SONICS: Treatment for Endogenous Cushing's Syndrome

• Sponsor: Cortendo AB (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01838551
• Collaborator: (none)
• Enrollment: 94
• Locations: 42
• Arms: 8
• Duration (Months): 51
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The primary objectives of this study are 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.

Condition or Disease	Intervention/Treatment	Phase
Endogenous Cushing's Syndrome	Drug: Levoketoconazole	Phase 3

Detailed Description

This is an open label, single arm study with a Screening Phase, a Dose Titration Phase, a 6-month Maintenance Phase, and a 6-month Extended Evaluation Phase designed to assess efficacy, safety, tolerability, and PK of COR-003 in subjects with endogenous CS.

Following an initial screening and washout period, as applicable, this study will be conducted in three treatment phases as follows:

• Dose Titration Phase: approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose). Dose titration will occur in increments of 150 mg with a starting dose of 150 mg twice daily (BID) over a period of approximately 2 to 21 weeks to achieve an effective and tolerable maximum dose (the Therapeutic Dose).

• Maintenance Phase: 6 months of treatment at the Therapeutic Dose following the Dose Titration Phase. Once the Therapeutic Dose has been reached and confirmed from the mean of a total of four adequately collected 24 hour urine collections for UFC measurements, subjects will enter into the Maintenance Phase of the study and will be asked to return to the clinic monthly for 6 months for assessment of efficacy and safety. During the Maintenance Phase, doses may not be increased to maintain UFC levels at or below ULN of the assay unless it is confirmed that a dose increase is deemed medically necessary at the discretion of the Investigator after discussion with the Medical Monitor. Prior to the End of Maintenance Phase Visit, four complete 24 hour urine collections will be obtained and subjects may enter the Extended Evaluation Phase.

• Extended Evaluation Phase: 6 months of continued treatment after the Maintenance Phase. In the 6-month Extended Evaluation Phase, subjects will return to the clinical site every 90 days (±14 days) for safety and efficacy evaluations.

Efficacy will be assessed primarily by measuring mean UFC concentrations at specified times as described in the clinical protocol. Safety will be assessed primarily by physical examinations with vital sign measurements, adverse events, clinical laboratory measures, electrocardiography, and pituitary MRI.

An independent Data Safety Monitoring Board (DSMB) will review the safety of the drug throughout the study. Membership of the DSMB is described in a Charter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose titrationDose titration
• Masking: None (Open Label)
• Masking Description: A data integrity plan prevented the Sponsor from accessing summary efficacy data prior to locking the clinical database.
• Primary Purpose: Treatment
• Official Title: An Open Label Study to Assess the Safety and Efficacy of COR-003 (Levoketoconazole) in the Treatment of Endogenous Cushing's Syndrome
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Apr 1, 2018
• Actual Study Completion Date: Nov 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Levoketoconazole DL0 Levoketoconazole Tablets Dose Level 0 Once Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL1 Levoketoconazole Tablets Dose Level 1 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL2 Levoketoconazole Tablets Dose Level 1 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL3 Levoketoconazole Tablets Dose Level 3 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL4 Levoketoconazole Tablets Dose Level 4 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL5 Levoketoconazole Tablets Dose Level 5 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL6 Levoketoconazole Tablets Dose Level 6 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003
Experimental: Levoketoconazole DL7 Levoketoconazole Tablets Dose Level 7 Twice Daily	Drug: Levoketoconazole; Levoketoconazole is the 2S,4R- enantiomer derived from racemic ketoconazole; Other Names: COR-003

Outcome Measures

Primary Outcome Measures

1. Normalization in Urinary Free Cortisol in Patients With Endogenous Cushing's Syndrome. [6 months of maintenance phase therapy without a prior dose increase during that phase]

   The response to COR-003 is defined as mean UFC concentration ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase. The proportion of responders at the End of Maintenance Phase visit, following 6 months of treatment in the Maintenance Phase, for all dose groups combined was estimated using a generalized linear model with repeated measurements based on a binomial distribution with a logit link function and with region (US vs. non-US), concurrent CS medical conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded median split based on the ITT population), sex, disease duration (years), prior CS medication (Yes/No), prior radiation therapy (Yes/No) as Baseline covariates and visit as an independent factor. The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in the Maintenance Phase alongside its 95% Wald CI is presented.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key 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 Cushing's disease (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 adrenocorticotropic hormone (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.

1. 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.

2. 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 micrograms/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

1. 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.

2. 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.

3. Subjects on treatment for CD or endogenous CS of other etiology for whom treatment has been inadequate or not well tolerated must agree to minimum washout periods prior to the Baseline Visit as specified.

