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Effect of Multiple BI 1356 Doses of on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Healthy Female Premenopausal Subjects

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02175394
Recruitment Status : Completed
First Posted : June 26, 2014
Last Update Posted : July 8, 2014
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
The objective was to investigate the effect of multiple oral doses of 5 mg BI 1356 on the steady-state pharmacokinetics of ethinylestradiol (EE) and levonorgestrel (LNG), the components of Microgynon®

Condition or disease Intervention/treatment Phase
Healthy Drug: Microgynon® Drug: BI 1356 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open, Two-period, Fixed-sequence, Phase I Trial to Evaluate the Effect of Multiple Doses of BI 1356 on the Multiple-dose Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel
Study Start Date : July 2008
Actual Primary Completion Date : October 2008

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: Microgynon®
Microgynon® once daily during period 1 (day 1 to day 14)
Drug: Microgynon®
Experimental: Microgynon® and BI 1356
Microgynon® combined with BI 1356, once daily during period 2 (day 15 to day 21)
Drug: Microgynon®
Drug: BI 1356

Primary Outcome Measures :
  1. Area under the concentration-time curve of ethinylestradiol and levonogestrel (Microgynon®) in plasma over the dosing interval at steady-state (AUCτ,ss) [ Time Frame: On day 14 and on day 21 ]
  2. Maximum measured concentration of ethinylestradiol and levonogestrel (Microgynon®) in plasma at steady state (Cmax,ss) [ Time Frame: On day 14 and on day 21 ]

Secondary Outcome Measures :
  1. Time from last dosing to the maximum measured concentration of EE and LNG in plasma at steady state (tmax,ss) [ Time Frame: Up to day 22 after start of treatment ]
  2. Apparent clearance of EE and LNG in plasma following extravascular administration at steady state (CL/F,ss) [ Time Frame: Up to day 22 after start of treatment ]
  3. Apparent volume of distribution of EE and LNG during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) [ Time Frame: Up to day 22 after start of treatment ]
  4. Terminal half-life of EE and LNG in plasma at steady state (t1/2,ss) [ Time Frame: Up to day 22 after start of treatment ]
  5. Terminal rate constant of EE and LNG in plasma at steady state (λz,ss) [ Time Frame: Up to day 22 after start of treatment ]
  6. Mean residence time of EE and LNG in the body at steady state after oral administration (MRTpo,ss) [ Time Frame: Up to day 22 after start of treatment ]
  7. Pre-dose plasma concentrations of EE and LNG for attainment of steady state [ Time Frame: Up to day 21 after start of Microgynon® treatment ]
  8. Pre-dose plasma concentration of BI 1356 for attainment of steady state [ Time Frame: Day 15 up to 7 days after start of BI 1356 treatment (day 21) ]
  9. Plasma concentration of BI 1356 [ Time Frame: Day 21 ]
  10. Number of patients with adverse events [ Time Frame: Up to 14 weeks ]
  11. Number of patients with clinically relevant changes in vital signs (BP, HR) [ Time Frame: Up to 14 weeks ]
  12. Number of patients with clinical relevant changes in laboratory evaluation (haematology, clinical chemistry and urinalysis) [ Time Frame: Up to 14 weeks ]
  13. Number of patients with clinically relevant changes in ECG recordings [ Time Frame: Up to 14 weeks ]
  14. Assessment of global tolerability by the investigator, a 4-point scale [ Time Frame: Up to day 14 after last administration of study drug on day 21 ]

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy premenopausal female subjects as determined by the results of screening based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), heart rate (HR)), 12-lead electrocardiogram (ECG), clinical laboratory tests
  • Age 18 - 40 years
  • BMI 18.5 - 27 kg/m2 (Body Mass Index)
  • Signed and dated written informed consent prior to admission to the study in accordance with Good Clinical Practice (GCP) and the local legislation
  • Gynaecological examination without relevant findings

Exclusion Criteria:

  • Any finding of the medical examination deviating from normal and of clinical relevance. Systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg
  • Any evidence of a clinically relevant concomitant disease
  • Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
  • Surgery of the gastrointestinal tract (except appendectomy)
  • Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
  • History of relevant orthostatic hypotension, fainting spells or blackouts
  • Chronic or relevant acute infections
  • History of relevant allergy or hypersensitivity (including allergy to drug or its excipients)
  • Intake of drugs with a long half-life (greater than 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to day 1 or during the trial
  • Use of antibiotics and drugs known to inhibit or induce cytochrome P450 enzymes, especially CYP3A4, within one month prior to study day 1 or during the trial (CYP3A4 inhibitors are for example azole antimycotics, macrolides, CYP3A inducers are for example St. John's Wort or certain anticonvulsants)
  • Participation in another trial with an investigational drug within two months prior to day 1 or during the trial
  • Regular smokers of more than two cigarettes daily
  • Drug or alcohol abuse (more than 20 g alcohol/day)
  • Blood donation (more than 100 mL within four weeks prior to day 1)
  • Excessive physical activities within 48 hours prior to day 1)
  • Any laboratory value outside the reference range that is of clinical relevance
  • Inability to comply with dietary regimen of trial site
  • Positive pregnancy test, pregnancy or planning to become pregnant within 2 months of study completion, or lactation
  • No use of an additional contraceptive method until 6 weeks after last study drug administration, i.e. barrier method, sexual abstinence, non-hormone-containing intrauterine device (IUD), surgical sterilisation (incl. hysterectomy) or vasectomized partner
  • Use of oral contraceptive-containing intrauterine device, depot injection or contraceptive implants
  • Existing or a history of confirmed venous thromboembolism (VTE), family history of idiopathic VTE and other known risk factors for VTE. Existing or previous arterial thrombotic or embolic processes, conditions which predispose to them e.g. disorders of the clotting processes, valvular heart disease and atrial fibrillation
  • Relevant varicosis
  • History of migraine
  • History of liver disease, i.e. disturbances of liver function, jaundice or persistent itching during a previous pregnancy, Dubin-Johnson syndrome, Rotor syndrome, previous or existing liver tumours
  • Clinically relevant cycle anomalies and dysmenorrhoea within the last 12 months
  • Usual menstrual cycle duration outside of a 26-32 days range
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Responsible Party: Boehringer Ingelheim Identifier: NCT02175394    
Other Study ID Numbers: 1218.44
First Posted: June 26, 2014    Key Record Dates
Last Update Posted: July 8, 2014
Last Verified: July 2014
Additional relevant MeSH terms:
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Ethinyl estradiol, levonorgestrel drug combination
Ethinyl Estradiol-Norgestrel Combination
Hypoglycemic Agents
Physiological Effects of Drugs
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Contraceptives, Oral, Synthetic
Contraceptives, Postcoital, Synthetic
Contraceptives, Postcoital