Drug Action ReversalPhase 2NCT02463591
Reversal of Dabigatran With Prothrombin Complex Concentrate
A Phase 2 study testing Beriplex in people with Drug Action Reversal, run by University Medical Center Groningen at 1 site in Netherlands.
Trial summary
The purpose of this study is to investigate whether Prothrombin Complex Concentrate (PCC) is effective in reversing the anticoagulant effect of Dabigatran, as assessed by two modified skin-bleeding tests. Read more about this study
- Who is it for?
- Ages 18 to 50 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Drug Action Reversal
- What is being tested?
- Beriplex
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteNetherlands
- Study dates
- Jan 2015to Dec 2016
- Phase
- Phase 2
- 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 to 50 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy males
- Age between 18 and 50 years
- Weight <100 kg
- Signed informed consent
- eGFR ≥ 80ml/min*1.73m2
Who cannot join
- History of allergic reaction to blood products
- Current participation in any other investigational drug study or within the past 30 days
- Increased bleeding tendency or history of thrombosis
- Anticoagulant medication, platelet aggregation inhibitors or NSAIDs
- Use of any medication 14 days before start of dabigatran intake
Trial locations and contacts
1 site in 1 country.
Netherlands1 site, 1 recruiting
- Recruiting
University Medical Centre
Groningen, Provincie Groningen, 9713 GZ
A C Stehouwer, MD, 0031503610116, a.c.stehouwer@umcg.nl
H Hop, MD, 0031503610116, h.hop@umcg.nl
About this study
Official title: Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement
The purpose of this study is to investigate whether Prothrombin Complex Concentrate (PCC) is effective in reversing the anticoagulant effect of Dabigatran, as assessed by two modified skin-bleeding tests.
Read the detailed description
There is currently no treatment widely available for immediate reversal of Dabigatran anticoagulant effects, e.g. in case of major bleeding or when emergency surgery or invasive procedures are indicated.
Treatment with prothrombin complex concentrate (PCC) seems effective in reducing blood loss in animal models, but previous studies in humans have failed to show an effect on blood coagulation parameters. Recently, two novel methods of skin blood loss, one called "shed blood" and another "washed blood" were able to measure effects of anticoagulation, either as the inhibition of fibrin formation at the wound site by measuring Fibrinopeptide A (FPA) or as elevated blood loss, respectively, after oral administration of Dabigatran in healthy volunteers.
The investigators hypothesise that the shed/washed blood methods are able to measure Dabigatran reversal following administration of PCC (Beriplex).
The study will be performed as a randomised double blind cross-over study and 12 healthy human male subjects will be enrolled. Subjects will take Dabigatran 300 mg b.i.d. on day -2, -1 and 0. After the fifth dose (on day 0), subjects will be randomised to receive Beriplex (50 IU/kg) or a similar volume of saline as a single bolus dose i.v. over 20 minutes. After a 10 day minimum wash-out period this procedure will be repeated, and the alternative treatment (Saline or Beriplex) is administered.
The Shed / Washed Blood measurements will be performed at different time points before and after starting oral anticoagulants and before and after administration of Beriplex/Saline.
In addition to the Shed / Washed blood tests, several ex vivo standard coagulation tests will be performed. These include: activated partial thromboplastin time (aPTT), prothrombin time (PT), diluted thrombin time (DTT/Hemoclot), Dabigatran plasma levels (using liquid chromatography-tandem mass spectrometry (LC-MS/MS)), endogenous thrombin generation (ETG) and pre and post factor II, VII, IX and X.
- Conditions
- Drug Action Reversal
- Being tested
- Beriplex
- Keywords
- Direct Thrombin Inhibitor, Prothrombin Complex Concentrate, Dabigatran Etexilate, Beriplex, Shed Blood, Washed Blood, Fibrinopeptide A
- Medical subject headings
- Hemophilia B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BeriplexDrug
Also called Prothrombin Complex Concentrate, RVG 101094, B02BD01
Beriplex 50 IU/Kg i.v. , single dose.
| Study group | Role | What they receive |
|---|---|---|
| Beriplex 50 IU/Kg | Experimental | Cross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Placebo). Receives: Drug: Beriplex |
| Placebo | Placebo comparator | Cross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Placebo identically in appearance to Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Beriplex). Receives: Drug: Beriplex |
What is being measured
The primary outcome is the main question the study is designed to answer.
