Trial document





This trial has been registered retrospectively.
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  DRKS00000785

Trial Description

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Title

A randomised, two-period cross-over study on the bioequivalence of two different formulations of single doses of dexamethasone (phase I/IV, open-label) in healthy volunteers (fasted state)

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

The study has already been terminated. It was conducted in order to gain data on pharmacodynamics (effect of a drug), pharmacokinetics (absorption, distribution, metabolism and excretion of a drug) and safety / tolerability of a liquid dexamethasone preparation compared to a tablet preparation after sequential single ingestion of a dose of 2 mg of dexamethasone. The active ingredient dexamethasone is a registered compound and is being used internationally. The effect of dexamethasone is similar to that of cortisone (a hormone that is produced by the human body). This study is required for the registration and release of the liquid dexamethasone product; liquid drug products are especially important for the treatment of children. The study consisted of two periods which were conducted in the same way, with the only difference being the order of study treatments (application of first the tablet and then the liquid or the other way round). In both periods the volunteers ingested a single dose of the respective study drug in the morning (either 5 ml of liquid or 1 tablet)

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Brief Summary in Scientific Language

Objectives The study is conducted
• to assess the bioequivalence of a marketed liquid dexamethasone preparation (Dexsol = InfectoDex) intended for pediatric use relative to a marketed solid reference preparation (Dexamethasone Tablets BP 500 micrograms)
• to provide limited data on safety of respective preparations
Clinical Phase
Phase I/IV
Sample Size
In a previous study with this liquid preparation, the point estimates µTest/µReference were 1.01 for AUC and 1.22 for Cmax, respective intraindividual CVs were 11.6 % for AUC and 11.7 % for Cmax.
Based on the broad therapeutic range of dexamethasone for single doses, the individual adjustment of dosing for repeated doses based on individual effects, the lack of relevant immediate effects of the drug, and the dependence of effects on overall exposure (AUC) rather than on peak concentrations, widening of the acceptance range for Cmax to 0.75-1.33 is justified.
A sample size of n=24 is expected to allow rejection of the null hypotheses "lack of bioequivalence between TEST and REFERENCE treatments" with alpha = 0.05 and a power of at least 80% for AUC (and Cmax) if the true ratio µtest/µreference is in the 0.87 to 1.14 (0.82 to 1.22) range and intraindividual CV does not exceed 11.6 (11.7) %.
Design and Trial Medications • Statistical design: two-period cross-over study evaluating two single dose treatments:
TEST preparation: single oral dose of InfectoDex 5.0 ml (containing 2 mg of dexamethasone) manufactured by Rosemont Pharmaceuticals Ltd., Batch # 010296
REFERENCE preparation: single oral dose of 4 tablets Dexamethasone Tablets BP 500 micrograms (containing 2 mg of dexamethasone) manufactured by Organon Laboratories Limited, Batch # 301 451
• 24 individuals are included who receive the preparations in randomly allocated sequences: T-R or R-T
(12 subjects per sequence).
• wash-out interval: 7-21 days
• Blinding: open
Study Scheme & Methods Visits:
• Pre-study recruitment screen: 2-14 days before the first trial period
• Active trial periods: subjects are hospitalised 10 hours before until 24 hours after dosing in each of the study periods
• End-of-study evaluation: within 4 -14 days after dosing in the last study period
Investigations on recruitment and at the end-of-study evaluation
• Medical history / medical history update
• Physical examination, including body weight and height, supine blood pressure and pulse rate, body temperature
• 12-lead standard ECG
• Routine laboratory screen: haematology, clinical chemistry; urinalysis
• Blood analysis for serology of hepatitis B, hepatitis C and HIV (at recruitment only)
• Urine analysis for substances of abuse, ethanol breath test (at recruitment only)
• For female subjects only: pregnancy test
• Determination of adverse events (at the end-of-study evaluation)
Investigations on pharmacokinetic profiling visits