Key Exclusion Criteria

1. Subjects with Pseudo-Cushing's syndrome 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.

7. Subjects with QTc interval of >470 msec during the Screening Phase.

8. Pre-existing hepatic disease; subjects with mild to moderate hepatic steatosis consistent with fatty infiltration (non-alcoholic fatty liver disease [NAFLD] are allowed).

9. History of documented or suspected drug-induced liver injury requiring drug discontinuation of ketoconazole or any azole antifungals.

10. Subjects who receive any prohibited concomitant medication and cannot discontinue it safely prior to the Baseline Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA School of Medicine	Los Angeles	California	United States	90095
2	Johns Hopkins University	Baltimore	Maryland	United States	21287
3	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
4	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
5	University of New Mexico HSC	Albuquerque	New Mexico	United States	87131
6	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
7	Cleveland Clinic	Cleveland	Ohio	United States	44195
8	Oregon Health & Science University	Portland	Oregon	United States	97239
9	Allegheny Neuroendocrinology Center	Pittsburgh	Pennsylvania	United States	15212
10	University Hospitals Leuven Department of Endocrinology	Leuven		Belgium	3000
11	University Specialized Hospital for Active Treatment in Endocrinology (USHATE)	Sofia		Bulgaria	1431
12	St. Pauls Hospital/Vancouver General Hospital	Vancouver	British Columbia	Canada	V6Z 1Y6
13	Vseobecna fakultni nemocnice v Praze - III. Interni klinika VFN a 1. LF UK	Praha		Czechia	128 08
14	Aarhus University Hospital	Aarhus		Denmark	8000
15	Rigshospitalet,Copenhagen University Hospital	Copenhagen		Denmark	DK-2100
16	Hôpital de la CONCEPTION, Service d'Endocrinologie, Diabète et Maladies Métaboliques	Marseille Cedex		France	13385
17	Med Clinic I - University of Lueback	Lübeck		Germany	23538
18	Bnail Zion Medical Center Institute of Endocrinology & Metabolism	Haifa		Israel	31048
19	Institute of Endocrinology & Metabolism, Rabin Medical Center	Petah Tikva		Israel	49100
20	Sourasky Medical Center, Endocrinology & Metabolism	Tel Aviv		Israel	64239
21	Azienda Ospedaliera-Universitaria Ancona	Ancona		Italy	60126
22	UOC di Endocrinologia, Dipartimento di Medicina Clinica e Sperimentale	Messina		Italy	98125
23	Istituto Auxologico Italiano	Milan		Italy	20149
24	University of Naples Federico II	Naples		Italy	80131
25	SCDU Medicina Interna I Università di Torino Dipartimento di Scienze Cliniche e Biologiche	Orbassano		Italy	10043
26	University of Padua	Padova		Italy	35128
27	Institute of Medical Pathology	Roma		Italy	00168
28	Azienda Ospedaliero - Universitaria Città della Salute e della Scienza di Torino	Torino		Italy	10126
29	Policlinico GB Rossi	Verona		Italy	37134
30	Leiden University, Leiden University Medical Center, Dept. of Endocrinology	Leiden		Netherlands	2333 ZA
31	Erasmus MC, Dpt. Of Internal Medicine, Division of Endocrinology	Rotterdam		Netherlands	3015 CE
32	Terpa Sp.z.o.o	Lublin		Poland	20-333
33	Szpital Kliniczny im. Heliodora Swiecickiego	Poznań		Poland	60-355
34	Outpatient Clinic: Reuma Centrum	Warszawa		Poland	04-305
35	Samodzielny Publiczny Szpital Kliniczny Nr 1	Wroclaw		Poland	50367
36	Instytut Centrum Zdrowia Matki Polki	Łódź		Poland	93-338
37	Clinical Center of Serbia	Belgrade		Serbia	11000
38	Hospital Universidad De La Ribera	Alzira	Valencia	Spain	46600
39	Endocrinologia, Hospital Sant Pau,Universitat Autònoma de Barcelona	Barcelona		Spain	08026
40	Hospital Universitario Reina Sofía	Cordoba		Spain	14004
41	Bezmi Alem Vakıf Üniversitesi Endokrinoloji Bölümü Adnan	Istanbul		Turkey	34093
42	Istanbul University Medical Faculty	Istanbul		Turkey	34303

Sponsors and Collaborators

• Cortendo AB

Investigators

• Study Director: Fredric J Cohen, MD, Cortendo AB

Study Documents (Full-Text)

• Study Protocol - Oct 25, 2016
• Statistical Analysis Plan - Jun 19, 2018

More Information

Publications

None provided.

