Atrial FibrillationPhase 4WARFANCT02017197

Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil

A Phase 4 study testing Marevan®, generic warfarin #1 and generic warfarin #2 in people with Atrial Fibrillation, run by Federal University of São Paulo at 1 site in Brazil.

Completed

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

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Atrial Fibrillation
What is being tested?: Marevan®, generic warfarin #1 and generic warfarin #2
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 100 participants
Where: 1 siteBrazil
Study dates: Aug 2014to Aug 2016
Phase: Phase 4
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 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Who cannot join

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).

Trial locations and contacts

1 site in 1 country.

Brazil1 site

Hospital São Paulo/Hospital Universitário da UNIFESP (University Hospital of UNIFESP)
São Paulo, São Paulo, 04024-002

Other trials in Brazil

About this study

Official title: Therapeutic Equivalence Between Branded and Generic Warfarin Sodium Tablets in Adult Patients With Atrial Fibrillation in Brazil - Crossover Randomized Controlled Equivalence Trial

Read the detailed description

[Changes to the protocol made until the stage of the statistical analysis plan, before data analysis and also before unblinding.]

Objective 1.1 Main Objective We aim to determine, through mean INR difference between formulations, whether there is therapeutic equivalency between the branded warfarin sodium (Marevan®) and the generic formulations in atrial fibrillation patients in Brazil. 1.2 Specific Objective In order to achieve the objective, we aim to assess with each warfarin formulation :

Delta INR [new primary outcome];
mean INR [mean prothrombin time will not be analyzed since it will convey the same information as the mean INR];
mean dosage needed for anticoagulation [new outcome];
clinical events (the frequency of thromboembolic events, bleedings, deaths and adverse events);
the time in therapeutic range;
and compliance with treatment.

Hypothesis Our hypothesis is that the delta INR of patients when using the generic tablets of warfarin sodium does not differ by more than 0.49 (two-sided) from the mean INR obtained when using the branded formulation, thereby demonstrating therapeutic equivalence. We will also assess this same outcome to assess therapeutic equivalence between the generic formulations to each other.
Type of Study This study is a crossover randomized controlled equivalence trial. It comprises four phases, each one one-month long, being the first one a run-in period. Patients will use a different warfarin sodium tablet formulation in each one of the phases 2, 3 and 4: either the branded Marevan® (União Química/Farmoquímica, Brasil), or two generic drugs, (manufactured by União Química Farmacêutica Nacional S/A or Laboratório Teuto Brasileiro S/A, Brasil) purchased from Brazilian drugstores (not directly from the manufacturer). Every patient will use each one of the three formulations in a previously determined sequence (A, B, C, D, E or F) to which he was assigned by randomization. Since patients included in the study will already be using warfarin and it is not ethically acceptable to interrupt this treatment, we planned a run-in period equivalent to seven warfarin half-lives, long enough to washout any previous warfarin treatment. Then, in this first phase, patients will start treatment with the same warfarin formulation that will be used in the second phase thus avoiding the carry-over effect. This period will also be used to select patients compliant with treatment, accepting those that during the run-in have 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.
Methods An independent investigator (initials TFCP) will use a computer random number generator to allocate patients to one of the six sequences of treatment [update: we opted to apply randomization through numbered, opaque, sealed envelopes in order to facilitate allocation concealment]. The principal investigator (initials CGF) will separate, repack and dispense drugs for patients in opaque drug containers of identical appearance [update: the step of repacking the drugs in opaque containers was made by two investigators external to the study, BR and MFST, instead of the principal investigator]. This process will be based on the initials of the patient and the alphanumeric code, maintaining the allocation concealment since TFCP will be responsible for assigning to the repacked drugs the patient initials and the alphanumeric code correlated with the formulation of warfarin utilized. TFCP will also be accountable to conceal the allocation until the statistical analysis at the end of the study [update: BR and MFST created the coding and maintained its concealment]. Due to the features of the drug containers, physicians and the principal investigator (that assess patients and collect outcomes) will be blinded. Patients may not be blinded depending on the appearance of the manufactured tablets, but the main outcome will be a laboratory result (INR).
Sample Size Forty-eight patients (eight in each group) is the minimum necessary number of individuals to detect a clinically significant fluctuation of 0.49 in the mean INR, with a 90% power at a 5% level of significance, if one were present. This sample size was estimated considering the Pocock's statistical method for quantitative outcomes and an achieved mean INR and standard deviation with the branded warfarin of 2.45 and 0.29 respectively [update: later we considered a more conservative standard deviation of 0.34, which resulted in a sample size of 11 patients per group]. To compensate possible withdrawals or exclusions of patients we plan to recruit 60 patients.
Statistical Analysis For the INR, PT and TTR outcomes paired t-test will be used at a two-sided 5% level of significance. These analysis will be per protocol, i.e., data from patients that during the follow-up start treatment with substances or drugs that interact either in a moderate or major way or are contraindicated when used with warfarin (Annex I) will be excluded [update: multiple t-tests would not be adequate because nominal significance levels would not reflect the actual alfa, and thus we decided to apply multilevel mixed-effects linear regression. We have new definitions for per protocol analyses.]. Binary outcomes (thromboembolic or bleeding events) will be analysed by Mcnemar test at a 5% level of significance using intention to treat i.e. considering missing data as adverse outcomes. In this case sensibility analysis will be conducted [update: we decided for just presenting the events recorded during the trial without any hypothesis testing due to cross-over design limitations and lower power for these outcomes]. Exploratory analysis for subgroup of patients are not intended.
Annex I (obtained from the online database Micromedex ® 2.0 in September 13, 2013)

