EndotoxemiaPhase 4NCT01091571
The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia
A Phase 4 study testing Dipyridamole and LPS in people with Endotoxemia, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. Read more about this study
- Who is it for?
- Ages 18 to 35 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Endotoxemia
- What is being tested?
- Dipyridamole and LPS
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 30 participants
- Where
- 1 siteNetherlands
- Study dates
- Mar 2010to Oct 2010
- 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 to 35 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age ≥ 18 and ≤ 35 years
- Male
- Healthy
Who cannot join
- Use of any medication.
- History of allergic reaction to dipyridamole
- Bleeding disorder.
- Smoking.
- Previous spontaneous vagal collapse.
- History, signs or symptoms of cardiovascular disease.
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- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block.
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90).
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50).
- Renal impairment (defined as plasma creatinin >120 μmol/l).
- Liver enzyme abnormalities or positive hepatitis serology.
- Positive HIV serology or any other obvious disease associated with immune deficiency.
- Febrile illness in the week before the LPS challenge.
- Participation in another drug trial or donation of blood 3 months prior to the planned LPS challenge.
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Radboud University Nijmegen Medical Centre
Nijmegen, 6500 HB
About this study
Official title: The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.
During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. In the last few years adenosine is proposed to have a central role in the modulation of inflammation. In unfavorable conditions such as hypoxia, ischemia or inflammation adenosine is quickly up-regulated; with concentrations up to tenfold in septic patients. Many animal studies have shown that adenosine is able to attenuate the inflammatory response and decrease mortality rates. Therefore, pharmacological elevation of the adenosine concentration is an potential target to attenuate inflammation and limit organ injury. Dipyridamole, an adenosine re-uptake inhibitor is able to increase the adenosine concentration and limit ischemia-reperfusion injury. In order to study the effects of dipyridamole on the inflammatory response we aim to use the so called human endotoxemia model. This model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting.
- Conditions
- Endotoxemia
- Being tested
- Dipyridamole, Placebo, LPS
- Keywords
- Adenosine, Endotoxin, Innate Immunity, Dipyridamole
- Medical subject headings
- Endotoxemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DipyridamoleDrug
Also called Persantin retard
Oral treatment with dipyridamole 200 mg twice daily during seven consecutive days
PlaceboDrug
Placebo twice daily during seven consecutive days
LPSOther
Also called Human endotoxemia
The LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight.
| Study group | Role | What they receive |
|---|---|---|
| Endotoxemia placebo | Placebo comparator | Endotoxin combined with placebo Receives: Drug: Placebo; Other: LPS |
| Endotoxemia Dipyridamole | Experimental | Endotoxin combined with Dipyridamol treatment Receives: Drug: Dipyridamole; Other: LPS |
What is being measured
The primary outcome is the main question the study is designed to answer.
Circulating cytokines
TNFx, IL6, IL10, IL1RA
Measured: 24 hours after LPS administration
Secondary outcomes (8)
Hemodynamics
Continious heart rate and blood pressure measurement
Measured: 24 hours after LPS administration
Sensitivity to norepinephrine
Venous occlusion plethysmography
Measured: 24 hrs after LPS administration
Endothelial-dependent and independent vasorelaxation
Venous occlusion plethysmography
Measured: 24 hours after LPS administration
Markers of endothelial damage and circulating endothelial cells
circulating adhesion molecules (ICAM, VCAM, E-selectin, P-selectin) circulating endothelial cells
Measured: 24 hrs after LPS administration
Urinary excretion of markers of renal injury
GSTAlpha1-1 and GSTPi1-1
Measured: 24 hrs after LPS administration
Adenosine and related nucleotide concentrations
Measured: 24 hrs after LPS administration
Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism
Measured: 24 hours after LPS administration
Oxydative stress
Thiols, neutrophilic burst, calcium release of neuthrophils, TBARS, Carbonyls, FRAP, Myeloperoxidase, catalase, Griess assay
Measured: 24 hours after LPS administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2010 (estimated)
- Study startMar 2010
- Primary completionOct 2010
- Study completionOct 2010
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 EndotoxemiaStudies of the same condition, open and under way.
- More trials run by Radboud University Medical CenterThe 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 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 30 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Investigators
- Bart P Ramakers, MD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01091571
- Sponsor's protocol ID
- 2009/347
- Status last verified
- Mar 2010
- First submitted
- 18 Mar 2010
- Last updated
- 5 Nov 2010
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Dipyridamole augments the antiinflammatory response during human endotoxemia. Crit Care. 2011;15(6):R289. doi: 10.1186/cc10576. Epub 2011 Nov 30.
