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BleedingPhase 1NCT03083704

A Healthy Volunteer PK/PD, Safety and Tolerability Study of Second Generation Andexanet Alfa

A Phase 1 study testing Andexanet alfa (Gen 1 Process 2), Apixaban 5 MG and Rivaroxaban 20 MG in people with Bleeding, run by Portola Pharmaceuticals at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This is a randomized, double-blind, study in healthy volunteers dosed to steady state with fXa inhibitors, designed to (1) demonstrate PK/PD comparability between andexanet manufactured by the Generation 1 and Generation 2 processes, (2) evaluate the degree to which the Generation 2 andexanet reverses… Read more about this study

Who is it for?
Ages 18 to 75 yearsHealthy volunteers can take part
Conditions the study is for
Bleeding
What is being tested?
Andexanet alfa (Gen 1 Process 2), Apixaban 5 MG and Rivaroxaban 20 MG
Could I receive a placebo?
No, everyone receives an active treatment
How many people
153 participants
Where
1 siteUnited States
Study dates
26 Feb 2017to 28 Sep 2017
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 75 years
  • All sexes
  • Healthy volunteers accepted
  • Adult, Older adult

Who may be able to join

  • Must be in reasonably good health as determined by the Investigator based on medical history, full physical examination (including blood pressure and pulse rate measurement), 12-lead ECG, and clinical laboratory tests. Subjects with well-controlled, chronic, stable conditions (e.g., controlled hypertension, non-insulin dependent diabetes, osteoarthritis, hypothyroidism) may be enrolled based on the clinical judgment of the Investigator and if approved by the Medical Monitor.
  • Must be between the ages of 18 and 75 years, inclusive, at the time of signing of the informed consent form (ICF).
  • Agrees to have any dietary or nutritional supplements reviewed by the Investigator and potentially be withheld during the study if advised by the Investigator. Standard multivitamin and mineral supplementation will be permitted.
  • Agrees to comply with the contraception and reproduction restrictions of the study:
  • Men whose sexual partner is of childbearing potential and/or who are not monogamous must be using two acceptable methods of contraception, at least one of which must be a barrier method (e.g., spermicidal gel plus condom), for the entire duration of the study and for at least 1 month following study-drug administration; and men must refrain from attempting to father a child or donating sperm in the 1 month following the study-drug administration. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception;
  • Men who report surgical sterilization (e.g., bilateral vasectomy) must have had the procedure at least 6 months before study drug administration.
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  • Surgical sterilization procedures should be supported with clinical documentation and noted in the Relevant Medical History/Current Medical Conditions section of the case report forms (CRFs).
  • Women of childbearing potential must be using two medically acceptable methods of contraception, at least one of which must be a barrier method (e.g., non-hormone containing intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom), from the time of Screening and for the duration of the study, through at least 1 month following study drug administration. NOTE: Oral and topical hormonal contraceptive use, as well as the use of hormone-containing intra-uterine devices, is not permitted due to their increased risk of thromboembolism. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; OR
  • Postmenopausal women must have had no regular menstrual bleeding for at least 1 year before initial dosing and either be over the age of 60 years or have an elevated plasma follicle-stimulating hormone (FSH) level (i.e., > 40 mIU/mL) at Screening; OR
  • Women who report surgical sterilization (i.e., hysterectomy, tubal ligation, and/or bilateral oophorectomy) must have had the procedure at least 6 months before study drug administration. Surgical sterilization procedures should be supported with clinical documentation and noted in the Relevant Medical History/Current Medical Conditions section of the CRF; AND
  • All female subjects must have a documented negative pregnancy test result at Screening and on Study Day 1.
  • Systolic blood pressure < 160 mmHg and diastolic blood pressure < 90 mmHg at Screening and Day 1.
  • The following laboratory values must be within the normal laboratory reference range within 28 days of Day 1: prothrombin time (PT), activated partial thromboplastin time (aPTT), and activated clotting time (ACT); hemoglobin, hematocrit, and platelet count.
  • The following laboratory values must be equal to or below 2 times the upper limit of normal (ULN) range within 28 days of Day 1: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and total bilirubin.
  • The Screening serum creatinine must be below 1.5 mg/dL within 28 days of Day 1.
  • Body mass index between 19-30 kg/m2, inclusive, and body weight at least 50 kg.
  • Agrees to abstain from alcohol consumption for the duration of the domicile period, and from the use of drugs of abuse for the duration of the study.
  • Able to read and give written informed consent and has signed a consent form approved by the Investigator's Institutional Review Board (IRB) or Independent Ethics Committee (IEC).