abciximab
acarbose
acemetacin
acenocoumarol
acetaminophen
agrimony
alclofenac
alefacept
allopurinol
aloe
aminoglutethimide
amiodarone
amitriptyline
amobarbital sodium
amoxapine
amoxicillin
ampicillin trihydrate
amprenavir
angelica
anise
antithyroid agents
apazone
apixaban
aprepitant
aprobarbital
argatroban
armodafinil
arnica
asafetida
aspirin
astragalus
atazanavir
atenolol
atovaquone
avocado
azathioprine
azithromycin
bee pollen
benoxaprofen
benzbromarone
betamethasone
bicalutamide
bilberry
bismuth subsalicylate
bivalirudin
black cohosh extract
black currant
black haw
black tea
bladderwrack
boceprevir
bogbean
boldo
borage
bosentan
bromelain
bromfenac
buchu
bufexamac
butabarbital
butalbital
capecitabine
capsaicin
carbamazepine
carbenicillin disodium
carboplatin
carprofen
cassia
cat's claw
cefadroxil
cefamandole
cefazolin sodium
cefdinir
cefepime
cefixime
cefoperazone
cefotaxime
cefotetan
cefpodoxime
ceftazidime
ceftibuten
ceftizoxime
ceftriaxone
celecoxib
celery
cephalexin
cephalothin sodium
cephapirin
chamomile
chaparral
chitosan
chloral hydrate
chloramphenicol
chlordiazepoxide
chlorotrianisene
chlorpromazine hydrochloride
cholestyramine
chondroitin
cimetidine
cinchona
ciprofloxacin
cisapride monohydrate
cisplatin
citalopram
clarithromycin
clofibrate
clomipramine hydrochloride
clopidogrel
clove
clove oil
cloxacillin benzathine
coenzyme Q10
colesevelam
contraceptives, combination
cortisone
cranberry juice
curcumin
cyclophosphamide
cyclosporine, modified
dabigatran
dabrafenib
dalteparin
danaparoid
danazol
dandelion
dapsone
darunavir
deferasirox
delavirdine
demeclocycline
desipramine
desvenlafaxine
devil's claw
dexamethasone
dexlansoprazole
dexmethylphenidate
diazoxide
diclofenac
dicloxacillin
diethylstilbestrol
diflunisal
dipyridamole
dipyrone
disopyramide
disulfiram
dong quai
dothiepin
doxepin
doxorubicin
doxycycline calcium
dronedarone
droxicam
duloxetine
enoxacin
enoxaparin
enteral nutrition
enzalutamide
eptifibatide
erlotinib
erythromycin acistrate
escitalopram
esomeprazole
eterobarb
ethacrynic acid
ethanol
ethchlorvynol
ethotoin
etodolac
etoposide
etravirine
etretinate
evening primrose oil
exenatide
ezetimibe
felbamate
fenbufen
fenofibrate
fenofibric acid
fenoprofen
fenugreek
feverfew
fish oil
floctafenine
flosequinan
fluconazole
fludrocortisone acetate
flufenamic acid
fluorouracil
fluoxetine
fluoxymesterone
flurbiprofen
flutamide
fluvastatin
fluvoxamine
fosamprenavir
fosaprepitant
garlic
gatifloxacin
gefitinib
gemcitabine
gemfibrozil
gemifloxacin
ginger
ginkgo
ginseng, siberian
glimepiride
glipizide
glucagon
glucosamine
glutethimide
glyburide
goldenseal
green tea
griseofulvin
guggul
halothane
heparin calcium
heptabarbital
hexobarbital sodium
high protein food
horse chestnut
horseradish
hydrocortisone
ibritumomab
ibuprofen
