Heart DiseasesPRODOSENCT03532594
Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass
A study testing PRODOSE Algorithm in people with Heart Diseases and Cardiovascular Diseases, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
Trial summary
The PRODOSE trial is investigating a bespoke pharmacokinetic algorithm that calculates a tailored dose of protamine, required after cardiopulmonary bypass to reverse the action of heparin, based on individual patients and their actual bypass time. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Diseases, Cardiovascular Diseases
- What is being tested?
- PRODOSE Algorithm
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 228 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 16 Apr 2018to 30 Jan 2020
- Phase
- Interventional
- 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
- Patients scheduled to undergo elective cardiac surgery
Who cannot join
- Emergency surgery
- Age < 18 years
- Known or suspected coagulopathy or platelet dysfunction
- Adenosine diphosphate (ADP)-receptor antagonists within 7 days of surgery (clopidogrel, ticlopidine, prasugrel)
- Total body weight > 130kg
- End stage renal failure requiring dialysis
Show all 9Show fewer
- Plan for severe hypothermia (< 28°C) or deep hypothermic circulatory arrest
- Complex cardiac surgery (redo sternotomy, surgery on the thoracic aorta [excluding root])
- Transplantation
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Royal Papworth Hospital NHS Foundation Trust
Cambridge, Cambridgeshire, CB23 3RE
About this study
Official title: Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass (PRODOSE)
The PRODOSE trial is investigating a bespoke pharmacokinetic algorithm that calculates a tailored dose of protamine, required after cardiopulmonary bypass to reverse the action of heparin, based on individual patients and their actual bypass time.
The PRODOSE trial aims to demonstrate that the algorithm can be used to define a protamine dose that will more reliably return coagulation parameters to pre-heparin levels as well as decreasing the risk of post-operative bleeding and transfusion.
The trial aims to recruit 200 patients who will be randomised to either a bespoke or standard dose of protamine. The randomisation ratio will be 1:1 in the first instance but the trial uses an adaptive design and an interim analysis will be conducted after 100 patients have been randomised. The randomisation ratio could then be updated after the interim analysis to favour a superior arm whilst preserving statistical power levels.
Read the detailed description
Open-heart surgery is routinely conducted using a heart-lung machine. In order to conduct operations involving heart-lung machines a patient's coagulation system needs to be reliably suppressed to avoid clot formation. Clot in the extracorporeal circuit generally has fatal consequences.
In the vast majority of cases (>99%) the desired suppression of the blood clotting system is achieved by administering heparin. Although relatively short acting, with a half-life of about 150min for a full adult dose, heparin needs to be reversed after weaning from the heart-lung machine in order to avoid catastrophic bleeding post-operatively.
Heparin reversal is achieved by using protamine. This drug is derived from salmon sperm and is generally safe to use. However, in a reasonable number of cases it can have severe side effects, ranging from dangerous hypotension to high blood pressure in the lung circulation with adequately oxygenate the patient. Severe anaphylactic reactions have also been described. There is also increasing evidence that inadequately high doses of protamine may lead to an increased bleeding tendency.
There is controversy about the right dosing of protamine. Traditionally a pragmatic and empirical '1:1' formula is used reversing 100 Units of heparin with 1mg of protamine. This dosing regime does not take the decay of heparin during the time spent on the heart-lung machine into account and potentially exposes patients to unnecessarily high doses of protamine.
The research team was previously able to demonstrate in a pilot project that using a pharmacokinetic algorithm, which takes heparin decay into account, can reduce the protamine dose given to patients without increased bleeding or transfusion requirements.
The team have continued to develop this algorithm into a 2 compartmental model and are seeking to test the hypothesis that using the new formula can reduce patients' risk of the unwanted side-effects of protamine by reducing its dose.
