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Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil (WARFA)

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ClinicalTrials.gov Identifier: NCT02017197
Recruitment Status : Completed
First Posted : December 20, 2013
Last Update Posted : November 23, 2016
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Carolina Gomes Freitas, Federal University of São Paulo

Study Description
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Brief Summary:
The purpose of this study is to assess whether the switch from branded to generic warfarin or between different generic warfarin tablets may cause fluctuation in the results of coagulation tests (International Normalized Rate, acronym INR) in patients, thus predisposing them to unnecessary risks.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Drug: Marevan® Drug: generic warfarin #1 Drug: generic warfarin #2 Phase 4

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Therapeutic Equivalence Between Branded and Generic Warfarin Sodium Tablets in Adult Patients With Atrial Fibrillation in Brazil - Crossover Randomized Controlled Equivalence Trial
Study Start Date : August 2014
Actual Primary Completion Date : August 2016
Actual Study Completion Date : August 2016

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Arms and Interventions
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Arm Intervention/treatment
Sequence A

Phase 1 (run-in): Marevan®

Phase 2: Marevan®

Phase 3: generic warfarin #1

Phase 4: generic warfarin #2

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
Sequence B

Phase 1 (run-in): generic warfarin #1

Phase 2: generic warfarin #1

Phase 3: Marevan®

Phase 4: generic warfarin #2

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
Sequence C

Phase 1 (run-in): generic warfarin #1

Phase 2: generic warfarin #1

Phase 3: generic warfarin #2

Phase 4: Marevan®

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
Sequence D

Phase 1 (run-in): Marevan®

Phase 2: Marevan®

Phase 3: generic warfarin #2

Phase 4: generic warfarin #1

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
Sequence E

Phase 1 (run-in): generic warfarin #2

Phase 2: generic warfarin #2

Phase 3: Marevan®

Phase 4: generic warfarin #1

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
Sequence F

Phase 1 (run-in): generic warfarin #2

Phase 2: generic warfarin #2

Phase 3: generic warfarin #1

Phase 4: Marevan®

 Drug: Marevan®
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
Other Name: warfarin

Drug: generic warfarin #1
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Drug: generic warfarin #2
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.


Outcome Measures
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Primary Outcome Measures :
  1. Difference between Delta INR [ Time Frame: At the fourth week of each period ]

    INR: International normalized ratio. INR will be assessed twice a month during the 16 weeks of study.

    Delta INR will be calculated by the difference, in absolute numbers (i.e. in module), between the two valid INR measurements due for each patient with each formulation at each period. Difference between the delta INRs will be the outcome. We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.



Secondary Outcome Measures :
  1. Difference between mean INR [ Time Frame: At the fourth week of each period ]

    INR: International normalized ratio. INR will be assessed twice a month during the 16 weeks of study.

    We will calculate the mean INR for each formulation of warfarin; difference between the mean INRs will be the outcome. We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.


  2. Difference in warfarin dosage needed [ Time Frame: At the fourth week of each period ]

    The warfarin dosage will be calculated as the sum of the dosage taken in the week before the study visit, as referred by the patient. We will calculate the mean dosage for each formulation of warfarin; difference between the mean dosage will be the outcome.

    We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.


  3. Incidence of thromboembolic events [ Time Frame: At the fourth week of each period ]
    Includes ischemic stroke (differential diagnosis with hemorrhagic stroke by tomography) and thromboembolism of viscera or extremities (diagnosed by acute symptoms and relevant diagnostic tests).

  4. Incidence of bleeding events [ Time Frame: At the fourth week of each period ]

    Classified as major or minor bleeding events.

    Major: intracranial hemorrhage, fatal bleeding, bleeding resulting in hemoglobin loss equal to or greater than 2.0 g / L, hemorrhage requiring transfusion, bleeding in sensitive areas such as the retina or pericardium.

    Minor: all other bleeding.


  5. Time in therapeutic range (TTR) [ Time Frame: At the fourth week of each period ]

    TTR calculated by Rosendaal Method also known as linear interpolation method. We will calculate the mean TTR for each formulation of warfarin; difference between the mean TTRs will be the outcome.

    We will compare generic to branded warfarin (Marevan®) and the generic formulations to each other.



Other Outcome Measures:
  1. Compliance with treatment [ Time Frame: At the fourth week of each period ]
    Performed by counting of returned pills


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • diagnosis of nonvalvular atrial fibrillation atrial flutter by electrocardiogram and echocardiography;
  • CHA2DS2VASc score equal to or greater than 1;
  • already in use of warfarin for at least 2 months;
  • during the run-in, at least one of the three (including the baseline) INR results within 2.0 and 3.0 and a difference of INR results at the 3th and 4th week ≤ ±0.8
  • signing of Informed Consent Form.

Exclusion Criteria:

  • patients with serious contraindications to the use of anticoagulants (significant bleeding, known sensitivity to warfarin);
  • women of childbearing age, pregnant or breastfeeding;
  • patients with thrombocytopenia;
  • patients with hepatic or renal impairment;
  • patients with a history of bleeding episodes due to congenital deficiency of coagulation factors;
  • patients enrolled in another trial;
  • patients initiating treatment with drugs with major interactions or which are contraindicated when used concomitantly with warfarin, according to our list (Annex I).
Contacts and Locations
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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): NCT02017197


Locations
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Brazil
Hospital São Paulo/Hospital Universitário da UNIFESP (University Hospital of UNIFESP)
São Paulo, Brazil, 04024-002
Sponsors and Collaborators
Federal University of São Paulo
Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
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Principal Investigator: Carolina Gomes Freitas, BPharm Federal University of Sao Paulo (UNIFESP)
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Carolina Gomes Freitas, Graduate student (PhD), Federal University of São Paulo
ClinicalTrials.gov Identifier: NCT02017197    
Other Study ID Numbers: RCT 01 GW
U1111-1155-4833 ( Registry Identifier: Universal Trial Number (UTN) )
First Posted: December 20, 2013    Key Record Dates
Last Update Posted: November 23, 2016
Last Verified: November 2016
Keywords provided by Carolina Gomes Freitas, Federal University of São Paulo:
Therapeutic Equivalency
Warfarin
Drugs, Generic
 Anticoagulants
Anticoagulants [Pharmacological Action]
Coumarins
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
 Pathologic Processes
Warfarin
Anticoagulants