Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil

NCT02017197 | Completed Phase 4

• 2 other identifiers: RCT 01 GWU1111-1155-4833
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

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.

Conditions

Atrial Fibrillation

Keywords

Therapeutic Equivalency; Warfarin; Drugs, Generic; Anticoagulants; Anticoagulants [Pharmacological Action]; Coumarins

Outcome Measures

Primary Outcomes (1)

• Difference between Delta INR

  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.

  At the fourth week of each period

Secondary Outcomes (5)

• Difference between mean INR

  At the fourth week of each period

• Difference in warfarin dosage needed

  At the fourth week of each period

• Incidence of thromboembolic events

  At the fourth week of each period

• Incidence of bleeding events

  At the fourth week of each period

• Time in therapeutic range (TTR)

  At the fourth week of each period

Other Outcomes (1)

• Compliance with treatment

  At the fourth week of each period

Study Arms (6)

Sequence A

OTHER

Phase 1 (run-in): Marevan® Phase 2: Marevan® Phase 3: generic warfarin #1 Phase 4: generic warfarin #2

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Sequence B

OTHER

Phase 1 (run-in): generic warfarin #1 Phase 2: generic warfarin #1 Phase 3: Marevan® Phase 4: generic warfarin #2

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Sequence C

OTHER

Phase 1 (run-in): generic warfarin #1 Phase 2: generic warfarin #1 Phase 3: generic warfarin #2 Phase 4: Marevan®

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Sequence D

OTHER

Phase 1 (run-in): Marevan® Phase 2: Marevan® Phase 3: generic warfarin #2 Phase 4: generic warfarin #1

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Sequence E

OTHER

Phase 1 (run-in): generic warfarin #2 Phase 2: generic warfarin #2 Phase 3: Marevan® Phase 4: generic warfarin #1

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Sequence F

OTHER

Phase 1 (run-in): generic warfarin #2 Phase 2: generic warfarin #2 Phase 3: generic warfarin #1 Phase 4: Marevan®

Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

Interventions

Marevan® DRUG

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

Also known as: warfarin

Sequence A; Sequence B; Sequence C; Sequence D; Sequence E; Sequence F

generic warfarin #1 DRUG

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

Sequence A; Sequence B; Sequence C; Sequence D; Sequence E; Sequence F

generic warfarin #2 DRUG

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

Sequence A; Sequence B; Sequence C; Sequence D; Sequence E; Sequence F

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Federal University of São Paulo: lead
• Fundação de Amparo à Pesquisa do Estado de São Paulo: collaborator

Study Sites (1)

Hospital São Paulo/Hospital Universitário da UNIFESP (University Hospital of UNIFESP)

São Paulo, São Paulo, 04024-002, Brazil

Location

Related Publications (2)

• Gomes Freitas C, Walsh M, Coutinho EL, Vincenzo de Paola AA, Atallah AN. Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial. PLoS One. 2021 Apr 1;16(4):e0248567. doi: 10.1371/journal.pone.0248567. eCollection 2021.

  PMID: 33793580 DERIVED

• Freitas CG, Walsh M, Atallah AN. Design and rationale for the WARFA trial: a randomized controlled cross-over trial testing the therapeutic equivalence of branded and generic warfarin in atrial fibrillation patients in Brazil. BMC Cardiovasc Disord. 2017 Jun 7;17(1):148. doi: 10.1186/s12872-017-0584-4.

  PMID: 28592234 DERIVED

MeSH Terms

Conditions

Atrial Fibrillation

Interventions

Warfarin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Carolina Gomes Freitas, BPharm

  Federal University of Sao Paulo (UNIFESP)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Graduate student (PhD)

Study Record Dates

• First Submitted: December 11, 2013
• First Posted: December 20, 2013
• Study Start: August 1, 2014
• Primary Completion: August 1, 2016
• Study Completion: August 1, 2016
• Last Updated: November 23, 2016

Record last verified: 2016-11

Locations

BR (1)