- Conditions
- Heart Diseases, Cardiovascular Diseases
- Being tested
- PRODOSE Algorithm, Standard Care
- Keywords
- Protamine, Heparin Antagonists, Cardiopulmonary Bypass
- Medical subject headings
- Heart Diseases, Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PRODOSE AlgorithmProcedure or surgery
Protamine administered according to PRODOSE algorithm
Standard CareProcedure or surgery
Protamine administered according to Standard Care
| Study group | Role | What they receive |
|---|---|---|
| Standard Care | Other | At the conclusion of cardiopulmonary bypass, protamine administration will be undertaken at surgical request. For patients in the control group, protamine will be dosed on a 1:1 ratio according to the total dose of heparin initially required to establish a therapeutic activated clotting time (ACT) (i.e. if 30,000 IU were required prior to initiating cardiopulmonary bypass, then the protamine dose will be 300mg). Receives: Procedure: Standard Care |
| Algorithm | Experimental | For patients in the intervention group, protamine will be administered according to the PRODOSE algorithm, which has been incorporated into an Excel spread sheet for ease of use (Microsoft Corporation). Receives: Procedure: PRODOSE Algorithm |
What is being measured
The primary outcome is the main question the study is designed to answer.
Return to normal coagulation after cessation of cardiopulmonary bypass and reversal of heparin
Kaolin Thrombelastography (TEG) r-time
Measured: 3 minutes post-protamine administration after cessation of cardiopulmonary bypass.
Secondary outcomes (2)
Blood loss
Intercostal drain output
Measured: 4 hours post-surgery
Blood products usage
Use of blood products
Measured: 24 hours post-surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 May 2018
- Study start16 Apr 2018
- Primary completion30 Oct 2019
- Study completion30 Jan 2020
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 Heart DiseasesStudies 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- The randomisation ratio will be 1:1 in the first instance but the trial uses an adaptive design and an interim analysis will be conducted after 100 patients have been randomised.
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 228 participants (actual)
Sponsor and investigators
- Lead sponsor
- Papworth Hospital NHS Foundation Trust
- Sponsor type
- Other government
- Collaborators
- Austin Health
- Responsible party
- Sponsor
- Investigators
- Florian Falter, FRCA, Principal investigator, Papworth Hospital NHS Foundation TrustLachlan Miles, FRCA, Principal investigator, Austin Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03532594
- Sponsor's protocol ID
- P02337
- Acronym
- PRODOSE
- Status last verified
- Jun 2020
- First submitted
- 26 Apr 2018
- Last updated
- 23 Jun 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Miles LF, Burt C, Arrowsmith J, McKie MA, Villar SS, Govender P, Shaylor R, Tan Z, De Silva R, Falter F. Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial. PLoS Med. 2021 Jun 7;18(6):e1003658. doi: 10.1371/journal.pmed.1003658. eCollection 2021 Jun.
PubMed 34097705
Study at a glance
From the registry record, last updated by the sponsor on 23 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Algorithmic Protamine Dosing for Reversal of Heparin After Cardiopulmonary Bypass (PRODOSE)
- ClinicalTrials.gov ID
- NCT03532594
- Acronym / sponsor ID
- PRODOSE / P02337
- Conditions
- Heart Diseases, Cardiovascular Diseases
- Keywords
- Protamine, Heparin Antagonists, Cardiopulmonary Bypass
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 228 participants (actual)
- Lead sponsor
- Papworth Hospital NHS Foundation TrustOther government
- Collaborators
- Austin Health
- Study start
- 16 Apr 2018 (actual)
- Primary completion
- 30 Oct 2019 (actual)
- Study completion
- 30 Jan 2020 (actual)
- First posted
- 22 May 2018 (actual)
- 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 PRODOSE trial is investigating a bespoke pharmacokinetic algorithm that calculates a tailored dose of protamine, required after cardiopulmonary bypass to reverse the action of heparin, based on individual patients and their actual bypass time.
The PRODOSE trial aims to demonstrate that the algorithm can be used to define a protamine dose that will more reliably return coagulation parameters to pre-heparin levels as well as decreasing the risk of post-operative bleeding and transfusion.
The trial aims to recruit 200 patients who will be randomised to either a bespoke or standard dose of protamine. The randomisation ratio will be 1:1 in the first instance but the trial uses an adaptive design and an interim analysis will be conducted after 100 patients have been randomised. The randomisation ratio could then be updated after the interim analysis to favour a superior arm whilst preserving statistical power levels.
Detailed description
Open-heart surgery is routinely conducted using a heart-lung machine. In order to conduct operations involving heart-lung machines a patient's coagulation system needs to be reliably suppressed to avoid clot formation. Clot in the extracorporeal circuit generally has fatal consequences.
