Study of the Excretion of Orally Administered Corticosteroids for the Improval of the Detection of Said Substances in Anti-doping Controls

Study Overview
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Brief Summary
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Background: Glucocorticoids (GC) were included in the list of banned substances in sports in 1986, because of evidences of positive effects on physical performance and the important health risks associated with its consumption. Due to the fact that GC are commercialized in a variety of pharmaceutical forms and are administered in different ways, it is necessary to establish discrimination criteria to guarantee the therapeutic use of these drugs and to prevent doping. Hypothesis: Discrimination criteria between allowed and prohibited administrations of GC must be specific for each of the compounds. Further studies are needed to provide discrimination criteria related to oral administration of GC. Objectives: To conduct excretion studies with dexamethasone, methylprednisolone and deflazacort in order to define notification levels and wash-out periods after the administration of a single dose (DEX, MP and DEF) or repeated doses (DEX and MP) of these drugs. Methods: Non-randomized, open-label, pharmacokinetics clinical trial where a single dose of DEF, MP and DEX and also a multi-dose of DEX and MP will be administered orally to healthy volunteers (total n=50).

Detailed Description
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The World Anti-Doping Agency (WADA) has established a general notification level of 30 ng/mL for GC to discriminate allowed and not allowed administrations. However, recent studies have proven that the use of a unique criteria is not adequate given the diversity of administration routes, doses and pharmacokinetics and pharmacodynamics properties of each drug. The goal of this study is to conduct additional studies using dexamethasone (DEX), methylprednisolone (MP) and deflazacort (DEF) in order to generate additional data of urinary concentrations and wash-out periods after single and repeated oral doses of these drugs.

Official Title
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Study of the Excretion of Orally Administered Corticosteroids for the Improval of the Detection of Said Substances in Anti-doping Controls