Inhibition of the anticoagulant effect of Dabigatran, assessed by the "shed and washed blood" methods
The Shed blood test allows assessment of thrombin activity and subsequent fibrinogen conversion to fibrin in vivo by measuring fibrinopeptide A (FPA) generation. A standardized wound, using a disposable device (Surgicutt® Adult) is made on the volar surface of the forearm, from which blood is collected during 4 minutes. The total amount of shed blood is measured in addition to Fibrinopeptide A levels. FPA levels are compared to FPA levels in systemic venous samples collected at corresponding timepoints.
The washed blood test measures both the time until bleeding stops and sensitively measures small volumes of blood loss as area under the curve (AUC).
Measured: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=40 min.), After Dabigatran / After PCC (T=360 min.)
Secondary outcomes (1)
Change in Standard Coagulation Assays before / after Dabigatran and before / after PCC.
aPTT, PT, Diluted Thrombin Time (Hemoclot), Dabigatran Plasma Levels, Endogenous thrombin generation, pre- and Post coagulation factor II / VII / IX / X
Measured: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=20 min., T=40 min., T=60 min., T=120 min., T=240 min., T=360 min.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jun 2015 (estimated)
- Study startJan 2015
- Primary completionJul 2016 (estimated)
- Study completionDec 2016 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Drug Action ReversalStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Boehringer Ingelheim, CSL Behring
- Responsible party
- Principal investigator, Pieter W. Kamphuisen, MD PhD, University Medical Center Groningen
- Investigators
- Pieter Willem Kamphuisen, Prof. Dr., Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02463591
- Sponsor's protocol ID
- BI 1160.203
- Other IDs
- 2014-002204-24, 2014
- Status last verified
- May 2016
- First submitted
- 27 May 2015
- Last updated
- 12 May 2016
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Wolzt M, Eder M, Weltermann A, Entlicher J, Eichler HG, Kyrle PA. Comparison of the effects of different low molecular weight heparins on the hemostatic system activation in vivo in man. Thromb Haemost. 1997 Aug;78(2):876-9.
PubMed 9268188
Study at a glance
From the registry record, last updated by the sponsor on 12 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reversal of Anticoagulant Effect of Dabigatran® by Prothrombin Complex Concentrate (Beriplex®), Assessed With a Novel Method of Blood Loss Measurement
- ClinicalTrials.gov ID
- NCT02463591
- Acronym / sponsor ID
- BI 1160.203
- Conditions
- Drug Action Reversal
- Keywords
- Direct Thrombin Inhibitor, Prothrombin Complex Concentrate, Dabigatran Etexilate, Beriplex, Shed Blood, Washed Blood, Fibrinopeptide A
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Boehringer Ingelheim, CSL Behring
- Study start
- Jan 2015
- Primary completion
- Jul 2016 (estimated)
- Study completion
- Dec 2016 (estimated)
- First posted
- 4 Jun 2015 (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.
The purpose of this study is to investigate whether Prothrombin Complex Concentrate (PCC) is effective in reversing the anticoagulant effect of Dabigatran, as assessed by two modified skin-bleeding tests.
Detailed description
There is currently no treatment widely available for immediate reversal of Dabigatran anticoagulant effects, e.g. in case of major bleeding or when emergency surgery or invasive procedures are indicated.
Treatment with prothrombin complex concentrate (PCC) seems effective in reducing blood loss in animal models, but previous studies in humans have failed to show an effect on blood coagulation parameters. Recently, two novel methods of skin blood loss, one called "shed blood" and another "washed blood" were able to measure effects of anticoagulation, either as the inhibition of fibrin formation at the wound site by measuring Fibrinopeptide A (FPA) or as elevated blood loss, respectively, after oral administration of Dabigatran in healthy volunteers.
The investigators hypothesise that the shed/washed blood methods are able to measure Dabigatran reversal following administration of PCC (Beriplex).
