Clinical trial NCT03532022: Open-label Comparison of Chronocort® Versus Standard Glucocorticoid Replacement Therapy
Official 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
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Congenital Adrenal Hyperplasia
Lead sponsor: Neurocrine UK Limited
Sponsor class: INDUSTRY
Collaborators: name: National Institutes of Health (NIH)
First posted: 2018-05-22
Enrollment: 0
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is an open-label, randomised, titration-blinded, parallel arm, multicenter study to compare twice daily Chronocort® with standard care in participants with Congenital Adrenal Hyperplasia (CAH). This study will be conducted in the USA.

Detailed description: It will compare the efficacy, safety and tolerability of twice daily Chronocort® with standard care (using the participant's usual individualized standard glucocorticoid regimen) over a treatment period of 52 weeks in participants aged 16 years and over 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).

Eligibility 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.

Primary outcomes:
measure: Non-inferiority of Chronocort® versus standard care in terms of responder rate.
timeFrame: 52 weeks
Secondary outcomes:
measure: Impact of both treatments on markers of fertility.
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on hirsutism in female participants.
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on acne.
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on glycated hemoglobin (HbA1c) levels.
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on waist circumference (in centimetres).
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on body weight (in kilograms).
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on quality of life (QoL) using SF-36® total score and the sub-domain of vitality.
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on Quality of Life using Multidimensional Assessment of Fatigue (MAF).
timeFrame: Weeks 26 & 52
measure: Impact of both treatments on Quality of Life using EQ-5D™.
timeFrame: Weeks 26 & 52
measure: Safety and tolerability of Chronocort® relative to standard care
timeFrame: 52 weeks
measure: The need for additional glucocorticoid doses
timeFrame: 52 weeks
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - Red blood cell count and platelet count
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - haemaglobin
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - haematocrit
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean corpuscular volume (MCV)
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean cell haemoglobin (MCH)
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - mean cell haemoglobin concentration (MCHC)
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of routine safety haematology assessments - Red cell distribution width (RDW)
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: 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
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of physical examinations.
timeFrame: Baseline (Day 1), Week 26 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of vital signs - Blood pressure
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of vital signs - Heart rate
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of vital signs - Respiratory rate
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of vital signs - Oral body temperature
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Specific gravity
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - pH
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Glucose
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Proteins
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Blood
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Ketones
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Bilirubin
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of urinalysis - Urobilinogen by dipstick
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
measure: Safety of Chronocort® compared to standard care by assessment of electrocardiogram (ECG).
timeFrame: Baseline (Day 1), Week 2, Week 6, Week 12, Week 26, Week 39 & Week 52
Other outcomes:
Locations:
city: Morehead City
country: United States
facility: Diabetes and Endocrinology Consultants PC
state: North Carolina
Study officials:
References: