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Protocol Details

A Phase 1b/2a Open-label Multiple-ascending Dose Exploratory Study of CRN04894 in ACTH-dependent Cushing's Syndrome (Cushing's Disease or Ectopic ACTH Syndrome)

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

001058-DK

Sponsoring Institute

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18 Years
Max Age: 75 Years

Referral Letter Required

No

Population Exclusion(s)

None

Keywords

Cushing's Syndrome;
Cushing's Disease;
Ectopic Acth Syndrome;
Adrenocorticotropic Hormone [acth] Receptor Antagonist

Recruitment Keyword(s)

None

Condition(s)

Acth-Dependent Cushing's Syndrome

Investigational Drug(s)

CRN04894

Investigational Device(s)

None

Intervention(s)

Drug: CRN04894

Supporting Site

National Institute of Diabetes and Digestive and Kidney Diseases

Background:

Cushing s syndrome (CS) is a set of disorders caused when the body makes too much of a hormone called cortisol. Too much cortisol can cause a range of problems such as high blood pressure, fatigue, weight gain, and diabetes. These problems can lead to long-term issues with the heart, metabolism, and other body systems that can diminish quality of life and lead to early death. Better treatments are needed.

Objectives:

To test a study drug (CRN04894) for treating CS.

Eligibility:

People aged 18 to 75 years who have a confirmed diagnosis of CS.

Design:

This study requires a 14-day inpatient stay at the NIH Clinical Center. Same participants may need to stay longer.

Participants will be screened. They will have a physical exam and a test of their heart function. They will give blood, saliva, and urine samples. Their skin will be photographed. They will answer questions about their symptoms.

The study drug is a tablet taken by mouth with water. While staying in the clinic, participants will take the drug each morning for 10 days.

Participants will continue to give blood, urine, and saliva samples throughout their inpatient stay.

Participants will have a magnetic resonance imaging (MRI) scan of the head. They will lie on a bed that slides into a tube. A substance called a contrast agent will be injected into a vein in their arm during the scan.

Participants will have a follow-up visit 2 to 3 weeks after taking their last dose of the study drug. This visit may be by telehealth.

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Eligibility

INCLUSION CRITERIA:

General Considerations:

To participate in this study, participants must have active ACTH-dependent Cushing's syndrome. They may be participants currently under the care of the research team who are awaiting surgery or radiation therapy, or who have failed surgery and/or are awaiting a response to radiotherapy. Participants who do not meet remission criteria within five (5) days after resection of a possible ACTH-producing tumor may not initiate screening until 6 weeks after the surgical date. Alternatively, they may be participants who will be admitted for evaluation of the cause of Cushing's syndrome.

To be eligible to participate in this study, an individual must meet all of the following criteria:

-Provision of signed and dated informed consent form

-Ability to understand and willingness to sign a written informed consent document.

-Willingness to comply with all study procedures and interventions

-Ability to take oral medication

-Male or female, aged 18-75 years

-Evidence in support of the diagnosis of Cushing s syndrome, defined as meeting 2 of the following 3 criteria performed up to 56 days prior to Day 1:

--Failure of serum cortisol to suppress to <=1.8 microgram/dL during a 1 mg Dexamethasone Suppression Test (DST) may be used in all participants except for women taking oral estrogen-containing medication.

--At least 4 (at 7 - 14-day intervals) consecutive bedtime salivary cortisol values >ULN

--At least 4 (at 7 - 14-day intervals) consecutive 24-hour urine free cortisol (UFC) values >1.3 x ULN without any lower values

However, for participants with previously confirmed ACTH-dependent Cushing s syndrome who are awaiting surgery or radiation therapy, or who have failed surgery or are awaiting the effects of radiation therapy, a DST is not required and only one (1) additional elevated UFC or bedtime salivary cortisol value is required within three (3) weeks of Day 1.

-Evidence of active ACTH-dependent Cushing s syndrome within 14 days of Day 1, defined as:

--Late-night (approximately 2300 - 0000) serum cortisol >7.5 microgram/dL (for inpatients), or bedtime salivary cortisol >ULN (for outpatients), and

--Early morning (approximately 0530- 0800) plasma ACTH >10 pg/mL

-Agreement to adhere to Lifestyle Considerations throughout study duration.

-Sexually active women of reproductive potential must agree to use of highly effective contraception for at least 2 weeks prior to admission and 2 weeks after the last dose of study drug.

