Therapeutic Equivalence Between Branded and Generic WARFArin Tablets in Brazil

Sponsor

Federal University of São Paulo (Other)

Overall Status

Completed

CT.gov ID

NCT02017197

Collaborator

Fundação de Amparo à Pesquisa do Estado de São Paulo (Other)

100

Enrollment

Location

Arms

Duration (Months)

4.2

Patients Per Site Per Month

Study Details

Study Description

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

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

Study Type:

Interventional

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 :

Aug 1, 2014

Actual Primary Completion Date :

Aug 1, 2016

Actual Study Completion Date :

Aug 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: 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 Names: 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.
Other: 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 Names: 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.
Other: 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 Names: 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.
Other: 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 Names: 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.
Other: 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 Names: 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.
Other: 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 Names: 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

Primary Outcome Measures

Difference between Delta INR [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

Difference between mean INR [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.
Difference in warfarin dosage needed [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.
Incidence of thromboembolic events [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).
Incidence of bleeding events [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.
Time in therapeutic range (TTR) [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

Compliance with treatment [At the fourth week of each period]
Performed by counting of returned pills

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).