• For pharmacokinetic profiling, the subjects fast at least 10:00h before until 6:00h after dexamethasone dose. They take up a relaxed supine position and refrain from intake of fluids other than that provided by the study personnel from at least 1:00 h before until at least 6:00 h after dosing.
• Drug administration is carried out in sitting position. Administration of the liquid preparation is checked by weighing.
• Blood sampling for determination of dexamethasone concentrations in each period is carried out 5 min prior to dosing and 0:15, 0:30, 0:45, 1, 1:15, 1:30, 1:45, 2, 2:30, 3, 4, 5, 6, 8, 12, 16 and 24 hours postdose (18 samples); for each sample, 9 ml will be withdrawn.
• Body temperature is measured 9 hours prior to dosing.
• Ethanol breath test
• For female subjects only: pregnancy test
• Blood pressure and pulse rate by oscillometric method are measured predose and 0:55, 1:55, 2:55, 3:55, 4:55, 5:55, 7:55, 11:55, 15:55 and 23:55 hours postdose
• Adverse events are surveyed throughout the study by non-leading questions asked 8h prior to dosing and with each blood pressure control
• Medical history is updated each visit
• Plasma cortisol concentrations are quantified -24 h, -16 h,
-8h, 0h, 8h, 16h and 24 h relative to dosing; for each sample, 4.7 ml will be withdrawn.
Diagnosis young healthy male and female Caucasian non-smokers
Inclusion criteria • Caucasian
• age: 18-55 years
• body weight of 60 kg or higher, Body Mass Index 19 – 27 kg/m2
• considered to be healthy on the basis of extensive pre-study screening
• willing and capable to confirm written consent to enrolment after sample information has been provided
Exclusion criteria • standard criteria plus specific criteria according to dexamethasone safety as outlined in the study protocol
Duration of treatment • The study consists of 2 study periods, separated by wash-out phases of 7 - 21 days, when the subject each time receives dexamethasone as a single dose, respectively
• Each period consists of detailed investigations from the day prior to medication up to 24:00 hours after the dose
• For each study period, the subjects are hospitalised from 10 hours prior to the dose until 24:00 hours thereafter.
• The pre-study recruitment investigation takes place within 2-14 days before the first trial period; the end-of-study evaluation takes place within 4-14 days after the last study period.
Main
characteristics • Main pharmacokinetic parameters of dexamethasone:
AUC0-t, Cmax
Further characteristics • Additional pharmacokinetic parameters of dexamethasone: AUC0-∞, tmax, MRT-∞, t½ lambda z (apparent terminal elimination half-life)
• pharmacodynamic parameters of dexamethasone: cortisol plasma concentrations, including predose/postdose changes of individual concentrations and of AUEC
• Safety and Tolerability:
 Medical history, adverse events and well-being
 Laboratory screen (haematology, clinical chemistry and urinalysis)
 Physical examination
 Vital functions: blood pressure, pulse rate, body temperature
 12-lead ECG
Statistics  Primary (confirmative) comparison: standard bioavailability testing TEST vs. REFERENCE for main characteristics, using the acceptance ranges of 0.8-1.25 for AUC and of 0.75-1.33 for Cmax
 Secondary (descriptive) comparisons: standard bioavailability testing TEST vs. REFERENCE for further pharmacokinetic and for pharmacodynamic characteristics
 Descriptive statistics for all other characteristics
Anticipated study duration 2 months

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Organizational Data

  •   DRKS00000785
  •   2011/04/06
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  •   no
  •   Approved
  •   08-059, Ethik-Kommission der Medizinischen Fakultät der Universität zu Köln
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Secondary IDs

  •   U1111-1120-3351 
  •   2008-001389-10 
  •   4034028 
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Health Condition or Problem studied

  •   Not applicable; the study participants were healthy volunteers
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Interventions/Observational Groups

  •   TEST treatment: administration of a single oral dose of "InfectoDex" 5.0 ml (containing approx. 2 mg of dexamethasone)
  •   REFERENCE treatment: administration of a single oral dose of 1 tablet "Dexamethasone Tablets B.P. 2.0 mg" (containing 2 mg of dexamethasone)
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control
  •   Treatment
  •   Crossover
  •   I
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Primary Outcome

Main pharmacokinetic parameters of dexamethasone for the assessment of bioequivalence: AUC0-t, Cmax (for assessment of bioequivalence after blood sampling / concentration measurement in the 24 volunteers). Blood sampling for determination of dexamethasone concentrations in each period was carried out approx. 5 min prior to dosing and 0:15, 0:30, 0:45, 1, 1:15, 1:30, 1:45, 2, 2:30, 3, 4, 5, 6, 8, 12, 16 and 24 hours postdose (18 samples); for each sample, 9 ml were withdrawn. Plasma concentrations of dexamethasone were determined using a specific and sensitive HPLC method.

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Secondary Outcome

• Additional pharmacokinetic parameters of dexamethasone: AUC0-∞, tmax, MRT-∞, t½ lambda z (apparent terminal elimination half-life). Blood sampling for determination of dexamethasone concentrations in each period was carried out approx. 5 min prior to dosing and 0:15, 0:30, 0:45, 1, 1:15, 1:30, 1:45, 2, 2:30, 3, 4, 5, 6, 8, 12, 16 and 24 hours postdose (18 samples); for each sample, 9 ml were withdrawn. Plasma concentrations of dexamethasone were determined using a specific and sensitive HPLC method.
• pharmacodynamic parameters of dexamethasone: cortisol plasma concentrations, including predose/postdose changes of individual concentrations and of AUEC. Blood sampling for determination of endogenous cortisol concentrations in each period was carried out -24 h, -16 h,
-8h, 0h, 8h, 16h and 24 h (relative to dosing; for each sample, 4.7 ml were withdrawn).
For measurement of endogenous cortisol, a specific and validated clinical laboratory routine method (University Hospital Cologne, Germany) was used.
• Safety and Tolerability:
 Medical history, adverse events and well-being
 Laboratory screen (haematology, clinical chemistry and urinalysis)
 Physical examination
 Vital functions: blood pressure, pulse rate, body temperature
 12-lead ECG

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2008/06/10
  •   24
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   55   Years
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Additional Inclusion Criteria

• caucasian
• male / female
• age: 18-55 years
• body weight of 60 kg or higher, Body Mass Index 19 – 27 kg/m2
• considered to be healthy on the basis of extensive pre-study screening
• willing and capable to confirm written consent to enrolment after ample information has been provided