ifosfamide
imatinib
imipramine hydrochloride
indomethacin
indoprofen
infliximab
influenza virus vaccine
ipriflavone
isoniazid
isoxicam
itraconazole
ivacaftor
ivermectin
kava
ketoconazole
ketoprofen
ketorolac tromethamine
lactulose
lansoprazole
leflunomide
lepirudin
levamisole
levofloxacin
licorice
lopinavir
lornoxicam
lovastatin
lycium
marijuana
meadowsweet
mechlorethamine
meclofenamate
mefenamic acid
melatonin
meloxicam
menthol
mephobarbital
mercaptopurine
mesalamine
mesna
methandrostenolone
methicillin
methotrexate
methyl salicylate
methylphenidate
methylprednisolone acetate
methyltestosterone
metronidazole
miconazole
mifepristone
milnacipran
minocycline hydrochloride
mistletoe
mitotane
moricizine hydrochloride
motherwort
moxalactam
moxifloxacin
nabumetone
nafcillin
nalidixic acid
nandrolone
naproxen
nelfinavir
neomycin
nettle extract
nevirapine
niacin
nilutamide
nimesulide
norfloxacin
nortriptyline hydrochloride
noscapine
ofloxacin
omega-3-acid ethyl esters
omeprazole
onion oil
orlistat
oseltamivir
oxacillin
oxandrolone
oxaprozin
oxymetholone
oxyphenbutazone
oxytetracycline
pantoprazole
papaya
paramethasone
paroxetine
parsley
passionflower
pau d'arco
penicillin G
penicillin V benzathine
pentosan polysulfate sodium
pentoxifylline
phenindione
phenobarbital
phenprocoumon
phenylbutazone
phenytoin
phytonadione
piperacillin
piracetam
pirazolac
piroxicam
pirprofen
policosanol
pomegranate
poplar
posaconazole
prasugrel
prednisolone
prednisone
prickly ash
primidone
procarbazine
proguanil
propafenone hydrochloride
propoxyphene
propranolol
propyphenazone
proquazone
protriptyline
pumpkin seed
quassia
quetiapine
quinestrol
quinidine
quinine
rabeprazole sodium
raloxifene
ranitidine
red clover
rifabutin
rifampin
rifapentine
rifaximin
rilonacept
ritonavir
rivaroxaban
rofecoxib
romidepsin
ropinirole
rosuvastatin
roxithromycin
salicylates
saquinavir
sarsaparilla
saw palmetto extract
secobarbital
senega
sertraline
simvastatin
sitaxsentan
skullcap
sorafenib
soybean
spironolactone
st john's wort
stanozolol
sucralfate
sulfamethoxazole
sulfasalazine
sulfinpyrazone
sulfisoxazole
sulindac
sulofenur
suprofen
sweet woodruff
tamarind
tamoxifen
tan shen
teduglutide
telaprevir
telithromycin
tenidap sodium
tenoxicam
terbinafine
teriflunomide
testosterone
tetracycline
thyroid hormones
tiaprofenic acid
tibolone
ticarcillin
ticlopidine
tigecycline
tinidazole
tinzaparin
tirofiban
tocilizumab
tolmetin
tolterodine tartrate
tonka
toremifene citrate
torsemide
tramadol
trastuzumab
treprostinil
triamcinolone acetonide
trimipramine
valdecoxib
valproic acid
vancomycin
vemurafenib
venlafaxine
vilazodone
vincristine
vindesine
vitamin A
vitamin E
vitamin K
voriconazole
vorinostat
wild lettuce
willow
wintergreen
yarrow
zafirlukast
zileuton
zomepirac sodium
zotepine

Conditions: Atrial Fibrillation
Being tested: Marevan®, generic warfarin #1, generic warfarin #2
Keywords: Therapeutic Equivalency, Warfarin, Drugs, Generic, Anticoagulants, Anticoagulants [Pharmacological Action], Coumarins
Medical subject headings: Atrial Fibrillation

What participants receive

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

Marevan®Drug
Also called warfarin
Branded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.
generic warfarin #1Drug
Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.
generic warfarin #2Drug
Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.

Study groups in NCT02017197
Study group	Role	What they receive
Sequence A	Other	Phase 1 (run-in): Marevan® Phase 2: Marevan® Phase 3: generic warfarin #1 Phase 4: generic warfarin #2 Receives: 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 Receives: 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® Receives: 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 Receives: 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 Receives: 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® Receives: Drug: Marevan®; Drug: generic warfarin #1; Drug: generic warfarin #2

What is being measured

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

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.
Measured: At the fourth week of each period

Secondary outcomes (5)

Difference between mean INR
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.
Measured: At the fourth week of each period
Difference in warfarin dosage needed
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.
Measured: At the fourth week of each period
Incidence of thromboembolic events
Includes ischemic stroke (differential diagnosis with hemorrhagic stroke by tomography) and thromboembolism of viscera or extremities (diagnosed by acute symptoms and relevant diagnostic tests).
Measured: At the fourth week of each period
Incidence of bleeding events
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.
Measured: At the fourth week of each period
Time in therapeutic range (TTR)
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.
Measured: At the fourth week of each period

Timeline

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

Aug 2014Aug 2016

First posted20 Dec 2013 (estimated)
Study startAug 2014
Primary completionAug 2016
Study completionAug 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (2)Papers the sponsor has linked to this study.
Other trials for Atrial FibrillationStudies of the same condition, open and under way.
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 4
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Triple blind
Who is masked: Care provider, Investigator, Outcomes assessor
Enrolment: 100 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02017197
Sponsor's protocol ID: RCT 01 GW
Other IDs: U1111-1155-4833
Acronym: WARFA
Status last verified: Nov 2016
First submitted: 11 Dec 2013
Last updated: 23 Nov 2016
Results posted: No
Data monitoring committee: No

Publications

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.
PubMed 33793580
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.
PubMed 28592234

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 23 Nov 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Therapeutic Equivalence Between Branded and Generic Warfarin Sodium Tablets in Adult Patients With Atrial Fibrillation in Brazil - Crossover Randomized Controlled Equivalence Trial
ClinicalTrials.gov ID: NCT02017197
Acronym / sponsor ID: WARFA / RCT 01 GW
Conditions: Atrial Fibrillation
Keywords: Therapeutic Equivalency, Warfarin, Drugs, Generic, Anticoagulants, Anticoagulants [Pharmacological Action], Coumarins
Phase: Phase 4
Study type: Interventional
Recruitment status: Completed
Enrolment: 100 participants (actual)
Lead sponsor: Federal University of São PauloUniversity, hospital or other
Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
Study start: Aug 2014
Primary completion: Aug 2016 (actual)
Study completion: Aug 2016 (actual)
First posted: 20 Dec 2013 (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.

