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Drug Interaction Between Paracetamol and Warfarin (INPAWA2)

Primary Purpose

Deep Venous Thrombosis, Pulmonary Embolism, Atrial Fibrillation

Status

Completed

Phase

Phase 4

Locations

France

Study Type

Interventional

Intervention

paracetamol

Placebo

About this trial

This is an interventional screening trial for Deep Venous Thrombosis focused on measuring paracetamol, warfarin, drug interaction, pathogenic mechanism

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients treated with warfarin (target INR 2 to 3) stable anticoagulation at 2 to 9 mg for more than 30 days
Aged 18 years or older
Laboratory values (hemoglobin, blood cell counts, albumin, blood ionogram, complementary hemostasis parameters and aspartate, alanine transaminases (AST and ALT))remained within normal limits

Exclusion Criteria:

Any treatment change within 7 days before enrollment
Any paracetamol intake within the last 14 days
Drug allergy Concomitant drug ( 5-fluorouracile, acetylsalicylic acid, non steroidal anti-inflammatory drugs, chloramphenicol, diflunisal, miconazole)
St John's wort treatment
Pregnancy

Sites / Locations

Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Paracetamol 2g/d

Paracetamol 3g/d

Placebo

Arm Description

18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d

18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d

9 patients on stable warfarin therapy received a 10-day regimen of placebo

Outcomes

Primary Outcome Measures

The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))

Secondary Outcome Measures

The mean maximum INR (INRmax)

The time to the first variation of INR observed

Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups.

Day 10 - Day 1 differences in paracetamol plasma concentration between groups.

Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups.

Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups.

Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1)

Relation between age and INR (max-D1)is measured using regression analysis.

Full Information

NCT ID

NCT01104337

First Posted

April 12, 2010

Last Updated

April 13, 2010

Sponsor

Hopital Lariboisière

1. Study Identification

Unique Protocol Identification Number

NCT01104337

Brief Title

Drug Interaction Between Paracetamol and Warfarin

Acronym

INPAWA2

Official Title

Dose-dependent Drug-drug Interaction Between Paracetamol and Warfarin in Adults Receiving Long-term Oral Anticoagulants: A Randomized Controlled Trial

Study Type

Interventional

2. Study Status

Record Verification Date

February 2010

Overall Recruitment Status

Completed

Study Start Date

March 2007 (undefined)

Primary Completion Date

November 2008 (Actual)

Study Completion Date

February 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Hopital Lariboisière

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The objective of this study is to investigate whether paracetamol, given at therapeutic doses (2g/day and 3 g/day), may potentiate the anticoagulant effect of warfarin.

Detailed Description

Paracetamol is recommended as a first-line analgesic and antipyretic therapy in patients receiving short- and long-term oral anticoagulation, especially elderly patient.However,Increased INR was previously observed in patients treated with warfarin and paracetamol given at the maximum recommended dose (4g/day). To date, the mechanism of this interaction has not been determined.A recent in vitro study suggested that the toxic metabolite N-acetyl-para-benzoquinoneimine (NAPQI) appeared to interfere with vitamin K-dependent γ-carboxylase (VKD-carb) and vitamin K epoxide reductase (VKOR) activites12. The question remaining to be dealt with is whether this in vitro observation can explain the in vivo paracetamol-warfarin interaction. We aim to evaluate the effect of paracetamol at the most widely used doses 2 and 3g/day on INR in stable patients treated with warfarin in a double blind randomized placebo-controlled trial and to identify the mechanism involved in this interaction in vivo.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Deep Venous Thrombosis, Pulmonary Embolism, Atrial Fibrillation, Stroke, Antiphospholipid Syndrome

Keywords

paracetamol, warfarin, drug interaction, pathogenic mechanism

7. Study Design

Primary Purpose

Screening

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

45 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Paracetamol 2g/d

Arm Type

Experimental

Arm Description

18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 2g/d

Arm Title

Paracetamol 3g/d

Arm Type

Experimental

Arm Description

18 patients on stable warfarin therapy received a 10-day regimen of paracetamol 3g/d

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

9 patients on stable warfarin therapy received a 10-day regimen of placebo

Intervention Type

Drug

Intervention Name(s)

paracetamol

Intervention Description

Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets twice a day along with two matching placebo tablets once daily

Intervention Type

Drug

Intervention Name(s)

paracetamol

Intervention Description

Treatment consisted of two paracetamol 500mg (Doliprane® 500mg, Sanofi-aventis, Paris, France) tablets three times a day

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Treatment consisted of two matching placebo tablets three times a day.

Primary Outcome Measure Information:

Title

The mean maximum increase in INR from baseline to Day 10 (INR (max-D1))

Time Frame

10 days

Secondary Outcome Measure Information:

Title

The mean maximum INR (INRmax)

Time Frame

10 days

Title

The time to the first variation of INR observed

Time Frame

10 days

Title

Day 10 - Day 1 differences in factors II, V, VII, AT-III plasma concentrations between groups.

Time Frame

10 days

Title

Day 10 - Day 1 differences in paracetamol plasma concentration between groups.

Time Frame

10 days

Title

Day 10 - Day 1 differences in R(-), S(-)warfarin plasma concentrations between groups.

Time Frame

10 days

Title

Day 10 - Day 1 differences in Gla-type Osteocalcin (Gla-OC) and undercarboxylated Osteocalcin (Glu-OC)plasma concentrations between groups.

Time Frame

10 days

Title

Relation between age and the mean maximum increase in INR from baseline to Day 10 (INR (max-D1)

Description

Relation between age and INR (max-D1)is measured using regression analysis.

Time Frame

10 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients treated with warfarin (target INR 2 to 3) stable anticoagulation at 2 to 9 mg for more than 30 days Aged 18 years or older Laboratory values (hemoglobin, blood cell counts, albumin, blood ionogram, complementary hemostasis parameters and aspartate, alanine transaminases (AST and ALT))remained within normal limits Exclusion Criteria: Any treatment change within 7 days before enrollment Any paracetamol intake within the last 14 days Drug allergy Concomitant drug ( 5-fluorouracile, acetylsalicylic acid, non steroidal anti-inflammatory drugs, chloramphenicol, diflunisal, miconazole) St John's wort treatment Pregnancy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stephane Mouly, MD, PhD

Organizational Affiliation

Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Guy Simoneau, MD

Organizational Affiliation

Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboisière, Paris, France

Official's Role

Principal Investigator

Facility Information:

Facility Name

Therapeutic Research Unit, Department of Internal Medicine, Hospital Lariboière

City

Paris

ZIP/Postal Code

75010

Country

France

12. IPD Sharing Statement

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Drug Interaction Between Paracetamol and Warfarin

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