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Trial record 21 of 107 for:    "21-hydroxylase deficiency"

Comparison of Chronocort® With Standard Glucocorticoid Therapy in Patients With Congenital Adrenal Hyperplasia

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ClinicalTrials.gov Identifier: NCT02716818
Recruitment Status : Completed
First Posted : March 23, 2016
Results First Posted : September 4, 2019
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
Diurnal Limited

Brief Summary:
This study is a parallel arm, randomised, open-label study, including dose titration and admissions for four overnight stays for 24-hour endocrine profiles. It will compare the efficacy, safety and tolerability of Chronocort® with standard glucocorticoid replacement therapy in the treatment of congenital adrenal hyperplasia (CAH) over a treatment period of 6 months. Dose titration decisions in both treatment groups will be made by a central independent physician, blinded to the treatment arm, using information generated from the 24-hour endocrine profiles. Each treatment arm will be subject to the same titration rules throughout the study, ensuring that opportunities for optimisation and control of androgens are the same in both groups.

Condition or disease Intervention/treatment Phase
Congenital Adrenal Hyperplasia Drug: Chronocort® Drug: standard glucocorticoid therapy Phase 3

Detailed Description:

At baseline, subjects will be admitted overnight for a 24-hour endocrine profile whilst on their standard therapy. Subjects will attend the study site in the morning and have 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) levels assessed at 15:00, 17:00, 19:00, 21:00, 23:00, 01:00, 03:00, 05:00, 07:00, 09:00, 11:00, 13:00 and 15:00. Safety laboratory tests, a DEXA scan for body composition, and height, weight and waist circumference will be recorded. Subjects will then be randomised to Chronocort® or to continue on their standard care. Randomisation will be stratified by baseline treatment:

  1. hydrocortisone only or
  2. prednisone or prednisolone, alone or in combination with hydrocortisone
  3. dexamethasone only or in combination with any other glucorticoid

The initial dose setting at the start of the Chronocort® treatment will be based on hydrocortisone dose equivalent of baseline therapy in accordance with standard clinical practice. Further dose refinement/titration will be conducted in both treatment groups as necessary after 4 weeks and 12 weeks using a standardised titration algorithm after the subject has been re-admitted for further 24-hour endocrine profiles. Safety endpoints will also be measured at the 07:00 morning sample of each 24-hour profile assessment day. The decision to change doses in both treatment groups will be made by a central independent blinded physician, with the actual change in dose then being made by the local investigator looking after the subject. At 6 months, all the baseline tests will be repeated (including the 24-hour profile). All subjects may then continue on Chronocort®, whatever their randomised treatment, as part of an open-label extension study (to be conducted under a separate protocol). Stress doses of hydrocortisone will be given throughout the study for intercurrent illnesses as medically indicated according to "sick day rules".


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 122 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Study of Efficacy, Safety and Tolerability of Chronocort® Compared With Standard Glucocorticoid Replacement Therapy in the Treatment of Congenital Adrenal Hyperplasia
Actual Study Start Date : February 22, 2016
Actual Primary Completion Date : July 28, 2018
Actual Study Completion Date : July 28, 2018


Arm Intervention/treatment
Experimental: Chronocort®
Chronocort® will be provided as 5mg, 10mg and 20mg capsules for oral administration. The starting dose for each subject will be based on the subjects previous glucocorticoid therapy dose and then dose titrated to effect.
Drug: Chronocort®
Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol.
Other Name: Hydrocortisone

Active Comparator: standard glucocorticoid therapy
Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect.
Drug: standard glucocorticoid therapy
Subjects in this arm will continue on their standard hydrocortisone therapy
Other Names:
  • hydrocortisone
  • prednisone
  • prednisolone
  • dexamethasone




Primary Outcome Measures :
  1. Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP [ Time Frame: 24 weeks ]
    Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP (17-Hydroxyprogesterone). The primary efficacy variable was the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP when compared to baseline (0).


Secondary Outcome Measures :
  1. Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 [ Time Frame: 24 weeks ]
    Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for A4 (androstenedione). This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of A4 when compared to baseline (0).