Who cannot join

  • Previous use of andexanet or previous participation in the current study.
  • History of abnormal bleeding, signs or symptoms of active bleeding, or risk factors for bleeding.
  • Has a stool specimen that was positive for occult blood within 6 months of study Screening or during the Screening Period.
  • Past or current medical history of thrombosis, any sign or symptom that suggests an increased risk of a systemic thrombotic condition or thrombotic event, or recent events that may increase risk of thrombosis.
  • For example, subjects with a known or suspected hypercoagulable state, history of VTE, DVT, stroke, myocardial infarction [MI], cancer [other than non-melanoma skin cancer], atrial fibrillation, heart failure, cardiomyopathy, phlebitis, lower extremity edema, major surgery or trauma within 2 months of Study Day 1, airplane travel ≥ 2 hours during the 4 weeks prior to Study Day 1, or general immobility are excluded.
  • Absolute or relative contraindication to anticoagulation or treatment with apixaban, rivaroxaban, enoxaparin, or edoxaban.
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  • Prior consumption of (by any route) one or more doses of aspirin (including baby aspirin), salicylate or subsalicylate, other antiplatelet drugs (e.g., ticlopidine, clopidogrel), non-steroidal anti-inflammatory drugs, fibrinolytic, or any anticoagulant within 7 days prior to Day 1 or is anticipated to require such drugs during the study.
  • Receipt of (by any route) hormonal contraception, post-menopausal hormone replacement therapy (HRT) (including over-the-counter products), or testosterone during the 4 weeks prior to Study Day 1 or is anticipated to require such drugs during the study.
  • Family history of or risk factors for a hypercoagulable or thrombotic condition, including one of the following:
  • Factor V Leiden carrier or homozygote.
  • Protein C, S, or ATIII activity below the normal range.
  • History of adult asthma or chronic obstructive pulmonary disease or current regular or as-needed use of inhaled medications.
  • Active HBV, HCV, or HIV-1/2 infection
  • Use of any drugs that are strong dual inhibitors or inducers of CYP3A4 and P-gp within 7 days prior to Study Day 1 or anticipated need for such drugs during the study.
  • Participation in an investigational drug study within 28 days of Day 1 or Day 1 is within 5 half-lives of the investigational compound.
  • Positive screen for drugs of abuse at Day 1 that is not explained by a prescription medication that the subject is known to be taking.
  • A medical or surgical condition that may impair drug (fXa inhibitor or andexanet) metabolism.
  • Allergy to any of the vehicle ingredients: tris, arginine, sucrose, hydrochloric acid, mannitol, and polysorbate 80.
  • Current breastfeeding or a positive pregnancy test at Screening or Day 1.
  • Any condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that would in the opinion of the Investigator increase the risk of the subject's participation in the study. This would include but is not limited to alcoholism, drug dependency or abuse, psychiatric disease, epilepsy, or any unexplained blackouts.
  • The subject is not judged by the study staff to have adequate bilateral venous access.
  • Unwillingness to adhere to the activity requirements of the study.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • West Coast Clinical Trials

    Cypress, California, 90630

Other trials in United States

About this study

Official title: A Phase 1 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Second Generation Andexanet Alfa Administered to Healthy Subjects

This is a randomized, double-blind, study in healthy volunteers dosed to steady state with fXa inhibitors, designed to (1) demonstrate PK/PD comparability between andexanet manufactured by the Generation 1 and Generation 2 processes, (2) evaluate the degree to which the Generation 2 andexanet reverses fXa-inhibitor-induced anticoagulation in comparison to placebo, and (3) evaluate safety of Generation 2 andexanet.

Conditions
Bleeding
Being tested
Andexanet alfa (Gen 1 Process 2), Apixaban 5 MG, Rivaroxaban 20 MG, Enoxaparin sodium, Edoxaban 60 MG
Medical subject headings
Hemorrhage

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Andexanet alfa (Gen 1 Process 2)Biological

    factor Xa inhibitor antidote

  • Apixaban 5 MGDrug

    factor Xa inhibitor

  • Rivaroxaban 20 MGDrug

    factor Xa inhibitor

  • Enoxaparin sodiumDrug

    low molecular weight heparin

  • Edoxaban 60 MGDrug

    factor Xa inhibitor

  • Andexanet alfa (Gen 2)Biological

    factor Xa inhibitor antidote

  • Andexanet alfa (Gen 1 Process 3)Biological

    factor Xa inhibitor antidote

  • Apixaban 10 MGDrug

    factor Xa inhibitor

  • Rivaroxaban 10 MGDrug

    factor Xa inhibitor

Study groups in NCT03083704
Study groupRoleWhat they receive
Cohort 1ExperimentalNot described
Receives: Drug: Apixaban 5 MG; Biological: Andexanet alfa (Gen 1 Process 3)
Cohort 2ExperimentalNot described
Receives: Drug: Rivaroxaban 20 MG; Biological: Andexanet alfa (Gen 1 Process 3)
Cohort 3ExperimentalNot described
Receives: Biological: Andexanet alfa (Gen 1 Process 2); Drug: Apixaban 5 MG
Cohort 4ExperimentalNot described
Receives: Drug: Apixaban 5 MG; Biological: Andexanet alfa (Gen 2)
Cohort 5ExperimentalNot described
Receives: Drug: Rivaroxaban 20 MG; Biological: Andexanet alfa (Gen 2)
Cohort 6ExperimentalNot described
Receives: Drug: Enoxaparin sodium; Biological: Andexanet alfa (Gen 2)
Cohort 7ExperimentalNot described
Receives: Drug: Edoxaban 60 MG; Biological: Andexanet alfa (Gen 2)
Cohort 8ExperimentalNot described
Receives: Biological: Andexanet alfa (Gen 2); Drug: Apixaban 10 MG
Cohort 9ExperimentalNot described
Receives: Biological: Andexanet alfa (Gen 2); Drug: Rivaroxaban 10 MG
Cohort 10ExperimentalNot described
Receives: Drug: Enoxaparin sodium; Biological: Andexanet alfa (Gen 2)
Cohort 11ExperimentalNot described
Receives: Drug: Edoxaban 60 MG; Biological: Andexanet alfa (Gen 2)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Pharmacokinetics

    To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by AUC(0-∞)

    Measured: Day 1 through Day 7

  2. Reversal

    To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by anti-fXa activity

    Measured: Day 1 through Day 7

  3. Safety will be evaluated by assessment of adverse events, venous thromboembolic events, physical exam findings, vital signs, oxygen saturation, fecal occult blood testing, and 12-lead ECGs.

    Non-laboratory-based Endpoints

    Measured: Day 1 through Day 32

  4. Safety will be evaluated by analyzing the following: • Hematology, chemistry & urinalysis.

    Laboratory-based Endpoints

    Measured: Day 1 through Day 32

  5. Safety will be evaluated by analyzing the following: • Antibodies to andexanet, fX, & fXa, and neutralizing antibodies

    Laboratory-based Endpoints

    Measured: Day 1 through Day 32

  6. Safety will be evaluated by analyzing the following: • TFPI, D-dimer, F1+2, thrombin-antithrombin III, and Russell's viper venom time

    Laboratory-based Endpoints

    Measured: Day 1 through Day 32

  7. Safety will be evaluated by analyzing the following: fX, fibrinogen, tissue-type plasminogen activator, plasmin-alpha2-antiplasmin complexes, thrombin activatable fibrinolysis inhibitor, beta-thromboglobulin, platelet factor 4 & soluble thrombomodulin

    Laboratory-based Endpoints

    Measured: Day 1 through Day 32

Secondary outcomes (9)

  1. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Total area under the plasma concentration-time curve from time 0 to infinity (AUC(0 ∞)

    Pharmacokinetics

    Measured: Day 1 through Day 7

  2. Reversal

    To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by free fraction of the fXa inhibitor

    Measured: Day 1 through Day 7

  3. Reversal

    To evaluate reversal of fXa-inhibitor-mediated anticoagulation, as measured by restoration of thrombin generation

    Measured: Day 1 through Day 7

  4. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Cmax - Maximum Observed Concentration

    Pharmacokinetics

    Measured: Day 1 through Day 7

  5. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Tmax - Time to maximum observed plasma concentration (Tmax)

    Pharmacokinetics

    Measured: Day 1 through Day 7

  6. To evaluate pharmacokinetics of Generation 2 process andexanet as measured by following PK parameter: t1/2 - Plasma t½, determined by linear regression of the log concentration on the distribution & terminal portion of the plasma concentration-time curve

    Pharmacokinetics

    Measured: Day 1 through Day 7

  7. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: CL - Clearance

    Pharmacokinetics

    Measured: Day 1 through Day 7

  8. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: Vss - Volume of distribution at steady state (Vss)

    Pharmacokinetics

    Measured: Day 1 through Day 7

  9. To evaluate the pharmacokinetics of Generation 2 process andexanet, as measured by the following PK parameter: lamda z - The terminal or elimination rate constant (lamda z)

    Pharmacokinetics

    Measured: Day 1 through Day 7

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Mar 2017
  2. Study start26 Feb 2017
  3. Primary completion28 Sep 2017
  4. Study completion28 Sep 2017

Resources

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
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
153 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03083704
Sponsor's protocol ID
16-512
Status last verified
Aug 2023
First submitted
7 Mar 2017
Last updated
8 Aug 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Andexanet alfa (Gen 1 Process 2), Apixaban 5 MG and Rivaroxaban 20 MG in people with Bleeding, run by Portola Pharmaceuticals 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 18 inclusion and 22 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 8 Aug 2023. 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?

Pharmacokinetics (time frame: Day 1 through Day 7). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03083704.

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 8 Aug 2023.

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