-Men who engage in heterosexual intercourse with a female partner of childbearing potential must be of non-childbearing potential (ie, azoospermic); or remain abstinent; or agree to use a condom if the partner uses hormonal contraception, from Screening until at least 30 days after the last dose of study drug.

-Participants with documented ACTH-dependent Cushing's syndrome taking short-acting steroidogenesis inhibitors (ketoconazole, levoketoconazole, osilodrostat, cabergoline or metyrapone) may participate after a 14-day washout period, if they meet other study inclusion criteria.

-Willingness to have de-identified specimens sent outside NIH for measurements needed to meet study objectives.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

-Women who are pregnant or lactating.

-Prior participation in a study with CRN04894. This does not apply to participants who participate in another cohort of this study.

-History of bilateral adrenalectomy

-If previously experienced adrenal insufficiency when taking CRN04894 on this study

-Previous pituitary MRI findings of a putative ACTH-secreting lesion within 3 mm of the optic chiasm.

-Presence of any known malignancy.

-A UFC more than 8-fold ULN

-Use of mitotane

-Use of prohibited prescribed or non-prescribed medications and/or non-medications/alternative medicinal products (eg, vitamins, especially biotin-containing products) within 7 days prior to Screening and is not willing to forego use of these substances during the study. This includes ingestion of grapefruit juice or grapefruit preparations, such as capsules.

-Use of medications that are strong inducers of cytochrome (CYP)3A4 within 30 days prior to the day of enrollment. These include but are not limited to apalutamide, carbamazepine, enzalutamide, phenytoin, rifampin, St. John s wort.

-Use of medications (all routes of administration ie, oral, topical and inhaled) or ingestion of food that are strong or moderate inhibitors of CYP3A4 within 14 days prior to the day of enrollment. These include but are not limited to boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice (more than 8 ounces daily), indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, telithromycin, troleandomycin, voriconazole, clarithromycin, idelalisib, nefazodone, nelfinavir, aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, verapamil.

-Use of medications that are strong or moderate inducers of P-gp within 14 days prior to first dose of study drug. These include but are not limited to apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampicin, St. John's wort.

-Use of medications that are strong or moderate inhibitors of P-gp within 14 days prior to first dose of study drug. These include but are not limited to amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, verapamil

-Use of any investigational drug within the past 30 days or for 5 half-lives, whichever is longer, prior to the day of CRN04894 administration. This does not apply to participants who participate in another cohort of this study.

-Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.

-Any hematology or chemistry value at Screening that is >15% outside of the reference range, unless determined by the Investigator that the laboratory deviation is not clinically significant or believed to be a consequence of Cushing s syndrome.

-NIH staff and members of the investigators' families may not participate.

-Previous unsuccessful surgery for Cushing's syndrome within 6 weeks.

-Abnormal baseline ECG in any of the following ways

--Based on the average of triplicate ECGs, QTc, Fridericia s QT correction formulas (QTcF) >500 msec (or QTcF >530 msec in participants with a bundle branch block) repeated on a second set of ECGs at least 2 hours apart and confirmed by the Principal Investigator

--Any ventricular tachyarrhythmia associated with symptoms of hemodynamic response

--Sustained ventricular tachycardia (lasting >30 sec) irrespective of symptoms

--Torsades de pointes

--Cardiac arrest

--Pause >5 sec

--Type II second degree block or third-degree atrioventricular block

--Clinically significant, symptomatic bradycardia

--Any supraventricular tachyarrhythmia associated with symptoms of hemodynamic response

-Renal insufficiency as measured by estimated glomerular filtration rate (eGFR) <60 mL/min/1.73.

-Significant liver disease or Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) >3(SqrRoot) ULN, and/or total bilirubin >1.5(SqrRoot) ULN during Screening.


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Citations:

Not Provided

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Contacts:

Principal Investigator

Referral Contact

For more information:

Lynnette K. Nieman, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
NIHBC 10 - CRC BG RM 1-3121
10 CENTER DR
BETHESDA MD 20892
(301) 496-8935
niemanl@mail.nih.gov

Raven N. McGlotten, R.N.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health
Building 10
CRC/1-3121
10 Center Drive
Bethesda, Maryland 20892
(301) 827-0190
mcglottenr@mail.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT05804669

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