In the vast majority of cases (>99%) the desired suppression of the blood clotting system is achieved by administering heparin. Although relatively short acting, with a half-life of about 150min for a full adult dose, heparin needs to be reversed after weaning from the heart-lung machine in order to avoid catastrophic bleeding post-operatively.
Heparin reversal is achieved by using protamine. This drug is derived from salmon sperm and is generally safe to use. However, in a reasonable number of cases it can have severe side effects, ranging from dangerous hypotension to high blood pressure in the lung circulation with adequately oxygenate the patient. Severe anaphylactic reactions have also been described. There is also increasing evidence that inadequately high doses of protamine may lead to an increased bleeding tendency.
There is controversy about the right dosing of protamine. Traditionally a pragmatic and empirical '1:1' formula is used reversing 100 Units of heparin with 1mg of protamine. This dosing regime does not take the decay of heparin during the time spent on the heart-lung machine into account and potentially exposes patients to unnecessarily high doses of protamine.
The research team was previously able to demonstrate in a pilot project that using a pharmacokinetic algorithm, which takes heparin decay into account, can reduce the protamine dose given to patients without increased bleeding or transfusion requirements.
The team have continued to develop this algorithm into a 2 compartmental model and are seeking to test the hypothesis that using the new formula can reduce patients' risk of the unwanted side-effects of protamine by reducing its dose.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- The randomisation ratio will be 1:1 in the first instance but the trial uses an adaptive design and an interim analysis will be conducted after 100 patients have been randomised.
| Arm | Type | Receives |
|---|---|---|
| Standard Care | Other | Procedure: Standard CareAt the conclusion of cardiopulmonary bypass, protamine administration will be undertaken at surgical request. For patients in the control group, protamine will be dosed on a 1:1 ratio according to the total dose of heparin initially required to establish a therapeutic activated clotting time (ACT) (i.e. if 30,000 IU were required prior to initiating cardiopulmonary bypass, then the protamine dose will be 300mg). |
| Algorithm | Experimental | Procedure: PRODOSE AlgorithmFor patients in the intervention group, protamine will be administered according to the PRODOSE algorithm, which has been incorporated into an Excel spread sheet for ease of use (Microsoft Corporation). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Patients scheduled to undergo elective cardiac surgery
Key exclusion criteria (9 listed)
- Emergency surgery
- Age < 18 years
- Known or suspected coagulopathy or platelet dysfunction
- Adenosine diphosphate (ADP)-receptor antagonists within 7 days of surgery (clopidogrel, ticlopidine, prasugrel)
- Total body weight > 130kg
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 |
|---|---|---|
| PRODOSE AlgorithmProtamine administered according to PRODOSE algorithm | Procedure or surgery | Algorithm |
| Standard CareProtamine administered according to Standard Care | Procedure or surgery | Standard Care |
Primary outcome
Return to normal coagulation after cessation of cardiopulmonary bypass and reversal of heparin
Time frame: 3 minutes post-protamine administration after cessation of cardiopulmonary bypass.
Kaolin Thrombelastography (TEG) r-time
2 secondary outcomes
Blood loss
Time frame: 4 hours post-surgery
Blood products usage
Time frame: 24 hours post-surgery
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 Jun 2020.
- Derived from this study: PubMed 34097705Miles LF, Burt C, Arrowsmith J, McKie MA, Villar SS, Govender P, Shaylor R, Tan Z, De Silva R, Falter F. Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial. PLoS Med. 2021 Jun 7;18(6):e1003658. doi: 10.1371/journal.pmed.1003658. eCollection 2021 Jun.
- Individual participant dataSharing planned: No
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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.
Florian Falter, FRCA principal investigator
Papworth Hospital NHS Foundation Trust
Lachlan Miles, FRCA principal investigator
Austin Health
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing PRODOSE Algorithm in people with Heart Diseases and Cardiovascular Diseases, run by Papworth Hospital NHS Foundation Trust at 1 site in United Kingdom.
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 1 inclusion and 9 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 Jun 2020. 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 United Kingdom. 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.
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?
Return to normal coagulation after cessation of cardiopulmonary bypass and reversal of heparin (time frame: 3 minutes post-protamine administration after cessation of cardiopulmonary bypass.). 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 NCT03532594, 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 23 Jun 2020.