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Single Dose Crossover Comparative Bioavailability Study of Two Formulations of Fluconazole 200 mg in Healthy Adult Subjects Under Fasting Conditions

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ClinicalTrials.gov Identifier: NCT04038008
Recruitment Status : Not yet recruiting
First Posted : July 30, 2019
Last Update Posted : July 30, 2019
Sponsor:
Collaborator:
Altasciences Company, Inc.
Information provided by (Responsible Party):
Pharmtechnology LLC

Brief Summary:
This single dose study is designed in accordance with EMA (the European Medicines Agency) regulatory guidelines, with the aim of characterizing the comparative bioavailability of fluconazole in the two formulations in healthy subjects. As this is a bioequivalence trial where each subject will receive each study treatment in a crossover fashion, a control group is not included. Within the clinical portion of the study each subject will receive a single oral dose of the test and the reference formulation in compliance with the generated randomization code. The primary study endpoints are the pharmacokinetic (PK) parameters Cmax and AUC0-t of fluconazole.

Condition or disease Intervention/treatment Phase
Bioequivalence Drug: Fluconazole Drug: Diflucan® Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Masking Description: The randomization code will not be available to the personnel of the bioanalytical facility until the bioanalytical tables have been finalized and audited by the Quality Assurance (QA) department.
Primary Purpose: Other
Official Title: Single Dose Crossover Comparative Bioavailability Study of Fluconazole 200 mg Tablets Versus Diflucan® 200 mg Hard Capsules in Healthy Adult Subjects Under Fasting Conditions
Estimated Study Start Date : July 2019
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Fluconazole

Arm Intervention/treatment
Sequence AB
13 subjects assigned to the sequence AB will receive a single 200 mg dose of test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 1 and a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.
Drug: Fluconazole
Fluconazole is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 200 mg of fluconazole.
Other Name: Test Product

Drug: Diflucan®
Diflucan® is manufactured by Fareva Amboise, France (MAH: PFIZER PHARMA PFE GmbH, Germany). Each hard capsule contains 200 mg of fluconazole.
Other Name: Reference Product

Sequence BA
13 subjects assigned to the sequence BA will receive a single 200 mg dose of reference product Diflucan® (1 x 200 mg hard capsule), marked as B in the sequence, in Period 1 and test product Fluconazole (1 x 200 mg tablet), marked as A in the sequence, in Period 2. These treatments will be administered orally with approximately 240 mL of water at ambient temperature, in the morning, following a minimum of 10-hour overnight fast. The tablet or hard capsule must be swallowed whole and must not be chewed or broken.
Drug: Fluconazole
Fluconazole is manufactured by Pharmtechnology LLC, Republic of Belarus. Each tablet contains 200 mg of fluconazole.
Other Name: Test Product

Drug: Diflucan®
Diflucan® is manufactured by Fareva Amboise, France (MAH: PFIZER PHARMA PFE GmbH, Germany). Each hard capsule contains 200 mg of fluconazole.
Other Name: Reference Product




Primary Outcome Measures :
  1. Maximum observed concentration (Cmax) of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Maximum observed concentration in plasma

  2. AUC0-T of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Cumulative area under the concentration time curve calculated from 0 to TLQC using the linear trapezoidal method, where TLQC represents time of last observed quantifiable concentration

  3. AUC0-72 of fluconazole in plasma after administration of the test and the reference products (in case if AUC0-T is less than 80% of AUC0-∞ in more than 20% of the observations, truncated AUC0-72 will be used as primary endpoint instead of AUC0-T) [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Cumulative area under the concentration time curve calculated from 0 to 72 hours using the linear trapezoidal method. Nominal time will be used to estimate AUC0-72 using the NCA built-in tool in Phoenix® WinNonlin®. Any actual time that deviates by more than 1 minute from the 72-hour time point will be extrapolated/intrapolated as per Phoenix® WinNonlin®'s built-in formulas.


Secondary Outcome Measures :
  1. Tmax of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Time of maximum observed concentration; if it occurs at more than one time point, Tmax is defined as the first time point with this value

  2. TLQC of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Time of last observed quantifiable concentration

  3. AUC0-∞ of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Area under the concentration time curve extrapolated to infinity, calculated as AUC0-t + ĈLQC (the predicted concentration at time TLQC) / λZ (apparent elimination rate constant)

  4. Residual area of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Extrapolated area (i.e. percentage of AUC0-INF due to extrapolation from TLQC to infinity)

  5. Time point where the log-linear elimination phase begins (TLIN) of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Time point where the log-linear elimination phase begins

  6. λZ of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Apparent elimination rate constant, estimated by linear regression of the terminal linear portion of the log concentration versus time curve

  7. Terminal elimination half-life (Thalf) of fluconazole in plasma after administration of the test and the reference products [ Time Frame: 0.00 (prior to each drug administration) and 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 12.00, 24.00, 48.00, 72.00, 96.00, 120.00 hours after each drug administration ]
    Terminal elimination half-life, calculated as ln(2)/λZ

  8. Number of treatment-emergent adverse events for the test and the reference products [ Time Frame: Up to 30 days (after the first drug administration until 3 days following the last blood sample of the study) ]
    The safety population will include all subjects who received at least one dose of the test or the reference product. Any significant changes will be recorded as treatment-emergent adverse events only if they are judged clinically significant by the qualified investigator or delegate.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Provision of signed and dated informed consent form (ICF)
  2. Stated willingness to comply with all study procedures and availability for the duration of the study
  3. Healthy Caucasian adult male or female
  4. If female, meets one of the following criteria:

    1. Is of childbearing potential and agrees to use one of the accepted contraceptive regimens from at least 28 days prior to the first study drug administration through to at least 30 days after the last dose of the study drug. An acceptable method of contraception includes one of the following:

      • Abstinence from heterosexual intercourse
      • Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
      • Intrauterine device (with or without hormones)
      • Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository)
      • Male partner vasectomized at least 6 months prior to the first study drug administration

      Or

    2. Male partner has had a vasectomy less than 6 months prior to dosing, and agrees to use an additional acceptable contraceptive method from the first study drug administration through to at least 30 days after the last dose of the study drug

      Or

    3. Is of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or is in a postmenopausal state (i.e. at least 1 year without menses without an alternative medical condition prior to the first study drug administration)
  5. Aged at least 18 years but not older than 55 years
  6. Body mass index (BMI) within 18.5 kg/m2 to 30.0 kg/m2, inclusively
  7. Non- or ex-smoker (An ex-smoker is defined as someone who completely stopped using nicotine products for at least 180 days prior to the first study drug administration)
  8. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be without clinical significance, as determined by an investigator
  9. Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an investigator

Exclusion Criteria:

  1. Female who is lactating at screening
  2. Female who is pregnant according to the pregnancy test at screening or prior to the first study drug administration
  3. History of significant hypersensitivity to fluconazole, any related azole compounds, or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs
  4. Presence or history of significant gastrointestinal, liver or kidney disease, or any other condition that is known to interfere with drug absorption, distribution, metabolism or excretion, or known to potentiate or predispose to undesired effects
  5. History of significant cardiovascular, pulmonary, hematologic, neurological, psychiatric, endocrine, immunologic or dermatologic disease
  6. Presence of clinically significant ECG abnormalities at the screening visit, as defined by medical judgment
  7. Seated blood pressure below 110/60 mmHg at the screening visit
  8. History of rare hereditary problems of galactose and/or lactose intolerance, lactase deficiency or glucose-galactose malabsorption
  9. Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic)
  10. Any clinically significant illness in the 28 days prior to the first study drug administration
  11. Use of any prescription drugs (with the exception of hormonal contraceptives or hormone replacement therapy) in the 28 days prior to the first study drug administration, that in the opinion of an investigator would put into question the status of the participant as healthy
  12. Any history of tuberculosis
  13. Positive test result for alcohol and/or drugs of abuse at screening or prior to the first drug administration
  14. Positive screening results to HIV Ag/Ab Combo, Hepatitis B surface Antigen (HBsAG (B) (hepatitis B)) or Hepatitis C Virus (HCV (C)) tests
  15. Inclusion in a previous group for this clinical study
  16. Intake of fluconazole in the 28 days prior to the first study drug administration
  17. Use of terfenadine, astemizole, erythromycin, quinidine, pimozide, or cisapride in the 7 days prior to the first study drug administration
  18. Intake of an Investigational Product (IP) in the 28 days prior to the first study drug administration
  19. Donation of 50 mL or more of blood in the 28 days prior to the first study drug administration
  20. Donation of 500 mL or more of blood (Canadian Blood Services, Hema-Quebec, clinical studies, etc.) in the 56 days prior to the first study drug administration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04038008


Contacts
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Contact: Elena Koren +375293034791 pharmasector@ft.by
Contact: Andrei Andrei Yaremchuk +375291268246 1268246@gmail.com

Locations
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Canada, Quebec
Altasciences Company Inc.
Mont-Royal, Quebec, Canada, H3P 3P1
Sponsors and Collaborators
Pharmtechnology LLC
Altasciences Company, Inc.
Investigators
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Principal Investigator: Eric Sicard, MD Altasciences Company, Inc.
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Responsible Party: Pharmtechnology LLC
ClinicalTrials.gov Identifier: NCT04038008    
Other Study ID Numbers: PTL-P3-438 (v. 1.0 2019/07/12)
First Posted: July 30, 2019    Key Record Dates
Last Update Posted: July 30, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Pharmtechnology LLC:
fluconazole
Diflucan®
bioequivalence
Additional relevant MeSH terms:
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Fluconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors