV positive
19. History of persistent uncontrolled hypertension (>180/120 mmHg)
despite medical intervention.
20. Subjects with hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin and not willing or unable to change to alternative therapies i.e. pravastatin, fluvastatin, or rosuvastatin within 2 weeks of start of the Screening Phase.
21. Body habitus preventing repeated venipuncture as required by protocol.
22. Subject is currently in another study or has received any investigational treatment (drug, biological agent or device) within 30 days or five half-lives of treatment, whichever is longer.
23. Repeated hospitalization for hyperglycemia or for any complication of hyperglycemia and diabetes during the last 12 months
24. Subjects with decreased renal function as defined by eGFR <40 mL/min/1.73 m2, using MDRD equation.
25. 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 to perform the necessary procedures
26. Abnormal FT4. Subjects with TSH below the lower limit of normal
(<LLN) and normal free T4 are permitted to participate in the study.
27. Subjects who have a history of alcohol or drug abuse in the 6 month period prior to enrollment.
28. Subjects who have been treated with mitotane within 6 months of the Screening Phase.
29. Subjects who are currently taking any H2 receptor antagonists, proton-pump inhibitors, or sucralfate (all of which inhibit absorption of COR-003). A list of orally acceptable antacids (for example, Mylanta and Maalox) will be provided, and can only be taken a minimum of 2 hours after dosing of COR-003.
30. Subjects who receive any prohibited concomitant medication and cannot discontinue it safely prior to the Baseline Visit:
• Weight loss medications (prescription or over the counter)
• Acetaminophen (paracetamol) >3 g total daily dose
• Strong inducers or inhibitors of CYP3A4 enzyme system that may interfere with the metabolism of COR-003 and 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 tangand Salboku-to).
• Topical or inhaled corticosteroids
• Carbamazepine, fenofibrate, carbenoxolone.
• Drugs that might pose unacceptable risks due to overlapping toxicities
(eg. QT prolongation, liver toxicity);
• Genuine licorice

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects with response to COR-003, defined as reduction in mean 24-hour UFC levels to below or equal to the upper limit of normal (≤ ULN) following 6 months of Maintenance Phase therapy without a dose increase during that phase, summarized by Maintenance Phase
dose level and overall.

E.5.1.1

Timepoint(s) of evaluation of this end point

Following 6 months of maintenance phase therapy

E.5.2

Secondary end point(s)

• Proportion of subjects with clinical response to COR-003, defined as mean UFC level ≤ ULN, to be determined after 1, 2, 3, 4 and 5 months of dosing without a dose increase in the Maintenance Phase;
• Proportion of subjects with complete or partial response to COR-003, defined as mean UFC level ≥ 50% reduction from Baseline after 1, 2, 3,
4, 5 and 6 months of dosing without a dose increase in the Maintenance
Phase;
• Change and percentage change from Baseline in mean 24-hour UFC levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases;
• Shift in UFC normality categories from Baseline to 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase regardless of dose increases;
• Change and percentage change from Baseline in serum and late night salivary cortisol levels after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase;
• Changes from Baseline in Clinical Signs and Symptoms of CS after 1, 2,
3, 4, 5 and 6 months of dosing in the Maintenance Phase;
• Changes from Baseline in the QoL measures obtained from the Cushing QoL questionnaire and the severity of depression obtained from the Beck's Depression Inventory II after 3 and 6 months of dosing in the Maintenance Phase;
• Change from Baseline in CS comorbidities biomarkers (fasting glucose, hemoglobin A1C [HbA1c], systolic blood pressure [SBP], diastolic blood pressure [DBP], total cholesterol, low and high density lipoproteins
[LDL, HDL, respectively], and body weight) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase;
• Changes from Baseline for oral glucose tolerance test (OGTT) (pre- diabetics only) and spot albumin/creatinine ratio as a measure of microalbuminuria (only if abnormal at Baseline) after 3 and 6 months of dosing in the Maintenance Phase;
• Changes from Baseline for C-reactive protein (CRP) after 1, 2, 3, 4, 5 and 6 months of dosing in the Maintenance Phase;
• Safety evaluations will include clinical observations and adverse event (AE) reporting, vital signs (SBP, DBP, body weight, body mass index [BMI]), electrocardiograms (ECGs), hematology, chemistry panels (inclusive of expanded markers of liver function, ACTH, Insulin-like Growth Factor-1 (IGF-1) and testosterone concentrations), dipstick urinalysis (microscopic evaluation, if dipstick positive), tumor size by magnetic resonance imaging (MRI) as applicable.

E.5.2.1

Timepoint(s) of evaluation of this end point

Depending on criteria being measured. 1, 2, 3, 4, 5 & 6 months in maintenance phase. 9 and 12 months in extended evaluation phase.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Belgium

Bulgaria

Canada

Czech Republic

Denmark

France

Georgia

Germany

Hungary

Israel

Italy

Netherlands

Poland

Romania

Serbia

Spain

Sweden

Turkey

United Kingdom

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After the end of the study COR-003 may be provided under an expanded access or extension protocol for subjects who wish to continue treatment, who benefit from the treatment and for who the benefits outweigh the risks.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2014-05-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-31

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-20

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IMP with orphan designation in the indication
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