The primary purpose of this study is to assess the dose response of several doses of tildacerfont in controlling hormone levels and reducing testicular tumors over 12 weeks by comparing the tildacerfont hormonal control response to a placebo, a *…
ID
Source
Brief title
Condition
- Endocrine disorders congenital
- Adrenal gland disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
An important goal of treatment in CAH is the reduction of adrenal hormone
levels. To that end, this study will evaluate the effect of tildacerfont on A4
levels as its primary endpoint.
Secondary outcome
An important goal of treatment in CAH is the reduction of adrenal hormone
levels. To that end, this study will evaluate the effect of tildacerfont on
17-OHP as a secondary endpoint. Exploratory efficacy endpoints will assess
additional clinical benefit associated with biomarker control in terms of
improvements to QoL, acne, hirsutism in females, and TARTs in males.
Background summary
CAH is an inherited genetic disorder that affects the adrenal glands, a pair of
walnut-sized organs above the kidneys. The disease affects the production of
steroid hormones by the adrenal glands, which include *glucocorticoids* such as
cortisol, which regulate the body*s response to illness or stress. People with
CAH often have abnormal levels of certain adrenal sex hormones, which can have
negative effects on overall health. The current standard of care for CAH is the
use of glucocorticoids (GCs). These can have significant side effects and do
not always work well in treating CAH. A non-steroidal treatment option like the
investigational drug, tildacerfont (SPR001) that helps control adrenal hormone
levels may benefit CAH patients. Investigational means that the study drug has
not been approved by regulatory agencies for use as a prescription or
over-the-counter medicine. The purpose of this study is to see if tildacerfont
is safe and effective in reducing the level of certain hormones in the
patient's body.
Because this is a scientific study, it is also important to collect information
about patients with CAH who are not receiving tildacerfont. Therefore,
tildacerfont will be compared to *placebo*, which is a medication that looks
like investigational drug but does not contain any tildacerfont or any other
active compound.
Study objective
The primary purpose of this study is to assess the dose response of several
doses of tildacerfont in controlling hormone levels and reducing testicular
tumors over 12 weeks by comparing the tildacerfont hormonal control response to
a placebo, a *fake drug,* and then to assess if increasing the tildacerfont
dose improves the hormonal control response in individual subjects over the
remaining 40 weeks.
The secondary objectives of this study are to assess the safety of tildacerfont
over a period of 77 weeks, evaluate if improving hormonal control will also
improve clinical outcomes in CAH subjects over 12 and 77 weeks and assess if
treatment with tildacerfont will allow a reduction on subjects total daily dose
of steroid.
Study design
This study*s design is composed of a run-in period and 3 treatment periods (A,
B, and C). In the run-in period, compliance to subjects background steroid
therapy will be confirmed. In Part A (12 weeks duration), subjects will be
randomized to tildacerfont treatment at one of three doses or placebo in a one
to one manner. Subjects will have monthly assessments of their hormones,
clinical symptoms and safety parameters. In Part B (12 weeks duration),
subjects who achieved control of their hormones, specifically androstenedione,
will continue on the dose they received in Part A. In subjects who did not
achieve control of androstenedione or placebo subjects, the dose in Part A
(tildacerfont or placebo) will be escalated at Week 12 to the next highest
dose. Subjects who still have not achieve hormonal control will be escalated to
the next highest dose at Week 24. In Part C (46 weeks duration), all subjects
who have achieved hormonal control of androstenedione will be allowed to reduce
their daily steroid dose by 5 mg in hydrocortisone equivalents up to 2 times.
Subjects who did not meet control will continue to receive the dose from Week
24 through Week 77.
An optional Open-Label Extension Period will provide additional open-label
treatment with tildacerfont at 200 mg QD for up to 240 weeks.
Intervention
Subjects will take placebo (during the Run-in Period) or assigned study drug
(during the Treatment Period) orally each day with dinner, which should be
eaten at 6 PM or later. Study drug may be consumed up to 30 minutes after
completing dinner, if necessary.
Part A: The first 12 weeks of the Treatment Period will be a randomized,
double-blind, placebo-controlled, dose-ranging study. Subjects will be
randomized in a 1:1:1:1 ratio to receive either placebo or tildacerfont at a
dose of 50 mg once daily (QD), 100 mg QD, or 200 mg QD. Visits will occur every
4 weeks.
Part B: During the second 12 weeks of the Treatment Period, all subjects will
receive active drug (tildacerfont), with possible dose escalation for eligible
subjects. Subjects and Investigators will remain blinded to previous treatment
in Part A and dose level of tildacerfont in Part B. Visits will occur every 6
weeks.
Part C: During the last 46 weeks of the Treatment Period, all subjects will be
escalated to 200 mg QD, with periodic opportunities for GC reduction for
eligible subjects. Subjects and Investigators will continue to remain blinded
to previous treatment in Part A and dose level of tildacerfont in Part B.
Visits will occur every 6 to 12 weeks.
Subjects continuing into the optional Open-Label Extension Period will receive
up to 240 weeks of treatment with tildacerfont 200 mg QD and will be eligible
to adjust GC-dose level at each visit. Upon completion of the Open-Label
Extension Period, subjects will enter a 30-day Follow-up Period.
Subjects who do not continue to the Open-Label Extension period upon completion
of Treatment Period Part C, subjects will enter a 30-day Follow-up Period. At
the end of the study treatment, subjects will maintain the GC regimen and
mineralocorticoid regimen (as applicable) established during the course of the
study until the 30-day follow-up visit unless the Investigator determines that
the subject*s clinical status necessitates a dosing change. After completion of
the study, GC therapy will be managed at the discretion of the subject's
treating physician.
Study burden and risks
Given the serious nature of CAH and the limitations and risks of chronic
steroid therapy, new treatment modalities are needed for patients with CAH.
Given 1) the acceptable overall safety and tolerability profile of tildacerfont
in healthy volunteers and subjects with CAH; 2) the ability to monitor the
observed risk of LFT elevation, which is reversible and occurred at higher
exposures than those expected in this study; and 3) the evidence of reductions
17-OHP and A4 at multiple dose levels tested in previous Phase 2 studies, the
Sponsor believes that the benefit-to-risk profile favors the continued clinical
investigation of tildacerfont, including this randomized, double-blind,
placebo-controlled investigation of extended treatment with tildacerfont for up
to 1 year in subjects with CAH. An optional Open-Label Extension Period will
provide additional open-label treatment with tildacerfont at 200 mg QD for up
to 240 weeks.
Junipero Serra Boulevard 2001 Suite 640
Daly City, CA 94014
US
Junipero Serra Boulevard 2001 Suite 640
Daly City, CA 94014
US
Listed location countries
Age
Inclusion criteria
1. Male and female subjects >=18 years old at screening
2. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase
deficiency based on genetic mutation in CYP21A2 and/or documented (at any time)
elevated 17-OHP and currently treated with HC, HC acetate, prednisone,
prednisolone, methylprednisolone (or a combination of the aforementioned GCs).
3. For subjects with the salt-wasting form of CAH, subject has been on a stable
dose of mineralocorticoid replacement for >= 1 month before screening
4. Agrees to follow contraception guidelines. Male subjects must also agree to
refrain from donating sperm throughout the treatment period and for 90 days
after the last dose of study drug.
5. Is able to understand all study procedures and risks involved and provides
written informed consent indicating willingness to comply with all aspects of
the protocol
6. Has androstenedione (A4) > ULN at both screening and Week 4 (measured before
any AM GC dose) if daily GC dose <30 mg OR has A4 > 2.5x ULN at both screening
and Week 4 (measured before any AM GC dose)
7. Has been on a stable, supraphysiologic dose of GC replacement (defined as
>=15 mg/day and <=60 mg/day in HCe for >=1 month before screening.
Exclusion criteria
1. Has a known or suspected diagnosis of any other known form of classic CAH
(not due to 21-hydroxylase deficiency)
2. Has a history that includes bilateral adrenalectomy or hypopituitarism
3. Has a history of allergy or hypersensitivity to tildacerfont, any of its
excipients, or any other CRF1 receptor antagonist
4. Current treatment with dexamethasone as GC therapy for CAH
a. Prior treatment with dexamethasone is allowed as long as the transition to
an alternative GC regimen (eg, HC, prednisone, or prednisolone) has resulted in
a stable dose of GC replacement for >=1 month before screening.
5. Is not adherent to GC or study drug dosing regimen during the Run-in Period
(defined as taking <80% of expected doses based on drug accountability)
6. Shows clinical signs or symptoms of adrenal insufficiency
7. Has had a clinically significant unstable medical condition, medically
significant illness, or chronic disease occurring within 30 days of screening,
including but not limited to:
a. An ongoing malignancy or <3 years of remission history from any malignancy,
other than successfully treated localized skin cancer.
b. Estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73 m2
c. Current or history of liver disease (with the exception of Gilbert*s
syndrome).
d. History of alcohol or substance abuse within the last year, or any
significant history of alcohol or substance abuse that would likely prevent the
subject from reliably participating in the study, based on the opinion of the
Investigator
e. Active hepaptitis B, hepatitis C, or human immunodeficiency virus (HIV) at
screening
f. Subjects who plan to undergo bariatric surgery during the study are
excluded.
g. Any other condition that would impact subject safety or confound
interpretation of study results.
8. Psychiatric conditions, including but not limited to bipolar disorder,
schizophrenia, or schizoaffective disorders that are not effectively controlled
on medication and may have an adverse impact on study compliance. Symptoms
including hallucinations, delusions, and psychosis are exclusionary.
Additionally:
a. Increased risk of suicide based on the Investigator*s judgment or the
results of the Columbia-Suicide Severity Rating Scale (C-SSRS) conducted at
screening and Week 6 (eg, C-SSRS Type 3, 4, or 5 ideation within the past 6
months or any suicidal behavior within the past 12 months)
b. Hospital Anxiety and Depression Scale (HADS) score >12 for either depression
or anxiety at screening or Week 6
9. Has clinically significant abnormal electrocardiogram (ECG) or clinical
laboratory results. Abnormal results that must be reviewed and discussed with
the Medical Monitor to determine eligibility for this study include but are not
limited to:
a. Any clinically meaningful abnormal ECG results, including
Fridericia-corrected QT interval (QTcF) >450 milliseconds (ms) for male
participants or >470 ms for female participants
b. Alanine aminotransferase (ALT) >2x ULN
c. Total bilirubin >1.5x ULN
d. Total bile acids >5x ULN
10. Routinely works overnight shifts
11. Subjects with travel plans/work schedules that result in significant and
frequent changes in time zones (>2 hours) will require Medical Monitor approval
for enrollment.
12. Females who are pregnant or nursing
13. Use of any other investigational drug from 30 days or 5 half-lives
(whichever is longer) before screening to the end of the study
14. Use of the following drugs from 30 days or 5 half-lives (whichever is
longer) before Day 1 to the end of the study
a. rosiglitazone, aromatase inhibitors, testosterone, growth hormones or any
other medication or supplement that could impact subject safety or confound
interpretation of study results
b. drugs listed in section 13.1
15. Donation or receipt of blood from 90 days before screening to the end of
the study; donation or receipt of platelets, white blood cells, or plasma from
30 days before screening to the end of the study
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 | EUCTR2019-004764-22-NL |
| CCMO | NL72678.091.20 |