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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.
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:
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Chronocort® | Experimental | 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. |
|
| standard glucocorticoid therapy | Active Comparator | Subjects in this arm will continue previous oral glucocorticoid therapy titrated to effect. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Chronocort® | Drug | Chronocort® is a patented oral modified release formulation of hydrocortisone which is intended to mimic, or closely match, the serum levels of endogenous cortisol. |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP | 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). | 24 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 | 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). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Debbie Merke, MD | National Institutes of Health (NIH) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| National Institutes of Health Clinical Center | Bethesda | Maryland | 20892-1932 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33527139 | Derived | Merke DP, Mallappa A, Arlt W, Brac de la Perriere A, Linden Hirschberg A, Juul A, Newell-Price J, Perry CG, Prete A, Rees DA, Reisch N, Stikkelbroeck N, Touraine P, Maltby K, Treasure FP, Porter J, Ross RJ. Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. J Clin Endocrinol Metab. 2021 Apr 23;106(5):e2063-e2077. doi: 10.1210/clinem/dgab051. |
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To be decided at a later date
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Following written informed consent and screening tests (Visit 0), eligible participants were called back for the baseline visit. As part of the baseline assessment, participants were admitted overnight for a 24- hour endocrine profile whilst remaining on their standard therapy. Participants were then randomised to Chronocort or standard therapy.
This study was conducted at 11 study sites in 7 countries: Denmark 1, France 2, Germany 1,Netherlands 1, Sweden 1, UK 4, and USA 1.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 subject's previous glucocorticoid therapy dose and then dose titrated to effect. 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. |
| FG001 | Standard Glucocorticoid Therapy | Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of:
|
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for 17-OHP | 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). | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105. | Posted | Mean | Standard Deviation | Z-score | 24 weeks |
Adverse event information was collected from the point of enrolment to completion of the study (6 months).
Adverse event information was collected at each visit by the investigator and reported accordingly.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastroenteritis | Infections and infestations | MedDRA 20.0 | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute Sinusitis | Infections and infestations | MedDRA 20.0 | Non-systematic Assessment |
A limitation of the pre-defined primary endpoint was that it included an unsigned SDS score over a 24-hour period.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Information Line | Diurnal Limited | +44 (0) 2920 682069 | info@diurnal.co.uk |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Aug 23, 2017 | Jul 10, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 13, 2018 | Jul 10, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000312 | Adrenal Hyperplasia, Congenital |
| ID | Term |
|---|---|
| D047808 | Adrenogenital Syndrome |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D006854 | Hydrocortisone |
| D011241 | Prednisone |
| D011239 | Prednisolone |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 |
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|
| standard glucocorticoid therapy | Drug | Subjects in this arm will continue on their standard hydrocortisone therapy |
|
|
| 24 weeks |
| 17-OHP and A4 by Individual Baseline Treatment Strata. | 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). | 24 weeks |
| Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 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. | 24 weeks |
| Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany. | Baseline and 24 weeks |
| Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. | Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany. | Baseline and 24 weeks |
| BG001 | Standard Glucocorticoid Therapy | Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of:
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ID | Title | Description |
|---|
| OG000 | 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. 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. |
| OG001 | Standard Glucocorticoid Therapy | Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of:
|
|
|
|
| Secondary | Change From Baseline to 24 Weeks of the Mean of the 24-hour Standard Deviation Score (SDS) Profile for A4 | 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). | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105. | Posted | Mean | Standard Deviation | Z-score | 24 weeks |
|
|
|
|
| Secondary | 17-OHP and A4 by Individual Baseline Treatment Strata. | 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). | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105. | Posted | Mean | Standard Deviation | Z-score | 24 weeks |
|
|
|
|
| Secondary | Number of Participants With 17-OHP and A4 Levels in the Optimal Range at 9:00 at Week 24 Visit | 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. | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. Total sum of participants in the EES = 105. | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
|
| Secondary | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Fat Mass and Lean Mass) | Changes relative to Standard glucocorticoid therapy in body composition (DEXA) (fat mass and lean mass) - measured at all sites except Germany. | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. German subjects were excluded from this analysis subset. | Posted | Mean | Standard Deviation | kilograms | Baseline and 24 weeks |