• Responsible Party: Cortendo AB
• ClinicalTrials.gov Identifier: NCT01838551
• Other Study ID Numbers: COR-2012-01
• First Posted: Apr 24, 2013
• Last Update Posted: Apr 19, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Cortendo AB: Cushing's disease; ectopic ACTH; adrenal Cushing's
• Additional relevant MeSH terms: Cushing Syndrome; Syndrome

Study Results

Participant Flow

Pre-assignment Detail	Following screening, subjects were considered enrolled in the study if they met eligibility criteria, which included confirmation of increased UFC levels as per the eligibility requirements and took at least 1 dose of levoketoconazole.

Arm/Group Title	Levoketoconazole All Doses
Arm/Group Description	All doses used in the study combined
Period Title: Overall Study
STARTED	94
COMPLETED	46
NOT COMPLETED	48

Baseline Characteristics

Arm/Group Title	Levoketoconazole All Doses
Arm/Group Description	All doses used in the study combined
Overall Participants	94
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.7 (13.4)
Sex: Female, Male (Count of Participants)
Female	77 81.9%
Male	17 18.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 9.6%
Not Hispanic or Latino	81 86.2%
Unknown or Not Reported	4 4.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 1.1%
White	90 95.7%
More than one race	0 0%
Unknown or Not Reported	3 3.2%
Region of Enrollment (participants) [Number]
United States	28 29.8%
Spain	3 3.2%
Canada	1 1.1%
Netherlands	5 5.3%
Turkey	3 3.2%
Belgium	3 3.2%
Denmark	4 4.3%
Poland	8 8.5%
Italy	20 21.3%
Israel	9 9.6%
Bulgaria	6 6.4%
France	2 2.1%
Serbia	1 1.1%
Germany	1 1.1%
Baseline 24-hour mUFC (nmol/day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/day]	671 (743)

Outcome Measures

1. Primary Outcome

Title	Normalization in Urinary Free Cortisol in Patients With Endogenous Cushing's Syndrome.
Description	The response to COR-003 is defined as mean UFC concentration ≤ULN following 6 months of maintenance phase therapy without a prior dose increase during that phase. The proportion of responders at the End of Maintenance Phase visit, following 6 months of treatment in the Maintenance Phase, for all dose groups combined was estimated using a generalized linear model with repeated measurements based on a binomial distribution with a logit link function and with region (US vs. non-US), concurrent CS medical conditions (diabetes [Yes/No], hypertension [Yes/No]), age (rounded median split based on the ITT population), sex, disease duration (years), prior CS medication (Yes/No), prior radiation therapy (Yes/No) as Baseline covariates and visit as an independent factor. The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in the Maintenance Phase alongside its 95% Wald CI is presented.
Time Frame	6 months of maintenance phase therapy without a prior dose increase during that phase

Outcome Measure Data

Analysis Population Description

The primary efficacy analysis was based on the ITT population. Subjects were imputed as non-responders under any of the following conditions: withdrew anytime prior to the Month 6 of Maintenance phase; had a dose increase relative to the therapeutic dose during Maintenance phase; Month 6 mUFC data were missing or inadequate; or had received radiation therapy and exhibited no rebound increase in mUFC following withdrawal of levoketoconazole immediately after the end of Maintenance phase.

Arm/Group Title	Levoketoconazole All Doses
Arm/Group Description	All doses used in the study combined
Measure Participants	94
Least Squares Mean (95% Confidence Interval) [proportion of subjects meeting endpoint]	.30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Levoketoconazole All Doses
	Comments	The least squares mean (LSMEAN) estimate of the UFC response after 6 months of treatment in the Maintenance Phase alongside its 95% Wald CI is presented. Supportive to the 95% CI, the p-value corresponding to the null hypothesis that the response rate is ≤ 20% is presented (1-sided test).
	Type of Statistical Test	Superiority
	Comments	Under the null hypothesis of at most 20% UFC responders, 90 subjects in the ITT population would provide 90% power, with two-sided type 1 error of 0.05, assuming an observed response of 35%.
Statistical Test of Hypothesis	p-Value	0.0154
	Comments	One-sided p-value is based on a null hypothesis that true response proportion is ≤ 0.20.
	Method	Mixed Models Analysis
	Comments	The Generalized Linear Model described above was used to generate the p-value.