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Methylprednisone
* Drug: Methylprednisone
* Drug: Deflazacort
* Drug: Dexamethasone
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male volunteers aged between 18 and 55 years. Able to understand and accept the trial procedures and able to sign an informed consent prior to any study-mandated procedure. History and physical examination that demonstrate not presenting organic or psychiatric disorders. ECG, blood and urine tests performed before the experimental session within normal limits. Minor or occasional variations of these limits will be allowed if, in the opinion of the Principal Investigator and taking into account the state of science, they have no clinical significance, do not pose a risk to the subject and do not interfere in the product evaluation. These variations and their non-relevance will be specifically justified in writing. Body mass index (weight/height^2) between 19 and 27 kg/m2 and weight between 50 and 100 kg. BMI of 27-28 kg/m2 may be included according to Principal Investigator's criteria. Exclusion Criteria: Failure to meet inclusion criteria. History of allergy, idiosyncrasy, hypersensitivity or adverse reactions to glucocorticoids or any of the excipients. Serious adverse reactions to any drug. Contraindications to treatment with study drugs (according to the respective summary of product characteristics, SmPC). Clinical background or evidence of gastrointestinal, hepatic, renal disorder or others that may involve an alteration of the absorption, distribution, metabolism or excretion of the drug. Clinical background or evidence of psychiatric disorders, alcoholism, drug abuse or habitual consumption of psychoactive drugs. Having participated in another clinical trial with medication in the three months prior to the start of the study. Having donated blood in the three months prior to the start of the study, in the event that blood extractions are made. Having suffered some organic disease or major surgery in the six months prior to the start of the study. Clinical background or evidence of cardiovascular, respiratory, renal, hepatic, endocrine, gastrointestinal, hematological, neurological, or other acute or chronic diseases that, in the opinion of the Principal Investigator or the collaborators designated by him/her, may pose a risk to the subjects or may interfere with the objectives of the study. Especially osteoporosis, hypertension, Cushing syndrome, diabetes mellitus, and viral infections such as herpes or varicella. Having taken medication regularly in the month prior to the study sessions -in case of glucocorticoids 3 months prior- with the exception of vitamins, herbal remedies or dietary supplements that, in the opinion of the Principal Investigator or the collaborators designated by him/her, may not pose a risk to the subjects or may not interfere with the objectives of the study. Treatment with a single dose of symptomatic medication in the week prior to the study sessions will not be a reason for exclusion if it is assumed that the drug has been completely eliminated on the day of the experimental session. Smokers of more than 20 cigarettes a day in the 3 months before the study. Consumption of more than 40 g of alcohol daily. Consumers of more than 5 coffees, teas, cola drinks, or other stimulant drinks or with xanthines daily in the 3 months prior to the study start. Being unable to understand the nature, consequences of the trial and the procedures that are asked to follow. Positive serology for hepatitis B, C or HIV.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-center, non-randomized, open-label clinical trial in healthy male volunteers. A single dose of DEX, MP and DEF, and multiple dose of DEX and MP will be administered to different subjects.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylprednisone single-dose<br>Subjects receive a single dose treatment. Urine samples will be collected until 5 days after administration in 10 fractions: 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration. Blood samples will be collected until 6 days after administration in 5 fractions: pre-administration and 24h, 48h, 72h and 120h post-administration. | Drug: Methylprednisone<br>* 12 mg of methylprednisone (3 pills of 4 mg each) administered orally in a single dose.<br>* Other names: Urbason®;|
| Experimental: Methylprednisone multiple-dose<br>Subjects receive a multiple dose treatment. Urine samples will be collected until 7 days after administration in 20 fractions. | Drug: Methylprednisone<br>* 12 mg of methylprednisone (3 pills of 4 mg each) administered orally every 24 hours during 3 days.<br>* Other names: Urbason®;|
| Experimental: Deflazacort single-dose<br>Subjects receive a single-dose treatment. Urine samples will be collected until 5 days after administration in 10 fractions: 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration. Blood samples will be collected until 6 days after administration in 5 fractions: pre-administration and 24h, 48h, 72h and 120h post-administration. | Drug: Deflazacort<br>* 30 mg of deflazacort (1 pill) administered orally in a single dose.<br>|
| Experimental: Dexamethasone single-dose<br>Subjects receive a single-dose treatment. Urine samples will be collected until 13 days after administration in 11 fractions: 0-4h, 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h, 120-144h post-administration. Blood samples will be collected until 9 days after administration in 6 fractions: pre-administration and 24h, 48h, 72h, 120h and 192h post-administration. | Drug: Dexamethasone<br>* 4 mg of dexamethasone (1 pill) administered orally in a single dose.<br>|
| Experimental: Dexamethasone multiple-dose<br>Subjects receive a multiple dose treatment. Urine samples will be collected until 10 days after administration in 34 fractions. Blood samples will be collected until 13 days after the first administration. | Drug: Dexamethasone<br>* 2 mg of dexamethasone (1/2 pill) administered orally every 12 hours during 5 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine concentration of methylprednisone | Concentration of methylprednisone in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration | 
| Urine concentration of methylprednisone metabolites | Concentration of methylprednisone metabolites in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration | 
| Urine concentrations of deflazacort | Concentration of deflazacort in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration | 
| Urine concentrations of deflazacort metabolites | Concentration of deflazacort metabolites in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h post-administration | 
| Urine concentration of dexamethasone | Concentration of dexamethasone in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h, 120-144h post-administration | 
| Urine concentration of dexamethasone metabolites | Concentration of dexamethasone metabolites in each fraction of urine samples | 0-4h (hours), 4-8h, 8-12h, 12-24h, 24-36h, 36-48h, 48-72h, 72-96h, 96-120h, 120-144h post-administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of drug metabolites | Concentrations of drug metabolites (DEX, MP, DEF) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of cortisol | Concentrations of cortisol in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of endogen steroids | Concentrations of endogen steroids in plasma [testosterone (T), epitestosterone (E), androsterone (A), etiocholanolone (Etio), 5α-androstane-3α,17β-diol (5aAdiol), 5β-androstane-3α,17β-diol (5bAdiol), and the quotients T/E, A/T, A/Etio, 5aAdiol/5bAdiol and 5aAdiol/ET] | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of testosterone | Concentrations of testosterone in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of epitestosterone | Concentrations of epitestosterone in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of androsterone | Concentrations of androsterone in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of etiocholanolone | Concentrations of etiocholanolone (Etio) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of 5α-androstane-3α,17β-diol | Concentrations of 5α-androstane-3α,17β-diol (5aAdiol) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Plasma concentrations of 5β-androstane-3α,17β-diol | Concentrations of 5β-androstane-3α,17β-diol (5bAdiol) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Quotient testosterone/epitestosterone in plasma | Concentrations of testosterone/epitestosterone (T/E) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Quotient androsterone/testosterone in plasma | Concentrations of androsterone/testosterone (A/T) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Quotient androsterone/Etio in plasma | Concentrations of androsterone/etiocholanolone (A/Etio) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Quotient 5aAdiol/5bAdiol in plasma | Concentrations of 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol (5aAdiol/5bAdiol) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Quotient 5aAdiol/ET in plasma | Concentrations of 5α-androstane-3α,17β-diol/etiocholanolone (5aAdiol/ET) in plasma | Before drug administration and at 0.5h (hours), 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 24h, 48h, 72h, 120h, 192h post-administration | 
| Hemoglobin concentration | Variation of hemoglobin concentrations in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Hematocrit | Variation of hematocrit value in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Mean corpuscular hemoglobin | Variation of mean corpuscular hemoglobin (MCH) levels in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Mean corpuscular volume of erythrocytes | Variation of mean corpuscular volume of erythrocytes (MCV) levels in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Erythrocytes count | Variation of erythrocytes count in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Standard deviation of the range of distribution of erythrocytes | Variation of standard deviation of the range of distribution of erythrocytes | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Platelet count | Variation of platelet count in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Reticulocyte count | Variation of reticulocyte count in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 
| Fraction of immature reticulocytes | Variation of immature reticulocytes fraction in blood | At -72h (hours), -48h, -24h (before first administration), and at 0h, 1h, 3h, 6h after each dose (in multiple-dose treatments) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-doping control, Glucocorticoids, Corticosteroids, Dexamethasone, Methylprednisolone, Deflazacort