This study is currently recruiting participants.
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)
Condition(s)
Acth-Dependent Cushing's Syndrome
Investigational Drug(s)
CRN04894
Investigational Device(s)
Intervention(s)
Drug: CRN04894
Supporting Site
National Institute of Diabetes and Digestive and Kidney Diseases
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.
--Back to Top--
INCLUSION CRITERIA: General Considerations: To participate in this study, participants must have active ACTH-dependent CS. 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 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 CS. 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 years or more -Evidence in support of the diagnosis of CS, defined as meeting 2 of the following 3 criteria: --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 2 abnormal bedtime salivary cortisol values --At least 2 abnormal 24-hour UFC values -Evidence of chronic active ACTH-dependent CS: --For participants with previously confirmed ACTH-dependent CS who are awaiting surgery or radiation therapy, or who have failed surgery, or are awaiting the effects of radiation therapy, or who are willing to discontinue medical therapy: one abnormal UFC, late night serum cortisol, or bedtime salivary cortisol value is required within 3 weeks of Day 1. --For participants without previously confirmed ACTH-dependent CS: at least 3 results that confirm hypercortisolism, obtained at weekly or greater intervals within 56 days of Day 1. These may include any combination of abnormal UFC, bedtime salivary cortisol values or late night serum cortisol, without any lower values -Evidence of acutely active ACTH-dependent CS within 10 days of Day 1, defined as: --Abnormal late night serum cortisol, bedtime salivary cortisol or UFC, and --A single early morning (~0530 0800) plasma ACTH >10 pg/mL --Values used to satisfy criterion 7 may be used to satisfy criterion 8 if they were obtained within 10 days of Day 1. -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 nonchildbearing 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 CS 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. -Use of mitotane -Use of prohibited prescribed or nonprescribed medications and/or nonmedications/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 CS. -NIH staff and members of the investigators' families may not participate. -Previous unsuccessful surgery for CS 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.
General Considerations:
To participate in this study, participants must have active ACTH-dependent CS. 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 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 CS.
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 years or more
-Evidence in support of the diagnosis of CS, defined as meeting 2 of the following 3 criteria:
--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 2 abnormal bedtime salivary cortisol values
--At least 2 abnormal 24-hour UFC values
-Evidence of chronic active ACTH-dependent CS:
--For participants with previously confirmed ACTH-dependent CS who are awaiting surgery or radiation therapy, or who have failed surgery, or are awaiting the effects of radiation therapy, or who are willing to discontinue medical therapy: one abnormal UFC, late night serum cortisol, or bedtime salivary cortisol value is required within 3 weeks of Day 1.
--For participants without previously confirmed ACTH-dependent CS: at least 3 results that confirm hypercortisolism, obtained at weekly or greater intervals within 56 days of Day 1. These may include any combination of abnormal UFC, bedtime salivary cortisol values or late night serum cortisol, without any lower values
-Evidence of acutely active ACTH-dependent CS within 10 days of Day 1, defined as:
--Abnormal late night serum cortisol, bedtime salivary cortisol or UFC, and
--A single early morning (~0530 0800) plasma ACTH >10 pg/mL
--Values used to satisfy criterion 7 may be used to satisfy criterion 8 if they were obtained within 10 days of Day 1.
-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 nonchildbearing 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 CS 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.
-Use of mitotane
-Use of prohibited prescribed or nonprescribed medications and/or nonmedications/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 CS.
-NIH staff and members of the investigators' families may not participate.
-Previous unsuccessful surgery for CS 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.
Principal Investigator
Referral Contact
For more information: