Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy

• Register: ClinicalTrials.gov
• Last refreshed on: 19 April 2022
• Main ID: NCT03532022
• Date of registration: 18/04/2018
• Prospective Registration: Yes
• Primary sponsor: Diurnal Limited
• Public title: Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy RESTORE
• Scientific title: An Open-label, Randomized, Titration-blinded, Phase III Study of Efficacy, Safety and Tolerability Of Chronocort® Compared With Standard Glucocorticoid REeplacement Therapy in the Treatment of Participants Aged 16 Years and Over With Congenital Adrenal Hyperplasia
• Date of first enrolment: October 4, 2018
• Target sample size: 0
• Recruitment status: Withdrawn
• URL: https://clinicaltrials.gov/show/NCT03532022
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 3

Countries of recruitment

United States

Key inclusion & exclusion criteria

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria
apply (note: if a participant fails to meet an inclusion criterion, re-screening is
permitted if the Investigator considers that the circumstances leading to screening failure
will not be relevant when the participant is re-screened at a later time):

Age

1. Participant must be aged 16 years or older at the time of signing the informed
consent.

2. In participants aged <18 years, height velocity must be less than 2 cm in the last
year and puberty must be completed.

Type of Participant and Disease Characteristics

3. Participants with known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed
in childhood with documented (at any time) elevated 17-OHP or A4 and currently treated
with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of
the aforementioned glucocorticoids).

Sex

4. Male and female participants

1. Male participants:

- A male participant must agree to use contraception as detailed in Section 10.4
of this protocol during the treatment period and refrain from donating sperm
during this period.

2. Female participants:

- A female participant is eligible to participate if she is not pregnant
(Section 10.4), not breastfeeding, and at least one of the following
conditions applies:

i. Not a woman of childbearing potential (WOCBP) as defined in Section 10.4. OR ii. A
WOCBP with a negative pregnancy test at entry into the study who agrees to follow the
contraceptive guidance in Section 10.4 during the treatment period.

Note: females presenting with oligomenorrhea or amenorrhea who are aged =55 years
should be considered potentially fertile and therefore, as well as undergoing
pregnancy testing like all other female participants, will be expected to be using an
acceptable method of contraception which should have been ongoing for =90 days prior
to the study.

Informed Consent

5. Capable of giving signed informed consent as described in Section 10.1 which includes
compliance with the requirements and restrictions listed in the informed consent form
(ICF) and in this protocol.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply (note: if a
participant meets an exclusion criterion, re-screening is permitted if the Investigator
considers that the circumstances leading to screening failure will not be relevant when the
participant is re-screened at a later time):

Medical Conditions

1. Clinical or biochemical evidence of hepatic or renal disease e.g. creatinine > 2 times
the upper limit of normal (ULN) or elevated liver function tests (alanine
aminotransferase [ALT] or aspartate aminotransferase [AST] >2 times the ULN).

2. History of bilateral adrenalectomy.

3. History of malignancy (other than basal cell carcinoma successfully treated >26 weeks
prior to entry into the study).

4. Participants who have type 1 diabetes or any participant who is receiving insulin.

5. Participants with any other significant medical or psychiatric conditions that in the
opinion of the Investigator would preclude participation in the study.

Prior/Concomitant Therapy

6. Participants on regular daily oral steroids for any indication other than CAH. Note: a
participant should not be given any steroids (even on an irregular basis) within 5
days of a study visit. If there is a medical need for steroid treatment within this
time frame then the visit should be postponed until a 5-day interval has elapsed.

7. Co-morbid condition requiring daily administration of a medication or consumption of
any material that interferes with the metabolism of glucocorticoids (examples provided
at http://medicine.iupui.edu/clinpharm/ddis/clinical-table/).

8. Participants who are receiving <10 mg hydrocortisone dose at baseline or the
hydrocortisone dose equivalent.

Prior/Concurrent Clinical Study Experience

9. Participation in another clinical study of an investigational or licensed drug or
device within the 12 weeks prior to screening or during the study.

10. Inclusion in any natural history or translational research study that would require
evaluation of androgen levels during the study period outside of this study protocol
assessments.

11. Participants who have previously been exposed to Chronocort in studies DIUR-003,
DIUR-005 or DIUR-006.

Other Exclusions

12. Participants who routinely work night shifts and so do not sleep during the usual
night-time hours.

13. Participants unable to comply with the requirements of the protocol.



Age minimum: 16 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Congenital Adrenal Hyperplasia

Intervention(s)

Drug: Standard Care

Drug: Chronocort®

Primary Outcome(s)

Non-inferiority of Chronocort® versus standard care in terms of responder rate. [Time Frame: 52 weeks]

Secondary Outcome(s)

Impact of both treatments on hirsutism in female participants. [Time Frame: Weeks 26 & 52]

Impact of both treatments on Quality of Life using Multidimensional Assessment of Fatigue (MAF). [Time Frame: Weeks 26 & 52]

Safety of Chronocort® compared to standard care by assessment of physical examinations. [Time Frame: Baseline (Day 1), Week 26 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - pH [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of vital signs - Heart rate [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of vital signs - Oral body temperature [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Blood [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Impact of both treatments on acne. [Time Frame: Weeks 26 & 52]

Impact of both treatments on markers of fertility. [Time Frame: Weeks 26 & 52]

Impact of both treatments on body weight (in kilograms). [Time Frame: Weeks 26 & 52]

Safety and tolerability of Chronocort® relative to standard care [Time Frame: 52 weeks]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean cell haemoglobin concentration (MCHC) [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - White blood cell count with differential (absolute and %): Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Specific gravity [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Impact of both treatments on quality of life (QoL) using SF-36® total score and the sub-domain of vitality. [Time Frame: Weeks 26 & 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - Red cell distribution width (RDW) [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Bilirubin [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Urobilinogen by dipstick [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

The need for additional glucocorticoid doses [Time Frame: 52 weeks]

Impact of both treatments on glycated hemoglobin (HbA1c) levels. [Time Frame: Weeks 26 & 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - haemaglobin [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Impact of both treatments on Quality of Life using EQ-5D™. [Time Frame: Weeks 26 & 52]

Impact of both treatments on waist circumference (in centimetres). [Time Frame: Weeks 26 & 52]

Safety of Chronocort® compared to standard care by assessment of electrocardiogram (ECG). [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean corpuscular volume (MCV) [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Ketones [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - haematocrit [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean cell haemoglobin (MCH) [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - Red blood cell count and platelet count [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Proteins [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of vital signs - Respiratory rate [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of urinalysis - Glucose [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Safety of Chronocort® compared to standard care by assessment of vital signs - Blood pressure [Time Frame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52]

Secondary ID(s)

DIUR-007

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

National Institutes of Health (NIH)