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Assessment of 2012 Bioequivalence Standards for Warfarin

1. august 2019 oppdatert av: University of California, San Francisco

Assessment of 2012 Bioequivalence Standards for Narrow Therapeutic Index Drugs: a Study With Warfarin

The purpose of this study is to assess the 2012 bioequivalence statistical criteria for warfarin, a narrow therapeutic index drug, set forth in the draft guidance issued by the Food and Drug Administration (FDA).

Studieoversikt

Status

Fullført

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

This study is a reasonable starting point to assess the appropriateness of the 2012 FDA bioequivalence (BE) statistical criteria for narrow therapeutic index drugs (NTIDs). The idea stems from an earlier study conducted in Dr. Benet's lab with the drug furosemide. The furosemide study yielded triplicate data that were unable to purely meet the BE statistical criteria set forth by the FDA due to the inherent study design. Furosemide is not an NTID to be considered by the FDA for BE studies, however. Hence, the investigators have proposed a new study to assess the BE statistical criteria with warfarin, an NTID with a draft guidance issued by the FDA. By providing the reference product (brand name warfarin) three times to each study participant and recording the relevant pharmacokinetic parameters for BE (AUC and Cmax), the investigators can make three comparisons between the data (R1 and R2 vs. R2 and R3; R1 and R2 vs. R1 and R¬3; R2 and R3 vs. R1 and R3).

The investigators have three concerns that can be tested here.

  1. Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations?
  2. Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin?
  3. Provide a comparison of the within-subject variance for the 2.5 ratio comparison.

Studietype

Intervensjonell

Registrering (Faktiske)

10

Fase

  • Fase 1

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • California
      • San Francisco, California, Forente stater, 94143
        • University of California, San Francisco

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 60 år (Voksen)

Tar imot friske frivillige

Ja

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

Inclusion Criteria:

  • Male or female aged 18-60 years
  • Healthy adult without active medical problems or chronic diseases based on medical history, physical exam, and laboratory results
  • BMI 18.5-32 kg/m2
  • Ceased all medications 2 weeks prior to start of study and during study enrollment (includes drugs of abuse, prescription medications, and over-the-counter (OTC) medications [exception: acetaminophen])
  • Maintain adequate birth control independent of hormonal contraceptive use throughout study
  • Provide written informed consent to take part in and comply with the requirements of the study
  • Speak, read, and understand English
  • Avoid alcohol, caffeine, and orange juice from 6pm the night before the study day until the completion of the study day
  • Avoid contact sports and/or other activities with significant risk of trauma injury for 7 days after each study day
  • Do not eat food or consume beverages at least 8 hours before medication dosing
  • Present with wild type VKORC1, VKORC-1639G>A and wild type CYP2C9 genotype

Exclusion Criteria:

  • Subjects on prescription or chronic OTC medications (including hormonal contraceptives)
  • Subjects with known allergy to warfarin
  • Subjects with a history of or diagnosis of hemorrhagic tendencies or blood dyscrasias
  • Subjects with liver failure or liver function tests (LFTs) > 2x upper limit normal
  • Subjects with clinically significant elevations of international normalized ratio (INR), prothrombin time (PT), partial thromboplastin time (PTT), serum creatinine (Scr), blood urea nitrogen (BUN), or other screening laboratory tests as determined by study physician
  • Subjects with hematocrit (Hct) < 30 mg/dL
  • Subjects with history of GI bleed or peptic ulcer disease
  • Subjects with recent history of trauma
  • Subjects with recent history of or upcoming plan for surgery
  • Subjects who smoke tobacco
  • Subjects with ongoing alcohol use
  • Subjects with ongoing illegal drug use
  • Subjects who are pregnant, attempting to become pregnant, or lactating
  • Subjects who are unable to maintain adequate birth control during the study
  • Subjects who are unable to follow protocol instructions or criteria
  • Subjects with genotypes that are not wild type VKORC1, VKORC-1639G>A and wild type CYP2C9

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Grunnvitenskap
  • Tildeling: N/A
  • Intervensjonsmodell: Enkeltgruppeoppdrag
  • Masking: Ingen (Open Label)

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: warfarin
Subjects will receive a single dose of warfarin 10 mg PO at each of 3 visits. The study days will be separated by at least 14 days to allow adequate time for the drug to reach washout.
Legemiddel: warfarin
warfarin 10 mg PO x 1
Andre navn:
  • Coumadin
  • Jantoven

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-Time Curve (AUC) from 0 to 72 hours
Tidsramme: 0 to 72 hours after warfarin dosing
The primary outcome measure will be warfarin area-under-the-concentration-time curve (AUC) values from zero to seventy-two (0-72) hours. Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations. Blood collection at 0, 1, 2, 3, 4, 6, 8, 12 hours after warfarin dosing.
0 to 72 hours after warfarin dosing

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) from time zero to infinity hours
Tidsramme: 0 to 8 weeks after warfarin dosing
A secondary outcome measure will be warfarin area-under-the-concentration-time curve (AUC) values from zero to infinite time (0-inf) where infinite time represents the duration of the study (8 weeks). Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations. Analysis of all concentration-time data; blood collection at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours after warfarin dosing.
0 to 8 weeks after warfarin dosing
Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin
Tidsramme: 0 to 72 hours after warfarin dosing
A secondary outcome measure will be maximum plasma concentration (Cmax). Values from the Experimental Arm (warfarin) of each the 3 study periods will be compared against each other and analyzed for intra-individual variability and tested for bioequivalence using the new narrow therapeutic index drug (NTID) regulations. Blood collection 0, 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after warfarin dosing.
0 to 72 hours after warfarin dosing

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

University of California, San Francisco

Etterforskere

  • Hovedetterforsker: Leslie Z Benet, PhD, University of California, San Francisco
  • Hovedetterforsker: Lynda A Frassetto, MD, University of California, San Francisco

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart

1. mai 2016

Primær fullføring (Faktiske)

1. februar 2019

Studiet fullført (Faktiske)

1. februar 2019

Datoer for studieregistrering

Først innsendt

9. september 2015

Først innsendt som oppfylte QC-kriteriene

9. oktober 2015

Først lagt ut (Anslag)

14. oktober 2015

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

5. august 2019

Siste oppdatering sendt inn som oppfylte QC-kriteriene

1. august 2019

Sist bekreftet

1. august 2019

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 15-17226

Denne informasjonen ble hentet direkte fra nettstedet clinicaltrials.gov uten noen endringer. Hvis du har noen forespørsler om å endre, fjerne eller oppdatere studiedetaljene dine, vennligst kontakt register@clinicaltrials.gov. Så snart en endring er implementert på clinicaltrials.gov, vil denne også bli oppdatert automatisk på nettstedet vårt. .

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