The purpose of this study is to see if Crinecerfont is effective in reducing daily glucocorticoid dosage while maintaining adrenal androgen control.The purpose of the study is also to see if Crinecerfont is effective in reducing adrenal steroid…
ID
Source
Brief title
Condition
- Adrenal gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint: Percent change from baseline in glucocorticoid daily dose (in
hydrocortisone equivalents adjusted for BSA [mg/m2/day]) at Week 24
Secondary outcome
- Change from baseline in serum androstenedione at Week 4
- Achievement of a reduction in glucocorticoid daily dose to physiologic levels
Week 24
- Changes from baseline in HOMA-IR, weight, and fat mass at Week 24.
Background summary
Classic congenital adrenal hyperplasia (C-CAH) is a rare genetic disorder that
affects the adrenal glands. The condition results in an enzyme deficiency (in
our patient population 21-hydroxylase enzyme deficiency) altering the
production of adrenal steroids and because of this the adrenal glands have
little to no cortisol biosynthesis (hormone which regulates body*s response to
illness or stress) resulting in a potentially life-threatening condition.
If left untreated, C-CAH can result in salt wasting, dehydration and eventually
death due to lack of mineralocorticoids (such as aldosterone) which regulate
sodium and potassium level. Even with cortisol replacement, persistent
elevation of adrenocorticotropic hormone (ACTH) from the pituitary gland
results in excessive androgen levels (such as testosterone) leading to
virilization and menstrual irregularities in females. Both males and females
may also experience precocious puberty, short stature, hirsutism, acne and
fertility problems.
Corticosteroids are the current standard of care for C-CAH. They are used to
both correct the endogenous cortisol deficiency and reduce the excessive ACTH
levels and androgen excess. However, the dose and long-term duration of steroid
use required to suppress ACTH is well above the normal physiological level of
cortisol that often results in bone loss, growth impairment, metabolic
syndrome, and Cushing*s syndrome as common and serious side effects.
Crinecerfont (NBI-74788) is a proprietary, potent, selective, orally-active,
non-peptide corticotropin-releasing factor type 1 (CRF1) receptor antagonist
that works by blocking corticotropin-releasing factor receptors in the
pituitary gland that leads to decrease of the ACTH release, which in turn
decreases the production of adrenal steroids, including androgens, and
potentially the symptoms associated with C-CAH. Blockade of CRF1 receptors has
been shown to decrease the release of ACTH in both animals and humans.
As research suggests that lowering ACTH levels could reduce the amount of
corticosteroid treatment necessary for CCAH patients, the novel CRF1 receptor
antagonist, Crinecerfont, may provide an important therapeutic approach while
enabling using of lower, more physiological doses of corticosteroids to treat
patients with C-CAH.
Study objective
The purpose of this study is to see if Crinecerfont is effective in reducing
daily glucocorticoid dosage while maintaining adrenal androgen control.
The purpose of the study is also to see if Crinecerfont is effective in
reducing adrenal steroid levels following an initial 4-week treatment period.
Additionally, the purpose of the trial is also to assess the safety and
tolerability of Crinecerfont.
Study design
This is a Phase 3, randomized, double-blind, placebo-controlled study to
evaluate the efficacy, safety, and tolerability of Crinecerfont versus placebo
administered twice daily (bid) with breakfast and the evening meal (doses
separated by approximately 12 hours) for 24 weeks in approximately 165 adult
subjects with classic CAH due to 21-hydroxylase deficiency.
Intervention
Eligible subjects will be randomly assigned in a 2:1 ratio (active:placebo) to
2 treatment groups, Crinecerfont 100 mg bid or placebo. After the 24-week
randomized treatment period, there will be a 6-month, open-label treatment
period, during which all subjects will receive Crinecerfont 100 mg bid. At
Month 12, subjects who have not reduced their glucocorticoid dose to <=11
mg/m2/day will be re-randomized (2:1) to receive 100 mg every morning (qAM) and
200 mg every evening (qPM) or to continue 100 mg bid, in a blinded fashion.
Subjects who have reduced their glucocorticoid dose to <=11 mg/m2/day will
continue to receive 100 mg bid in an open label fashion.
At Month 18, subjects will review applicable portions of the informed consent
form and confirm whether they will participatein the optional open-label
extension (OLE) treatment period for continued access to crinecerfont.
Starting at Month 18, all subjects who are continuing in the OLE will initially
receive crinecerfont 100 mg bid. Ifthe subject has inadequate disease control
despite receiving glucocorticoid treatment at their target dose (in the opinion
of the investigator), the crinecerfont dose may be increased to 100 mg qAM and
200mgqPM. After the Month 24 visit, an alternative dosing regimen of once daily
200 mg qPM can be considered per the investigator.
Study burden and risks
Risks of crinecerfont (study drug)
The most commonly reported side effects in participants who have received
crinecerfont were:
• Headache
• Nausea
• Diarrhea
• Constipation
• Dizziness
• Postural dizziness (dizziness upon standing up)
• Dry mouth
• Somnolence (drowsiness)
• Fatigue
• Blood creatine kinase increase (may indicate muscle injury)
• Neutropenia (decreased white blood cells)
• Contact dermatitis (skin rash)
Risk mitigation: Because of possible side effects such as fatigue, drowsiness,
and dizziness that have been reported from previous studies, participants
should not drive or operate heavy machinery after taking the study drug.
Other Risks, Side Effects or Discomforts:
Participants may feel discomfort during some of the tests and may also have
risks, such as:
•DXA scan: there is a very small amount of radiation exposure equivalent to
about 2 days of naturally occurring background radiation.
•Blood collection: possible side effects from blood draws include discomfort,
faintness, inflammation of the vein, pain, bruising, or bleeding at the site of
puncture. There is also a slight possibility of infection.
•ECG: skin irritation is rare but could occur from the electrodes or gel that
is used.
•Testicular ultrasound: the ultrasound itself does not cause any pain or has
any risks, but may feel uncomfortable.
•Mental health assessments: questionnaires may make a participant feel anxious
or uncomfortable.
•Fasting: participants will be asked to fast at certain times during this
study, this may cause discomfort.
•Glucocorticoid dose reduction: during the times when participant
glucocorticoid dose is reduced, they may feel fatigue, nausea, not want to eat,
experience vomiting, dizziness (especially when standing up), or worsening
symptoms of high male hormones (more hair growth, worse acne, more irregular
menstrual cycles).
Risk mitigation:
The participant is instructed to tell their study doctor or study staff if they
have these symptoms when their glucocorticoid dose is reduced.
•Glucose tolerance test: drinking the sugary drink (within a certain time
frame) may be unpleasant.
UNFORESEEN RISKS
Crinecerfont is investigational, which means that there may be side effects
that are not known about the study drug when taken alone or in combination with
other medications. It is not possible to know all side effects of an
investigational drug, and side effects not observed in previous studies could
occur. There is a chance that unknown side effects could be life-threatening.
As with any medication, there is a small but real risk of allergic reactions
that can be fatal. These reactions usually start very soon after taking the
study drug. They may start as skin itching and redness, difficulty breathing,
swelling, and may be severe in some cases.
Risk mitigation: If a participant experiences these reactions, they are
instructed to tell a study doctor or study staff immediately, or go to the
nearest hospital quickly.
PREGNANCY / BIRTH CONTROL
Birth defects, including physical deformities, mental retardation, and other
problems, as well as premature birth, are known risks of some drugs. Taking the
study drug may involve unknown risks to a pregnant woman, an embryo, fetus
(unborn baby) or nursing infant. Therefore, if a participant is pregnant,
planning to become pregnant or are breastfeeding, they cannot participate in
this study.
Females who can get pregnant, including women who have not been postmenopausal
[no longer having menses (periods)] for at least 1 year and who have not had a
hysterectomy or removal of both ovaries or both tubes, will be given a
pregnancy test, and the results must be negative to qualify to participate in
this study.
If a male participant*s partner becomes pregnant, there may be unknown risks to
the fetus or baby.
El Camino Real 12780
San Diego CA 92130
US
El Camino Real 12780
San Diego CA 92130
US
Listed location countries
Age
Inclusion criteria
• Subjects must provide written informed consent.
• Be a female or male at least 18 years of age.
• Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency.
• Be on a stable, supraphysiologic glucocorticoid dose regimen (defined as >13
mg/m2/day in hydrocortisone dose equivalents) that has been stable for at least
1 month prior to screening
• If treated with fludrocortisone, dose should be stable for at least 1 month
prior to screening with an upright plasma renin activity (PRA) during screening
that is not greater than ULN on the subject's usual sodium intake.
• Female subjects of childbearing potential with fertile male partners must
agree to use contraception consistently from screening until the final study
visit or 30 days after the last dose of study drug, whichever is longer. A
subject who is not of childbearing potential must meet one of the following:
- Postmenopausal
- Permanent sterilization procedure
Exclusion criteria
• Have a known or suspected diagnosis of any of the other forms of classic CAH
including 11-β-hydroxylase deficiency, 17-α-hydroxylase deficiency, 3-β-
hydroxysteroid dehydrogenase deficiency, P450 sidechain cleavage deficiency, or
P450 oxidoreductase deficiency.
• Have a history of bilateral adrenalectomy, hypopituitarism, or other
condition requiring chronic therapy with oral, glucocorticoids, or requiring
chronic therapy with inhaled glucocorticoids that based on dose and hormone
profile the investigator deems would yield significant systemic exposure
interfering with study endpoints.
• Have a clinically significant medical condition or chronic disease (including
history of neurological, hepatic, renal, cardiovascular, gastrointestinal,
significant malabsorption, hematologic, pulmonary, psychiatric, or endocrine
disease [excluding CAH]) that in the opinion of the investigator would preclude
the subject from participating in and completing the study or that could
confound interpretation of study outcome.
• History of malignancy, unless successfully treated with curative intent and
considered to be cured.
• Have a known history of clinically concerning cardiac arrhythmia (including
long QT syndrome) or prolongation of screening (pretreatment) QT interval
corrected for heart rate using Fridericia's correction (QTcF) of >450 msec
(males) or >470 msec (females).
• Known sensitivity (ie, hypersensitivity) or allergy to any
corticotropinreleasing hormone (CRH) receptor antagonist.
• Have evidence of chronic renal or liver disease Used any active
investigational drug within 30 days or 5 half-lives (whichever is longer)
before screening, or plans to use an investigational drug (other than the study
drug) during the study.
• Females who are pregnant or lactating.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004873-17-NL |
| CCMO | NL74387.091.20 |