PubMed 22129171
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2010. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Oral Dipyridamole Treatment on the Innate Immune Response During Human Endotoxemia.
- ClinicalTrials.gov ID
- NCT01091571
- Acronym / sponsor ID
- 2009/347
- Conditions
- Endotoxemia
- Keywords
- Adenosine, Endotoxin, Innate Immunity, Dipyridamole
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (estimated)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Mar 2010
- Primary completion
- Oct 2010 (actual)
- Study completion
- Oct 2010 (actual)
- First posted
- 24 Mar 2010 (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.
During sepsis and septic shock the immune response can be overwhelming leading to excessive tissue damage, organ failure and death. Ideally, the inflammatory response is modulated leading to both adequate protection to invading pathogens as well as limitation of an exuberant immune response. In the last few years adenosine is proposed to have a central role in the modulation of inflammation. In unfavorable conditions such as hypoxia, ischemia or inflammation adenosine is quickly up-regulated; with concentrations up to tenfold in septic patients. Many animal studies have shown that adenosine is able to attenuate the inflammatory response and decrease mortality rates. Therefore, pharmacological elevation of the adenosine concentration is an potential target to attenuate inflammation and limit organ injury. Dipyridamole, an adenosine re-uptake inhibitor is able to increase the adenosine concentration and limit ischemia-reperfusion injury. In order to study the effects of dipyridamole on the inflammatory response we aim to use the so called human endotoxemia model. This model permits elucidation of key players in the immune response to a gram negative stimulus in vivo, therefore serving as a useful tool to investigate potential novel therapeutic strategies in a standardized setting.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Endotoxemia placebo | Placebo comparator | Drug: Placebo, Other: LPSEndotoxin combined with placebo |
| Endotoxemia Dipyridamole | Experimental | Drug: Dipyridamole, Other: LPSEndotoxin combined with Dipyridamol treatment |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- Age ≥ 18 and ≤ 35 years
- Male
- Healthy
Key exclusion criteria (14 listed)
- Use of any medication.
- History of allergic reaction to dipyridamole
- Bleeding disorder.
- Smoking.
- Previous spontaneous vagal collapse.
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 |
|---|---|---|
| DipyridamoleAlso: Persantin retardOral treatment with dipyridamole 200 mg twice daily during seven consecutive days | Drug | Endotoxemia Dipyridamole |
| PlaceboPlacebo twice daily during seven consecutive days | Drug | Endotoxemia placebo |
| LPSAlso: Human endotoxemiaThe LPS derived from E. coli O:113 2ng/kg iv will be injected in 1 minute at a dosage of 2 ng/kg body weight. | Other | Endotoxemia Dipyridamole, Endotoxemia placebo |
Primary outcome
Circulating cytokines
Time frame: 24 hours after LPS administration
TNFx, IL6, IL10, IL1RA
8 secondary outcomes
Hemodynamics
Time frame: 24 hours after LPS administration
Sensitivity to norepinephrine
Time frame: 24 hrs after LPS administration
Endothelial-dependent and independent vasorelaxation
Time frame: 24 hours after LPS administration
Markers of endothelial damage and circulating endothelial cells
Time frame: 24 hrs after LPS administration
Urinary excretion of markers of renal injury
Time frame: 24 hrs after LPS administration
Adenosine and related nucleotide concentrations
Time frame: 24 hrs after LPS administration
Additional blood samples will be drawn for genetic testing and measurement of: mRNA and proteins part of the adenosine metabolism
Time frame: 24 hours after LPS administration
Oxydative stress
Time frame: 24 hours after LPS administration
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 5 Nov 2010.
- Derived from this study: PubMed 22129171Ramakers BP, Riksen NP, Stal TH, Heemskerk S, van den Broek P, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Dipyridamole augments the antiinflammatory response during human endotoxemia. Crit Care. 2011;15(6):R289. doi: 10.1186/cc10576. Epub 2011 Nov 30.
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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.
Bart P Ramakers, MD principal investigator
Radboud University Medical Center
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 Dipyridamole and LPS in people with Endotoxemia, run by Radboud University Medical Center 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 3 inclusion and 14 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 5 Nov 2010. 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 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?
Circulating cytokines (time frame: 24 hours after LPS administration). 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 NCT01091571, 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 5 Nov 2010.