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Exclusion Criteria

• subjects with any skin abnormality and / or neurodermatitis and / or chronic skin disease
• subjects with a history of any severe gastrointestinal disease with potential sequelae, esp. ulcer, haemorrhage, diverticulitis, ulcerative colitis
• subjects with corneal damage / ulcer
• subjects with glaucoma
• subjects with osteoporosis
• subjects with poliomyelitis
• subjects who had been vaccinated or planned to be vaccinated with a live virus vaccination (8 weeks before until 2 weeks after administration of study drugs)
• subjects with history of psychiatric diseases
• subjects with history of epilepsy
• subject with history of pancreatitis
• subjects with history of cerebrovascular events
• subjects with history of pulmonary embolism
• subjects with history of venous thromboembolic events
• subjects with history of hypertension
• subjects with any relevant clinical abnormality (as based on extensive medical history, physical examination, vital signs and 12-lead ECG);
• subjects with bronchial asthma, COPD, or actual obstructive bronchitis;
• subjects with hypothyroidism /hyperthyroidism;
• subjects with chronic heart failure;
• subjects with previous myocardial infarction;
• subjects with liver disease;
• subjects with cardiac arrhythmia;
• subjects with diabetes mellitus;
• subjects with any systemic or chronic infections (bacterial, viral, fungal, parasites);
• subjects with history of latent infections, esp. tuberculosis
• subjects with any acute infection or with actual therapy-requiring allergies (including drug allergies) within the last two weeks;
• subjects with suspicion of hypersensitivity to dexamethasone or to any of the excipients of the study medications
• subjects with any clinically relevant laboratory abnormality. Clinically relevant laboratory abnormality is formally defined as follows:
 Serology for hepatitis and HIV: any positive result in the initial examination which is confirmed by a second examination;
 Urine screen for substances of abuse: any positive result in the initial examination which is confirmed by a second examination;
 Urinalysis (Combur 9®): any more than borderline positive result in the initial examination which is confirmed by a second examination (no limitations apply for pH);
 Hematocrit, haemoglobin, MCV, MCH, MCHC, erythrocyte count (RBC), total leukocyte count, platelet count, prothrombin time (Quick), activated partial thromboplastin time (aPTT), SGOT (ASAT), SGPT (ALAT), potassium, sodium, chloride, creatinine, glucose: any value more than 10% outside the respective reference range in the initial examination which is confirmed by a second examination;
 Gamma-GT, alkaline phosphatase, lactic dehydrogenase (LDH), total protein, albumin, urea, uric acid, creatine kinase (CK): any value more than 20% outside the respective reference range in the initial examination which is confirmed by a second examination;
 total bilirubin, total cholesterol, triglycerides, differential leukocyte count: any value more than 50 % outside the respective reference range in the initial examination which is confirmed by a second examination.
Exceptions are possible upon decision of the Principal Investigator (e.g. exclusion of a subject with a less than 10 % elevation above the reference range for Gamma-GT, SGOT and SGPT).
• subjects receiving any medication within 2 weeks prior to study start or during the study (exceptions possible upon decision of Principal Investigator, e.g. paracetamol (acetaminophen) single dose for acute pain or topical aciclovir for herpes simplex);
• subjects who have taken a drug with a long half-life (> 24 hours) within four weeks before the first trial day;
• subjects who received chronic drug treatment (> 3 days) within eight weeks before the first trial day;
• subjects who participated in a clinical trial within the last 3 months before the start of the present study;
• subjects who donated blood or plasma within the last 12 weeks before the start of the present study;
• subjects who smoke, i.e. subjects who smoked one or more cigarettes during the last six months;
• subjects who are known or suspected to be (social) drug dependent, incl. those drinking more than 30 g alcohol per day;
• subjects with a history of alcohol or recreational drug addiction;
• subjects with a history of any severe disease that might interfere with the study objectives (e.g. psychiatric disease, epilepsy);
• subjects who are not willing or able to abstain from alcohol, methylxanthine-containing beverages and foods, and grapefruit flesh / juice for 72 hours before until 24 hours after each study drug administration;
• subjects who adhere to a special diet (e.g. vegetarians) or lifestyle (incl. working at night and extreme physical activities such as competitive sports and weight lifting) that might interfere with the investigation;
• subjects planning elective hospital treatment within one month after last intake of trial medication;
• subjects who are known or suspected not to comply with the study directives and/or known or suspected not to be reliable or trustworthy;
• subjects who are known or suspected not to be capable of understanding and evaluating the information that is given to them as part of the formal information policy (informed consent), in particular regarding the foreseeable risks and discomfort to which they will be exposed;
• subjects with anticipated problems of successfully placing an indwelling venous catheter at a forearm;
• female subjects only: positive results in pregnancy test;
• female subjects only: lactating women;
• female subjects only: subjects who do not use or do not agree to use appropriate contraceptive methods during the study as defined in the Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (CHMP/ICH/286/95, modification).

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Addresses

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    • InfectoPharm Arzneimittel und Consilium GmbH
    • Von-Humboldt-Straße 1
    • 64646  Heppenheim
    • Germany
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    • Uniklinik Köln, Institut für Pharmakologie
    • Mr.  Dr. med.   Christian  Queckenberg 
    • Gleueler Str. 24
    • 50931  Köln
    • Germany
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    • Uniklinik Köln, Institut für Pharmakologie
    • Mr.  Dr. med.  Christian  Queckenberg 
    • Gleueler Str. 24
    • 50931  Köln
    • Germany
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Sources of Monetary or Material Support

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    • InfectoPharm Arzneimittel und Consilium GmbH
    • Von-Humboldt-Str. 1
    • 64646  Heppenheim
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2008/07/18
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.