HealthyPhase 1NCT02574754
Assessment of 2012 Bioequivalence Standards for Warfarin
A Phase 1 study testing warfarin in people with Healthy, run by University of California, San Francisco at 1 site in United States.
Trial summary
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to assess the 2012 bioequivalence statistical criteria for warfarin, a narrow therapeutic index drug, set forth in the draft guidance issued by the Food and Drug Administration (FDA). Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- warfarin
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- May 2016to Feb 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California, San Francisco
San Francisco, California, 94143
About this study
Official title: 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).
Read the detailed description
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.
- Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations?
- Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin?
- Provide a comparison of the within-subject variance for the 2.5 ratio comparison.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
warfarinDrug
Also called Coumadin, Jantoven
warfarin 10 mg PO x 1
| Study group | Role | What they receive |
|---|---|---|
| warfarin | Experimental | 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. Receives: Drug: warfarin |
What is being measured
The primary outcome is the main question the study is designed to answer.
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-Time Curve (AUC) from 0 to 72 hours
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.
Measured: 0 to 72 hours after warfarin dosing
Secondary outcomes (2)
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) from time zero to infinity hours
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.
Measured: 0 to 8 weeks after warfarin dosing
Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin
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.
Measured: 0 to 72 hours after warfarin dosing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Oct 2015 (estimated)
- Study startMay 2016
- Primary completionFeb 2019
- Study completionFeb 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Leslie Z Benet, PhD, Principal investigator, University of California, San FranciscoLynda A Frassetto, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02574754
- Sponsor's protocol ID
- 15-17226
- Status last verified
- Aug 2019
- First submitted
- 9 Sep 2015
- Last updated
- 5 Aug 2019
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 5 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Assessment of 2012 Bioequivalence Standards for Narrow Therapeutic Index Drugs: a Study With Warfarin
- ClinicalTrials.gov ID
- NCT02574754
- Acronym / sponsor ID
- 15-17226
- Conditions
- Healthy
- Keywords
- warfarin, pharmacokinetics, bioequivalence, healthy volunteer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Study start
- May 2016
- Primary completion
- Feb 2019 (actual)
- Study completion
- Feb 2019 (actual)
- First posted
- 14 Oct 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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.
- Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations?
- Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin?
- Provide a comparison of the within-subject variance for the 2.5 ratio comparison.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| warfarin | Experimental | Drug: warfarinSubjects 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. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| warfarinAlso: Coumadin, Jantovenwarfarin 10 mg PO x 1 | Drug | warfarin |
Primary outcome
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-Time Curve (AUC) from 0 to 72 hours
Time frame: 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.
2 secondary outcomes
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-time Curve (AUC) from time zero to infinity hours
Time frame: 0 to 8 weeks after warfarin dosing
Maximum Plasma Concentration (Cmax) of S-warfarin and R-warfarin
Time frame: 0 to 72 hours after warfarin dosing
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Aug 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Leslie Z Benet, PhD principal investigator
University of California, San Francisco
Lynda A Frassetto, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing warfarin in people with Healthy, run by University of California, San Francisco at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
S- and R- enantiomers of warfarin (S-warfarin, R-warfarin) Area Under the Plasma Concentration-Time Curve (AUC) from 0 to 72 hours (time frame: 0 to 72 hours after warfarin dosing). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Aug 2019.