  2. 17-OHP and A4 by Individual Baseline Treatment Strata. [ Time Frame: 24 weeks ]
    17-OHP and A4 by individual baseline treatment strata presented in the same manner as the primary endpoint (using 24-hour SDS profile at 24 weeks). Change from baseline to 24 weeks of the mean of the 24-hour standard deviation score (SDS) - also referred to as a z-score - profile for 17-OHP and A4. This secondary efficacy variable was calculated as follows: the natural logarithm of the mean of the 24-hour SDS for the natural logarithm of 17-OHP and A4. The mean of the 24-hour SDS profile for each visit was the arithmetic mean of all the SDSs with the first and last (13th) weighted one half relative to the intermediate SDSs. For each of the 13 log-transformed 17-OHP and A4 values at each visit, an SDS was calculated by counting the number of SDs that were above or below the mean of the log-transformed range. A negative z-score indicated greater control of 17-OHP and A4 when compared to baseline (0).

  3. Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit [ Time Frame: 24 weeks ]

    17-OHP and A4 levels at 09:00 at the week 24 visit, as a responder analysis (i.e. the number of participants achieving results in the optimal range).

    Optimal range for 17-OHP (male) = 1.2* - 6.7 nmol/L (female) = 1.2* - 8.6 Optimal range for A4 (male) = 1.4 - 5.2 nmol/L (female) = 1.0 - 7.0 nmol/L

    * = There is no lower reference range available for 17-OHP, hence the lower limit of the optimal range was used in the derivation of the average Standard Deviation Score. This enabled calculation of an 'unsigned' SDS score which was used to assess potential over-treatment as well as under-treatment.


  4. Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) [ Time Frame: Baseline and 24 weeks ]
    Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany.

  5. Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. [ Time Frame: Baseline and 24 weeks ]
    Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Known CAH due to 21-hydroxylase deficiency (classic CAH) diagnosed in childhood with documented (at any time) elevated 17-OHP and/or A4 and currently treated with hydrocortisone, prednisone, prednisolone or dexamethasone (or a combination of the aforementioned glucocorticoids) on a stable glucocorticoid therapy for a minimum of 6 months.
  2. Provision of signed written informed consent.
  3. Non-pregnant, non-lactating females who are post menopausal, naturally or surgically sterile, or of childbearing potential with a negative urinary pregnancy test and using a medically acceptable method of contraception.
  4. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.
  5. Plasma renin activity (PRA) less than 1.5 times the upper limit of normal (ULN) at screening or within 3 months prior to screening, except in subjects who have been diagnosed with hypertension where the renin is not being used to monitor fludrocortisone replacement.

Exclusion Criteria:

  1. Co-morbid condition requiring daily administration of a medication (or consumption of any material) that interferes with the metabolism of glucocorticoids.
  2. Clinical or biochemical evidence of hepatic or renal disease. Creatinine over twice the ULN or elevated liver function tests (ALT or AST >2 times the ULN).
  3. Subjects on regular daily inhaled, topical, nasal or oral steroids for any indication other than CAH.
  4. Subjects with any other significant medical or psychiatric conditions that in the opinion of the investigator would preclude participation in the trial.
  5. History of malignancy (other than basal cell carcinoma successfully treated >6 months prior to entry into the study).
  6. Participation in another clinical trial of an investigational or licensed drug or device within the 3 months prior to inclusion in this study.
  7. Subjects with a history of bilateral adrenalectomy.
  8. Subjects having previously been exposed to Chronocort®.
  9. Subjects unable to comply with the requirements of the protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02716818


Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892-1932
Sponsors and Collaborators
Diurnal Limited
Investigators
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Principal Investigator: Debbie Merke, MD National Institutes of Health (NIH)
  Study Documents (Full-Text)

Documents provided by Diurnal Limited:
Study Protocol  [PDF] August 23, 2017
Statistical Analysis Plan  [PDF] September 13, 2018


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Responsible Party: Diurnal Limited
ClinicalTrials.gov Identifier: NCT02716818     History of Changes
Other Study ID Numbers: DIUR-005
First Posted: March 23, 2016    Key Record Dates
Results First Posted: September 4, 2019
Last Update Posted: September 4, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: To be decided at a later date
Keywords provided by Diurnal Limited:
Glucocorticoid therapy
Additional relevant MeSH terms:
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Adrenal Hyperplasia, Congenital
Adrenogenital Syndrome
Adrenocortical Hyperfunction
Hyperplasia
Pathologic Processes
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Genetic Diseases, Inborn
Steroid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases
Adrenal Gland Diseases
Endocrine System Diseases
Gonadal Disorders
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone hemisuccinate
Glucocorticoids
Anti-Inflammatory Agents
Physiological Effects of Drugs
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists