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

This study has been completed.
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
ClinicalTrials.gov Identifier:
NCT02017197
First received: December 11, 2013
Last updated: November 21, 2016
Last verified: November 2016
  Purpose
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 Intervention Phase
Atrial Fibrillation
Drug: Marevan®
Drug: generic warfarin #1
Drug: generic warfarin #2
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Caregiver, 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

Resource links provided by NLM:


Further study details as provided by Federal University of São Paulo:

Primary Outcome Measures:
  • Difference between Delta INR [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: Yes ]

    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:
  • Difference between mean INR [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: Yes ]

    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.


  • Difference in warfarin dosage needed [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: No ]

    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.


  • Incidence of thromboembolic events [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: No ]
    Includes ischemic stroke (differential diagnosis with hemorrhagic stroke by tomography) and thromboembolism of viscera or extremities (diagnosed by acute symptoms and relevant diagnostic tests).

  • Incidence of bleeding events [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: Yes ]

    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.


  • Time in therapeutic range (TTR) [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: Yes ]

    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:
  • Compliance with treatment [ Time Frame: At the fourth week of each period ] [ Designated as safety issue: No ]
    Performed by counting of returned pills


Enrollment: 100
Study Start Date: August 2014
Study Completion Date: August 2016
Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02017197

Locations
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
Principal Investigator: Carolina Gomes Freitas, BPharm Federal University of Sao Paulo (UNIFESP)
  More Information

Responsible Party: Carolina Gomes Freitas, Graduate student (PhD), Federal University of São Paulo
ClinicalTrials.gov Identifier: NCT02017197     History of Changes
Other Study ID Numbers: RCT 01 GW  U1111-1155-4833 
Study First Received: December 11, 2013
Last Updated: November 21, 2016
Health Authority: Brazil: Ethics Committee

Keywords provided by Federal University of São Paulo:
Therapeutic Equivalency
Warfarin
Drugs, Generic
Anticoagulants
Anticoagulants [Pharmacological Action]
Coumarins

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Warfarin
Anticoagulants

ClinicalTrials.gov processed this record on December 02, 2016