Study of the Excretion of Orally Administered Corticosteroids for the Improval of the Detection of Said Substances in Anti-doping Controls (DACORSIN/4)

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).

Study Overview

• Status: Recruiting
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Methylprednisone; Drug: Methylprednisone; Drug: Deflazacort; Drug: Dexamethasone; Drug: Dexamethasone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Rosa Ventura Alemany, PharmD, PhD; Phone Number: +34 933 160 471; Email: rventura@imim.es

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Recruiting
    • IMIM (Hospital del Mar Medical Research Institute)
    • Contact: Ana M Aldea Perona, MD, PhD; Phone Number: +34933160490; Email: aaldea@imim.es
    • Principal Investigator: Ana M Aldea Perona, MD, PhD
    • Principal Investigator: Rosa Ventura Alemany, PharmD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methylprednisone single-dose; 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; 12 mg of methylprednisone (3 pills of 4 mg each) administered orally in a single dose.; Other Names: Urbason®; Drug: Methylprednisone; 12 mg of methylprednisone (3 pills of 4 mg each) administered orally every 24 hours during 3 days.; Other Names: Urbason®
Experimental: Methylprednisone multiple-dose; Subjects receive a multiple dose treatment. Urine samples will be collected until 7 days after administration in 20 fractions.	Drug: Methylprednisone; 12 mg of methylprednisone (3 pills of 4 mg each) administered orally in a single dose.; Other Names: Urbason®; Drug: Methylprednisone; 12 mg of methylprednisone (3 pills of 4 mg each) administered orally every 24 hours during 3 days.; Other Names: Urbason®
Experimental: Deflazacort single-dose; 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; 30 mg of deflazacort (1 pill) administered orally in a single dose.
Experimental: Dexamethasone single-dose; 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; 4 mg of dexamethasone (1 pill) administered orally in a single dose.; Drug: Dexamethasone; 2 mg of dexamethasone (1/2 pill) administered orally every 12 hours during 5 days.
Experimental: Dexamethasone multiple-dose; 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; 4 mg of dexamethasone (1 pill) administered orally in a single dose.; Drug: Dexamethasone; 2 mg of dexamethasone (1/2 pill) administered orally every 12 hours during 5 days.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Parc de Salut Mar
• Investigators: Principal Investigator: Rosa Ventura Alemany, PharmD, PhD, IMIM (Hospital del Mar Medical Research Institute); Principal Investigator: Ana M Aldea Perona, MD, PhD, IMIM (Hospital del Mar Medical Research Institute)

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2021
• Primary Completion (Anticipated): February 26, 2022
• Study Completion (Anticipated): February 26, 2022

Study Registration Dates

• First Submitted: March 5, 2021
• First Submitted That Met QC Criteria: March 9, 2021
• First Posted (Actual): March 10, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2021
• Last Update Submitted That Met QC Criteria: March 31, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Dexamethasone; Glucocorticoids; Methylprednisolone; Corticosteroids; Anti-doping control; Deflazacort
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Neuroprotective Agents; Protective Agents; Dexamethasone; Dexamethasone acetate; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; BB 1101; Deflazacort
• Other Study ID Numbers: IMIMFTCL/DACORSIN/4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No