Detailed description

[Changes to the protocol made until the stage of the statistical analysis plan, before data analysis and also before unblinding.]

Objective 1.1 Main Objective We aim to determine, through mean INR difference between formulations, whether there is therapeutic equivalency between the branded warfarin sodium (Marevan®) and the generic formulations in atrial fibrillation patients in Brazil. 1.2 Specific Objective In order to achieve the objective, we aim to assess with each warfarin formulation :

Delta INR [new primary outcome];
mean INR [mean prothrombin time will not be analyzed since it will convey the same information as the mean INR];
mean dosage needed for anticoagulation [new outcome];
clinical events (the frequency of thromboembolic events, bleedings, deaths and adverse events);
the time in therapeutic range;
and compliance with treatment.

Hypothesis Our hypothesis is that the delta INR of patients when using the generic tablets of warfarin sodium does not differ by more than 0.49 (two-sided) from the mean INR obtained when using the branded formulation, thereby demonstrating therapeutic equivalence. We will also assess this same outcome to assess therapeutic equivalence between the generic formulations to each other.
Type of Study This study is a crossover randomized controlled equivalence trial. It comprises four phases, each one one-month long, being the first one a run-in period. Patients will use a different warfarin sodium tablet formulation in each one of the phases 2, 3 and 4: either the branded Marevan® (União Química/Farmoquímica, Brasil), or two generic drugs, (manufactured by União Química Farmacêutica Nacional S/A or Laboratório Teuto Brasileiro S/A, Brasil) purchased from Brazilian drugstores (not directly from the manufacturer). Every patient will use each one of the three formulations in a previously determined sequence (A, B, C, D, E or F) to which he was assigned by randomization. Since patients included in the study will already be using warfarin and it is not ethically acceptable to interrupt this treatment, we planned a run-in period equivalent to seven warfarin half-lives, long enough to washout any previous warfarin treatment. Then, in this first phase, patients will start treatment with the same warfarin formulation that will be used in the second phase thus avoiding the carry-over effect. This period will also be used to select patients compliant with treatment, accepting those that during the run-in have 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.
Methods An independent investigator (initials TFCP) will use a computer random number generator to allocate patients to one of the six sequences of treatment [update: we opted to apply randomization through numbered, opaque, sealed envelopes in order to facilitate allocation concealment]. The principal investigator (initials CGF) will separate, repack and dispense drugs for patients in opaque drug containers of identical appearance [update: the step of repacking the drugs in opaque containers was made by two investigators external to the study, BR and MFST, instead of the principal investigator]. This process will be based on the initials of the patient and the alphanumeric code, maintaining the allocation concealment since TFCP will be responsible for assigning to the repacked drugs the patient initials and the alphanumeric code correlated with the formulation of warfarin utilized. TFCP will also be accountable to conceal the allocation until the statistical analysis at the end of the study [update: BR and MFST created the coding and maintained its concealment]. Due to the features of the drug containers, physicians and the principal investigator (that assess patients and collect outcomes) will be blinded. Patients may not be blinded depending on the appearance of the manufactured tablets, but the main outcome will be a laboratory result (INR).
Sample Size Forty-eight patients (eight in each group) is the minimum necessary number of individuals to detect a clinically significant fluctuation of 0.49 in the mean INR, with a 90% power at a 5% level of significance, if one were present. This sample size was estimated considering the Pocock's statistical method for quantitative outcomes and an achieved mean INR and standard deviation with the branded warfarin of 2.45 and 0.29 respectively [update: later we considered a more conservative standard deviation of 0.34, which resulted in a sample size of 11 patients per group]. To compensate possible withdrawals or exclusions of patients we plan to recruit 60 patients.
Statistical Analysis For the INR, PT and TTR outcomes paired t-test will be used at a two-sided 5% level of significance. These analysis will be per protocol, i.e., data from patients that during the follow-up start treatment with substances or drugs that interact either in a moderate or major way or are contraindicated when used with warfarin (Annex I) will be excluded [update: multiple t-tests would not be adequate because nominal significance levels would not reflect the actual alfa, and thus we decided to apply multilevel mixed-effects linear regression. We have new definitions for per protocol analyses.]. Binary outcomes (thromboembolic or bleeding events) will be analysed by Mcnemar test at a 5% level of significance using intention to treat i.e. considering missing data as adverse outcomes. In this case sensibility analysis will be conducted [update: we decided for just presenting the events recorded during the trial without any hypothesis testing due to cross-over design limitations and lower power for these outcomes]. Exploratory analysis for subgroup of patients are not intended.
Annex I (obtained from the online database Micromedex ® 2.0 in September 13, 2013)