|
|
|
|
| Secondary | Changes Relative to Standard Glucocorticoid Therapy in Body Composition (DEXA - Bone Mineral Density) - Measured at All Sites Except Germany. | Changes relative to Standard glucocorticoid therapy in body composition (DEXA - bone mineral density only) - measured at all sites except Germany. | The efficacy evaluable analysis set (EES) comprised all participants who were randomised into the study, who received at least one dose of Chronocort or standard GC therapy, and who had an evaluable Week 24 17-OHP 24-hour hormone profile, and who had no major protocol violations. German subjects were excluded from this analysis subset. | Posted | Mean | Standard Deviation | g/cm^2 | Baseline and 24 weeks |
|
|
|
|
| 0 |
| 61 |
| 7 |
| 61 |
| 59 |
| 61 |
| EG001 | Standard Glucocorticoid Therapy | Subjects in this arm will continue their previous oral glucocorticoid therapy, titrated to effect. Standard glucocorticoid therapy may consist of:
| 0 | 61 | 5 | 61 | 48 | 61 |
| Gastroenteritis Viral | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Appendicitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Salpingitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Tonsilitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Herpes Zoster | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Adrenocortical Insufficiency (acute) | Endocrine disorders | MedDRA 20.0 | Systematic Assessment |
|
| Adrenal Insufficiency | Endocrine disorders | MedDRA 20.0 | Systematic Assessment |
|
| Oedema Peripheral | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Conjunctivitis viral | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Cystitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Ear infection fungal | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Influenza | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Lower Respiratory Tract Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Otitis media | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Paronychia | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Tonsilitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Urinary Tract Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Viral Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Viral Upper Respiratory Tract Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Diarrhoea Infectious | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Oral Candidiasis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Otitis Media Acute | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Tooth Infection | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Viral Rash | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Basal Cell Carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 20.0 | Systematic Assessment |
|
| Anaemia | Blood and lymphatic system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Iron Deficiency Anaemia | Blood and lymphatic system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abnormal Loss of Weight | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abnormal Weight Gain | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Decreased Appetite | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Fluid Retention | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Gluten Sensitivity | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hyperinsulinaemia | Metabolism and nutrition disorders | MedDRA 20.0 | Non-systematic Assessment |
|
| Impaired Fasting Glucose | Metabolism and nutrition disorders | MedDRA 20.0 | Non-systematic Assessment |
|
| Increased Appetite | Metabolism and nutrition disorders | MedDRA 20.0 | Non-systematic Assessment |
|
| Weight Fluctuation | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Alcohol Intolerance | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Affect Lability | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Burnout Syndrome | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Depressed Mood | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Irritability | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Libido Decreased | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Stress | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Agitation | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Emotional Distress | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Sleep Disorder | Psychiatric disorders | MedDRA 20.0 | Systematic Assessment |
|
| Carpal Tunnel Syndrome | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Circardian Rhythm Sleep Disorder | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dizziness Postural | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Memory Impairment | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Migraine | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Peripheral Nerve Lesion | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Poor Quality Sleep | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Sensory Loss | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Lethargy | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Psychomotor Hyperactivity | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Tension Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Chalazion | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vision Blurred | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Ear Pain | Ear and labyrinth disorders | MedDRA 20.0 | Systematic Assessment |
|
| Tinnitus | Ear and labyrinth disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA 20.0 | Systematic Assessment |
|
| Foreign Body Sensation in Eyes | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Lacrimation Increased | Eye disorders | MedDRA 20.0 | Systematic Assessment |
|
| Ear Deformity Acquired | Ear and labyrinth disorders | MedDRA 20.0 | Non-systematic Assessment |
|
| Tympanic Membrane Perforation | Ear and labyrinth disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vertigo Positional | Ear and labyrinth disorders | MedDRA 20.0 | Systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
|
| Sinus Tachycardia | Cardiac disorders | MedDRA 20.0 | Systematic Assessment |
|
| Haematoma | Vascular disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pallor | Vascular disorders | MedDRA 20.0 | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Nasal Congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abdominal Pain | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abdominal Pain Upper | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dental Caries | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Epigastric Discomfort | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Inguinal Hernia | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Abdominal Pain Lower | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Diverticulum Intestinal | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Faeces Soft | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Food Poisoning | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Gastrooesophageal Reflux Disease | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Cold Sweat | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Eczema | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hair Growth Abnormal | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Psoriasis | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Blister | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Chloasma | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Non-systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Joint Stiffness | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Muscle Fatigue | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Muscle Tightness | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Muscular Weakness | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Musculoskeletal Pain | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Neck Pain | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pain in Extremity | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Menstruation Irregular | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
|
| Erectile Dysfunction | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Chest Pain | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Fat Tissue Increased | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Inflammation | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Influenza-like Illness | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Malaise | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Therapeutic Response Unexpected | General disorders | MedDRA 20.0 | Systematic Assessment | AE of unexpected therapeutic benefit |
|
| Thirst | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Oedema Peripheral | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Peripheral Swelling | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Sensation of Foreign Body | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Alanine Aminotransferase Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Blood Sodium Decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Body Temperature Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Osteocalcin Decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Renin Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Urine Output Decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Aspartate Aminotransferase Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Blood Creatine Phosphokinase Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Blood Glucose Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| C-Telopeptide Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Haematocrit Decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Haemoglobin Decreased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Liver Function Test Abnormal | Investigations | MedDRA 20.0 | Non-systematic Assessment |
|
| Weight Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| White Blood Cell Count Increased | Investigations | MedDRA 20.0 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Head Fracture | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Limb Injury | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Procedural Pain | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Auricular Haematoma | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Ear Injury | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Ligament Sprain | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Procedural Complication | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Sunburn | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Toxicity to Various Agents | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Wound | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Mineralocorticoid Deficiency | Endocrine disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Salpingitis | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA 20.0 | Systematic Assessment |
|
Specified in the contractual agreements between the Sponsor and investigators: "Neither the CRO, nor the Heath Board, nor the Investigator shall register the Clinical Trial, or the results, on any publicly accessible clinical trial registry."
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D043202 | Steroid Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D006058 | Gonadal Disorders |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
| D011244 | Pregnadienediols |
| D011245 | Pregnadienes |
| D011246 | Pregnadienetriols |
| D013259 | Steroids, Fluorinated |
| Mean Difference (Final Values) |
| -0.135 |
| 2-Sided |
| 95 |
| -0.508 |
| 0.237 |
| Superiority |
| ANCOVA | =0.9081 | Mean Difference (Final Values) | 0.065 | 2-Sided | 95 | -1.32 | 1.451 | Superiority |
| ANCOVA | =0.6729 | Median Difference (Final Values) | 0.092 | 2-Sided | 95 | -0.343 | 0.527 | Superiority |
| ANCOVA | =0.5322 | Mean Difference (Final Values) | 0.116 | 2-Sided | 95 | -0.257 | 0.489 | Superiority |
| ANCOVA | =0.2885 | Mean Difference (Final Values) | -0.568 | 2-Sided | 95 | -1.799 | 0.662 | Superiority |
| Odds Ratio (OR) |
| 0.93 |
| 2-Sided |
| 95 |
| 0.43 |
| 2.02 |
| Superiority |
| ANCOVA |
| =0.3392 |
| Median Difference (Final Values) |
| 0.425 |
| 2-Sided |
| 95 |
| -0.455 |
| 1.305 |
| Superiority |