The study will be performed as a randomised double blind cross-over study and 12 healthy human male subjects will be enrolled. Subjects will take Dabigatran 300 mg b.i.d. on day -2, -1 and 0. After the fifth dose (on day 0), subjects will be randomised to receive Beriplex (50 IU/kg) or a similar volume of saline as a single bolus dose i.v. over 20 minutes. After a 10 day minimum wash-out period this procedure will be repeated, and the alternative treatment (Saline or Beriplex) is administered.
The Shed / Washed Blood measurements will be performed at different time points before and after starting oral anticoagulants and before and after administration of Beriplex/Saline.
In addition to the Shed / Washed blood tests, several ex vivo standard coagulation tests will be performed. These include: activated partial thromboplastin time (aPTT), prothrombin time (PT), diluted thrombin time (DTT/Hemoclot), Dabigatran plasma levels (using liquid chromatography-tandem mass spectrometry (LC-MS/MS)), endogenous thrombin generation (ETG) and pre and post factor II, VII, IX and X.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Beriplex 50 IU/Kg | Experimental | Drug: BeriplexCross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Placebo). |
| Placebo | Placebo comparator | Drug: BeriplexCross over design: After therapy with Dabigatran Etexilate 300mg BID for 2.5 days, subjects will receive a single dose of Placebo identically in appearance to Beriplex 50 IU/Kg. After a 10 day minimum wash-out period subjects will receive the alternative treatment (Beriplex). |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Healthy males
- Age between 18 and 50 years
- Weight <100 kg
- Signed informed consent
- eGFR ≥ 80ml/min*1.73m2
Key exclusion criteria (5 listed)
- History of allergic reaction to blood products
- Current participation in any other investigational drug study or within the past 30 days
- Increased bleeding tendency or history of thrombosis
- Anticoagulant medication, platelet aggregation inhibitors or NSAIDs
- Use of any medication 14 days before start of dabigatran intake
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 |
|---|---|---|
| BeriplexAlso: Prothrombin Complex Concentrate, RVG 101094, B02BD01Beriplex 50 IU/Kg i.v. , single dose. | Drug | Beriplex 50 IU/Kg, Placebo |
Primary outcome
Inhibition of the anticoagulant effect of Dabigatran, assessed by the "shed and washed blood" methods
Time frame: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=40 min.), After Dabigatran / After PCC (T=360 min.)
The Shed blood test allows assessment of thrombin activity and subsequent fibrinogen conversion to fibrin in vivo by measuring fibrinopeptide A (FPA) generation. A standardized wound, using a disposable device (Surgicutt® Adult) is made on the volar surface of the forearm, from which blood is collected during 4 minutes. The total amount of shed blood is measured in addition to Fibrinopeptide A levels. FPA levels are compared to FPA levels in systemic venous samples collected at corresponding timepoints. The washed blood test measures both the time until bleeding stops and sensitively measures small volumes of blood loss as area under the curve (AUC).
1 secondary outcome
Change in Standard Coagulation Assays before / after Dabigatran and before / after PCC.
Time frame: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=20 min., T=40 min., T=60 min., T=120 min., T=240 min., T=360 min.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 May 2016.
- Background: PubMed 9268188Wolzt M, Eder M, Weltermann A, Entlicher J, Eichler HG, Kyrle PA. Comparison of the effects of different low molecular weight heparins on the hemostatic system activation in vivo in man. Thromb Haemost. 1997 Aug;78(2):876-9.
- Individual participant dataSharing planned: No
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.
Pieter Willem Kamphuisen, Prof. Dr. principal investigator
University Medical Center Groningen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Beriplex in people with Drug Action Reversal, run by University Medical Center Groningen at 1 site in Netherlands.
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 5 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: status not confirmed, as of the sponsor's last update on 12 May 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 Netherlands. 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. Some participants in this study may receive a placebo. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Alexander C Stehouwer, MD (0031503610116, a.c.stehouwer@umcg.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Inhibition of the anticoagulant effect of Dabigatran, assessed by the "shed and washed blood" methods (time frame: Before Dabigatran (Baseline, T= day-2), After Dabigatran / Before PCC (T= day 0), After Dabigatran / After PCC (T=40 min.), After Dabigatran / After PCC (T=360 min.)). 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 NCT02463591, which also lists 1 linked publication.
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 12 May 2016.