abciximab
acarbose
acemetacin
acenocoumarol
acetaminophen
agrimony
alclofenac
alefacept
allopurinol
aloe
aminoglutethimide
amiodarone
amitriptyline
amobarbital sodium
amoxapine
amoxicillin
ampicillin trihydrate
amprenavir
angelica
anise
antithyroid agents
apazone
apixaban
aprepitant
aprobarbital
argatroban
armodafinil
arnica
asafetida
aspirin
astragalus
atazanavir
atenolol
atovaquone
avocado
azathioprine
azithromycin
bee pollen
benoxaprofen
benzbromarone
betamethasone
bicalutamide
bilberry
bismuth subsalicylate
bivalirudin
black cohosh extract
black currant
black haw
black tea
bladderwrack
boceprevir
bogbean
boldo
borage
bosentan
bromelain
bromfenac
buchu
bufexamac
butabarbital
butalbital
capecitabine
capsaicin
carbamazepine
carbenicillin disodium
carboplatin
carprofen
cassia
cat's claw
cefadroxil
cefamandole
cefazolin sodium
cefdinir
cefepime
cefixime
cefoperazone
cefotaxime
cefotetan
cefpodoxime
ceftazidime
ceftibuten
ceftizoxime
ceftriaxone
celecoxib
celery
cephalexin
cephalothin sodium
cephapirin
chamomile
chaparral
chitosan
chloral hydrate
chloramphenicol
chlordiazepoxide
chlorotrianisene
chlorpromazine hydrochloride
cholestyramine
chondroitin
cimetidine
cinchona
ciprofloxacin
cisapride monohydrate
cisplatin
citalopram
clarithromycin
clofibrate
clomipramine hydrochloride
clopidogrel
clove
clove oil
cloxacillin benzathine
coenzyme Q10
colesevelam
contraceptives, combination
cortisone
cranberry juice
curcumin
cyclophosphamide
cyclosporine, modified
dabigatran
dabrafenib
dalteparin
danaparoid
danazol
dandelion
dapsone
darunavir
deferasirox
delavirdine
demeclocycline
desipramine
desvenlafaxine
devil's claw
dexamethasone
dexlansoprazole
dexmethylphenidate
diazoxide
diclofenac
dicloxacillin
diethylstilbestrol
diflunisal
dipyridamole
dipyrone
disopyramide
disulfiram
dong quai
dothiepin
doxepin
doxorubicin
doxycycline calcium
dronedarone
droxicam
duloxetine
enoxacin
enoxaparin
enteral nutrition
enzalutamide
eptifibatide
erlotinib
erythromycin acistrate
escitalopram
esomeprazole
eterobarb
ethacrynic acid
ethanol
ethchlorvynol
ethotoin
etodolac
etoposide
etravirine
etretinate
evening primrose oil
exenatide
ezetimibe
felbamate
fenbufen
fenofibrate
fenofibric acid
fenoprofen
fenugreek
feverfew
fish oil
floctafenine
flosequinan
fluconazole
fludrocortisone acetate
flufenamic acid
fluorouracil
fluoxetine
fluoxymesterone
flurbiprofen
flutamide
fluvastatin
fluvoxamine
fosamprenavir
fosaprepitant
garlic
gatifloxacin
gefitinib
gemcitabine
gemfibrozil
gemifloxacin
ginger
ginkgo
ginseng, siberian
glimepiride
glipizide
glucagon
glucosamine
glutethimide
glyburide
goldenseal
green tea
griseofulvin
guggul
halothane
heparin calcium
heptabarbital
hexobarbital sodium
high protein food
horse chestnut
horseradish
hydrocortisone
ibritumomab
ibuprofen