Adverse Events

Time Frame	Reported adverse events are summarized for the period from the first day of study drug administration through the last day plus 30 days. For an individual subject, the maximum period of time for which adverse events were collected and summarized here (treatment-emergent only) was approximately 1 year, 11 months. For the ITT population, the median time period over which adverse events were collected and summarized was 1 year, 2 months; the mean time period was approximately 1 year.
Adverse Event Reporting Description	AEs were to be ascertained at each study visit by asking the subject how the subject had been since the last visit. A clinical observation, laboratory value, or imaging abnormality that the Investigator deemed clinically significant was to be recorded as an AE. An attempt was to be made to describe the AE in terms of a diagnosis. If a clear diagnosis could not be established, each sign and symptom was to be recorded individually.
Arm/Group Title	Levoketoconazole All Doses
Arm/Group Description	All doses used in the study combined
All Cause Mortality
	Levoketoconazole All Doses
	Affected / at Risk (%)	# Events
Total	1/94 (1.1%)
Serious Adverse Events
	Levoketoconazole All Doses
	Affected / at Risk (%)	# Events
Total	16/94 (17%)
Endocrine disorders
Adrenal insufficiency	1/94 (1.1%)
Eye disorders
Retinal artery occlusion	1/94 (1.1%)
Gastrointestinal disorders
Diarrhea	1/94 (1.1%)
Hemorrhoids	1/94 (1.1%)
General disorders
Fatigue	1/94 (1.1%)
Non-cardiac chest pain	1/94 (1.1%)
Infections and infestations
Pyelonephritis chronic	2/94 (2.1%)
Gastroenteritis	1/94 (1.1%)
Urinary tract infection	1/94 (1.1%)
Injury, poisoning and procedural complications
Hyphaema	1/94 (1.1%)
Investigations
Electrocardiogram QT prolonged	2/94 (2.1%)
Alanine aminotransferase increased	1/94 (1.1%)
Aspartate aminotransferase increased	1/94 (1.1%)
Gamma-glutamyltransferase increased	1/94 (1.1%)
Metabolism and nutrition disorders
Decreased appetite	1/94 (1.1%)
Hypoglycemia	1/94 (1.1%)
Musculoskeletal and connective tissue disorders
Muscular weakness	2/94 (2.1%)
Myalgia	1/94 (1.1%)
Pain in extremity	1/94 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/94 (1.1%)
Benign ovarian tumor	1/94 (1.1%)
Metastases to liver	1/94 (1.1%)
Nervous system disorders
Epilepsy	1/94 (1.1%)
Loss of consciousness	1/94 (1.1%)
Renal and urinary disorders
Renal impairment	1/94 (1.1%)
Reproductive system and breast disorders
Uterine polyp	1/94 (1.1%)
Vascular disorders
Hypotension	1/94 (1.1%)
Other (Not Including Serious) Adverse Events
	Levoketoconazole All Doses
	Affected / at Risk (%)	# Events
Total	92/94 (97.9%)
Cardiac disorders
Palpitations	7/94 (7.4%)
Gastrointestinal disorders
Abdominal pain	7/94 (7.4%)
Abdominal pain upper	9/94 (9.6%)
Diarrhea	14/94 (14.9%)
Dyspepsia	5/94 (5.3%)
Gastrooesophageal reflux disease	5/94 (5.3%)
Nausea	31/94 (33%)
Vomiting	10/94 (10.6%)
General disorders
Asthenia	6/94 (6.4%)
Edema peripheral	18/94 (19.1%)
Fatigue	16/94 (17%)
Infections and infestations
Nasopharyngitis	12/94 (12.8%)
Urinary tract infection	11/94 (11.7%)
Investigations
Alanine aminotransferase increased	15/94 (16%)
Aspartate aminotransferase increased	12/94 (12.8%)
Blood alkaline phosphatase increased	5/94 (5.3%)
Electrocardiogram QT prolonged	9/94 (9.6%)
Gamma-glutamyltransferase increased	11/94 (11.7%)
Metabolism and nutrition disorders
Decreased appetite	5/94 (5.3%)
Hypokalemia	13/94 (13.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	14/94 (14.9%)
Back pain	7/94 (7.4%)
Musculoskeletal pain	6/94 (6.4%)
Myalgia	9/94 (9.6%)
Pain in extremity	6/94 (6.4%)
Nervous system disorders
Dizziness	12/94 (12.8%)
Dysgeusia	6/94 (6.4%)
Headache	27/94 (28.7%)
Psychiatric disorders
Anxiety	7/94 (7.4%)
Insomnia	8/94 (8.5%)
Reproductive system and breast disorders
Menstruation irregular	5/94 (5.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	5/94 (5.3%)
Skin and subcutaneous tissue disorders
Alopecia	9/94 (9.6%)
Dry skin	11/94 (11.7%)
Hyperhidrosis	6/94 (6.4%)
Pruritus	6/94 (6.4%)
Rash	8/94 (8.5%)
Vascular disorders
Hypertension	18/94 (19.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All data generated from this study are the property of Cortendo Inc. (a subsidiary of Strongbridge Biopharma). Independent analyses and/or publication of data by Investigators is not permitted without prior written consent of Cortendo. Publication of results is to be conducted in accordance with Good Publication Practice as per Strongbridge publication policy.