臨床研究等提出・公開システム

A randomized, Double-Blind, Active-Controlled, Phase 3 Study of
Chronocort Compared with Immediate-Release Hydrocortisone Replacement Therapy in
Participants Aged 16 Years and Over with Congenital Adrenal Hyperplasia

Double-blind comparison of Chronocort versus standard hydrocortisone
replacement therapy in participants aged 16 years and over with congenital adrenal
hyperplasia

55

The mean (standard deviation [SD]) age of all participants was 34.0 (13.93) years, with the mean age being higher in the Chronocort group (mean [SD] age 36.7 [14.68] years) compared to the immediate release hydrocortisone replacement therapy (IRHC) group (mean [SD] age 31.6 [13.02] years). More females were also enrolled in the Chronocort group (64.0%) compared to the IRHC group (57.1%). The majority of participants where race was reported were White (67.6% of the 37 participants with reported race), but collection of race cannot be mandated in France so 16 French participants did not have race recorded or it was unknown. A total of 9 Asian participants (17.0%) were enrolled in the study, 4 participants (16.0%) in the Chronocort group and 5 participants (17.9%) in the IRHC group. The majority of participants were receiving fludrocortisone replacement at baseline (86.8%), with the incidence being similar in the 2 treatment groups. Baseline disease history was similar in the 2 treatment groups. Most participants had their congenital adrenal hyperplasia (CAH) diagnosed clinically (96.2%) and 64.2% had the diagnosis confirmed by genetic analysis. The overall mean time since CAH diagnosis was 32.8 years. The majority of participants (94.3%) had not had an adrenal crisis in the last year, and no participants had been hospitalised in the last year for CAH.

A total of 55 participants were screened for the study and entered the 4-week run-in period where they received IRHC (safety analysis set [SAF]). One participant withdrew consent during the run-in period and one participant was found to not meet the inclusion/exclusion criteria at the end of the run-in period so was withdrawn, so 53 (96.4%) participants were randomised to study intervention (28 to IRHC and 25 to Chronocort) and all 53 participants received the randomised treatment (full analysis set [FAS]). Three participants (all in the IRHC arm) withdrew during the study due to withdrawal of consent, physician decision and withdrawal by participant, so 50 (94.3%) of the randomised participants completed the randomised treatment period and the study. Of these 50 participants who completed the study, 44 (83.0%) entered the long-term safety follow-up study. The primary and key secondary analyses were conducted using the FAS (N=53).

A total of 92 treatment emergent adverse events (TEAEs) were reported by 85.7% of participants in the IRHC group and 100 TEAEs reported by 88.0% of participants in the Chronocort group. The most common TEAEs by preferred term (PT) were fatigue (17.0% of participants overall) and headache (13.2% of participants overall). Most TEAEs were reported with a similar frequency in the 2 treatment groups; however, pyrexia was only reported in the IRHC group (21.4%) and weight increased was only reported in the Chronocort group (12.0%). Most participants had TEAEs that were considered mild (47.2%) or moderate (37.7%), with only 1 participant in the IRHC group having a TEAE that was considered severe (pneumonia). This event was reported as a serious adverse event (SAE). TEAEs considered by the Investigators to be causally related to study intervention were reported in 25.0% of participants in the IRHC group and 40.0% of participants in the Chronocort group. The most common treatment-related TEAEs by PT were fatigue (13.2% of participants overall) and headache (5.7% of participants overall). Three SAEs were reported for 3 participants (2 in the Chronocort group [COVID-19 and malignant melanoma] and 1 in the IRHC group [pneumonia, aforementioned]). None of the SAEs were considered by the Investigators to be causally related to study intervention and none had a fatal outcome by the end of the study. There were no TEAEs that led to withdrawal of the study intervention or withdrawal of the participant from the study, and none of the TEAEs led to a change in study intervention dose or interruption of the study intervention. No clinically relevant changes or differences were seen between the 2 treatment groups for any of the laboratory parameters. No notable changes were seen in vital signs, physical examination findings or electrocardiogram (ECG) results during the study.

Primary Efficacy Endpoint After 28 weeks of treatment, 10 participants (40.0%) in the Chronocort group were considered a biochemical responder compared to 4 participants (14.3%) in the IRHC group. The difference (SE) in biochemical response rates (Chronocort - IRHC) was 25.7 (11.82) (95% confidential interval [CI]: 2.5, 48.9). This difference was statistically significant in favour of Chronocort when tested for non-inferiority (1-sided p=0.0003) and superiority (1-sided p=0.015). Key Secondary Efficacy Endpoints 1. Dose Responder Rate Results showed more participants were a dose responder following Chronocort treatment (9 participants, 36.0%) compared to IRHC treatment (3 participants, 10.7%). The difference (SE) in dose response rates (chronocort - IRHC) was 25.3 (11.24) (95%CI: 3.3, 47.3). This difference was statistically significant in favour of Chronocort when tested for superiority (1-sided p=0.012). 2. Mean Total Daily Dose of Hydrocortisone Results showed that participants had a lower mean daily dose following Chronocort treatment (least square [LS] mean (SE) was 20.2 (1.19) mg (95% CI: 17.8, 22.6))]) compared to IRHC treatment (LS mean (SE) was 26.0 (1.15) mg (95% CI: 23.7, 28.3)).The difference in LS means (SE) was -5.8 (1.66) (95% CI: -9.2, -2.5),, which was statistically significant in favour of Chronocort (1-sided p=0.0005).

The primary and key secondary objectives of this study were all met, with Chronocort showing statistical non-inferiority and superiority and a clinically significant improvement over IRHC (Cortef) in biochemical control and dose response. Also, the safety profile was as expected from studies in patients with CAH, with no new safety signals being identified.

Yes

Diurnal abides by the PhRMA/EFPIA Principles for Responsible Clinical Trial Data Sharing, and will share individual de-identified participant data and supporting study documents upon request from qualified external researchers based on specific criteria.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210491

Fujii Katsuya

Syneos Health Clinical K.K.

27F Shinagawa Season Terrace, 1-2-70 Konan, Minato-ku

katsuya.fujii@syneoshealth.com

Fujii Katsuya

Syneos Health Clinical K.K.

27F Shinagawa Season Terrace, 1-2-70 Konan, Minato-ku,

+81-90-9133-2809

katsuya.fujii@syneoshealth.com

Complete

Jan. 04, 2022

Interventional

randomized controlled trial

double blind

active control

parallel assignment

treatment purpose

1. Participant must be aged 16 years or older at the time of signing the informed consent/assent.
2. In participants aged <18 years, height velocity must be less than 2 cm/year in the last year and puberty must be completed (Tanner stage V).
3. Participants with known classic CAH due to 21-hydroxylase deficiency diagnosed in childhood with documented (at any time) elevated 17-OHP and with or without elevated A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) and on stable glucocorticoid therapy for a minimum of 3 months.
4. Participants who are receiving fludrocortisone must be on a documented stable dose for a minimum of 3 months prior to enrollment and must have stable renin levels at screening.
5. Male and female participants.
Female participants of childbearing potential and all male participants must agree to the use of an accepted method of contraception during the study.
A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies:
Not a woman of childbearing potential (WOCBP)
OR
A WOCBP with a negative pregnancy test at entry into the study.
Note: females presenting with oligomenorrhea or amenorrhea who are aged =< 55 years should be considered potentially fertile and therefore should undergo pregnancy testing like all other female participants.
6. Capable of giving signed informed consent/assent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

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, receive regular insulin, have uncontrolled diabetes, or have a screening HbA1c greater than 8%.
5. Persistent signs of adrenal insufficiency or the participant does not tolerate treatment
at the end of the 4-week run-in period.
6. Participants with any other significant medical or psychiatric conditions that in the
opinion of the Investigator would preclude participation in the study.
7. Participants on regular daily inhaled, topical, nasal or oral steroids for any indication
other than CAH.
8. 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/).
9. Participants who are receiving <10 mg hydrocortisone dose at screening or the
hydrocortisone dose equivalent.
10. Participants anticipating regular prophylactic use of additional steroids e.g. for
strenuous exercise.
11. Participation in another clinical study of an investigational or licensed drug or device
within the 12 weeks prior to screening.
12. Inclusion in any natural history or translational research study that would require
evaluation of androgen levels during the study period outside of this protocol's
assessments.
13. Participants who have previously been exposed to Chronocort in any Diurnal study.
14. Participants who routinely work night shifts and so do not sleep during the usual
night-time hours.
15. Participants, who in the opinion of the Investigator, will be unable to comply with the requirements of the protocol.
16. Participants with a known hypersensitivity to any of the components of the Chronocort capsules, the Cortef tablets, or the placebo capsules.
17. Participants with congenital galactosemia, malabsorption of glucose and galactose, or who are lactase deficient.
18. Participants with a body weight of 45 kg or less.

Both

Congenital adrenal hyperplasia (CAH)

Participants randomized to Chronocort will receive 10 mg Chronocort in the morning on waking (typically between 06:00 and 08:00), placebo in the afternoon (between 15:00 and 17:00) and 20 mg Chronocort at night just prior to going to bed (typically between 22:00 and midnight). A maximum of 3 dose reductions will be allowed, resulting in a minimum final dose of 15 mg a day. Participants randomized to immediate-release hydrocortisone (IRHC) will receive 20 mg IRHC in the morning on waking (typically between 06:00 and 08:00), 10 mg IRHC in the afternoon (between 15:00 and 17:00) and placebo at night just prior to going to bed (typically between 22:00 and midnight). A maximum of 3 dose reductions will be allowed, resulting in a minimum final dose of 15 mg a day. The dose for both groups will be adjusted by an Independent blinded physician based on the androgen levels and adrenal function at Weeks 4, 10, and 16. At Week 16 the dose will be fixed and should remain unchanged. If a participant shows persistent signs of under replacement the Investigator can request 1 dose reversion of 5 mg, this will be discussed and agreed by the medical monitor.

To compare Chronocort to IRHC in terms of biochemical responder rate after 28 weeks of randomized treatment

- To compare Chronocort to IRHC in terms of dose responder rate after 28 weeks of randomized treatment.
- To compare Chronocort to IRHC in terms of total daily dose after 28 weeks of randomized treatment.

+81-3-5494-7297

Nov. 17, 2021

US/France