ifosfamide
imatinib
imipramine hydrochloride
indomethacin
indoprofen
infliximab
influenza virus vaccine
ipriflavone
isoniazid
isoxicam
itraconazole
ivacaftor
ivermectin
kava
ketoconazole
ketoprofen
ketorolac tromethamine
lactulose
lansoprazole
leflunomide
lepirudin
levamisole
levofloxacin
licorice
lopinavir
lornoxicam
lovastatin
lycium
marijuana
meadowsweet
mechlorethamine
meclofenamate
mefenamic acid
melatonin
meloxicam
menthol
mephobarbital
mercaptopurine
mesalamine
mesna
methandrostenolone
methicillin
methotrexate
methyl salicylate
methylphenidate
methylprednisolone acetate
methyltestosterone
metronidazole
miconazole
mifepristone
milnacipran
minocycline hydrochloride
mistletoe
mitotane
moricizine hydrochloride
motherwort
moxalactam
moxifloxacin
nabumetone
nafcillin
nalidixic acid
nandrolone
naproxen
nelfinavir
neomycin
nettle extract
nevirapine
niacin
nilutamide
nimesulide
norfloxacin
nortriptyline hydrochloride
noscapine
ofloxacin
omega-3-acid ethyl esters
omeprazole
onion oil
orlistat
oseltamivir
oxacillin
oxandrolone
oxaprozin
oxymetholone
oxyphenbutazone
oxytetracycline
pantoprazole
papaya
paramethasone
paroxetine
parsley
passionflower
pau d'arco
penicillin G
penicillin V benzathine
pentosan polysulfate sodium
pentoxifylline
phenindione
phenobarbital
phenprocoumon
phenylbutazone
phenytoin
phytonadione
piperacillin
piracetam
pirazolac
piroxicam
pirprofen
policosanol
pomegranate
poplar
posaconazole
prasugrel
prednisolone
prednisone
prickly ash
primidone
procarbazine
proguanil
propafenone hydrochloride
propoxyphene
propranolol
propyphenazone
proquazone
protriptyline
pumpkin seed
quassia
quetiapine
quinestrol
quinidine
quinine
rabeprazole sodium
raloxifene
ranitidine
red clover
rifabutin
rifampin
rifapentine
rifaximin
rilonacept
ritonavir
rivaroxaban
rofecoxib
romidepsin
ropinirole
rosuvastatin
roxithromycin
salicylates
saquinavir
sarsaparilla
saw palmetto extract
secobarbital
senega
sertraline
simvastatin
sitaxsentan
skullcap
sorafenib
soybean
spironolactone
st john's wort
stanozolol
sucralfate
sulfamethoxazole
sulfasalazine
sulfinpyrazone
sulfisoxazole
sulindac
sulofenur
suprofen
sweet woodruff
tamarind
tamoxifen
tan shen
teduglutide
telaprevir
telithromycin
tenidap sodium
tenoxicam
terbinafine
teriflunomide
testosterone
tetracycline
thyroid hormones
tiaprofenic acid
tibolone
ticarcillin
ticlopidine
tigecycline
tinidazole
tinzaparin
tirofiban
tocilizumab
tolmetin
tolterodine tartrate
tonka
toremifene citrate
torsemide
tramadol
trastuzumab
treprostinil
triamcinolone acetonide
trimipramine
valdecoxib
valproic acid
vancomycin
vemurafenib
venlafaxine
vilazodone
vincristine
vindesine
vitamin A
vitamin E
vitamin K
voriconazole
vorinostat
wild lettuce
willow
wintergreen
yarrow
zafirlukast
zileuton
zomepirac sodium
zotepine

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Triple blind (care provider, investigator, outcomes assessor)
Number of arms: 6

Arm	Type	Receives
Sequence A	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): Marevan® Phase 2: Marevan® Phase 3: generic warfarin #1 Phase 4: generic warfarin #2
Sequence B	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): generic warfarin #1 Phase 2: generic warfarin #1 Phase 3: Marevan® Phase 4: generic warfarin #2
Sequence C	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): generic warfarin #1 Phase 2: generic warfarin #1 Phase 3: generic warfarin #2 Phase 4: Marevan®
Sequence D	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): Marevan® Phase 2: Marevan® Phase 3: generic warfarin #2 Phase 4: generic warfarin #1
Sequence E	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): generic warfarin #2 Phase 2: generic warfarin #2 Phase 3: Marevan® Phase 4: generic warfarin #1
Sequence F	Other	Drug: Marevan®, Drug: generic warfarin #1, Drug: generic warfarin #2Phase 1 (run-in): generic warfarin #2 Phase 2: generic warfarin #2 Phase 3: generic warfarin #1 Phase 4: Marevan®

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

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.

Key exclusion criteria (7 listed)

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;

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
Marevan®Also: warfarinBranded warfarin sodium tablets (manufacturer União Química Farmacêutica Nacional S/A, Brazil) by mouth; dose adjusted according to INR and medical judgement.	Drug	Sequence A, Sequence B, Sequence C, Sequence D, Sequence E, Sequence F
generic warfarin #1Generic warfarin sodium tablets, manufacturer (União Química Farmacêutica Nacional S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.	Drug	Sequence A, Sequence B, Sequence C, Sequence D, Sequence E, Sequence F
generic warfarin #2Generic warfarin sodium tablets, manufacturer (Laboratório Teuto Brasileiro S/A, Brazil), by mouth; dose adjusted according to INR and medical judgement.	Drug	Sequence A, Sequence B, Sequence C, Sequence D, Sequence E, Sequence F

Primary outcome

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.

5 secondary outcomes

Difference between mean INR
Time frame: At the fourth week of each period
Difference in warfarin dosage needed
Time frame: At the fourth week of each period
Incidence of thromboembolic events
Time frame: At the fourth week of each period
Incidence of bleeding events
Time frame: At the fourth week of each period
Time in therapeutic range (TTR)
Time frame: At the fourth week of each period

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 23 Nov 2016.
Derived from this study: PubMed 33793580Gomes 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.
Derived from this study: PubMed 28592234Freitas 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.

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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.

Carolina Gomes Freitas, BPharm principal investigator

Federal University of Sao Paulo (UNIFESP)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Marevan®, generic warfarin #1 and generic warfarin #2 in people with Atrial Fibrillation, run by Federal University of São Paulo at 1 site in Brazil.

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 5 inclusion and 7 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 23 Nov 2016. 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 Brazil. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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?

Difference between Delta INR (time frame: At the fourth week of each period). 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 NCT02017197, which also lists 2 linked publications.

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 23 Nov 2016.