EndotoxemiaPhase 1NCT00513110
A Possible Therapeutic Role for Adenosine During Inflammation
A Phase 1 study testing AMPD1 polymorphism and Caffeine infusion in people with Endotoxemia, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
The adenosine receptor is known for its anti-inflammatory actions and could therefore be a potential target in the treatment of sepsis and septic shock. Stimulation of the adenosine receptor could potentially lead to a decrease in inflammation and tissue damage. 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?
- AMPD1 polymorphism and Caffeine infusion
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 33 participants
- Where
- 1 siteNetherlands
- Study dates
- Aug 2007to Aug 2008
- Phase
- Phase 1
- 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
- Healthy male volunteers
Who cannot join
- Drug-, nicotine-, alcohol abuses
- Tendency towards fainting
- Relevant medical history
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Radboud University Nijmegen Medical Centre
Nijmegen, Gelderland, 6500 HB
About this study
The adenosine receptor is known for its anti-inflammatory actions and could therefore be a potential target in the treatment of sepsis and septic shock. Stimulation of the adenosine receptor could potentially lead to a decrease in inflammation and tissue damage.
Under normal conditions adenosine is formed either by an intracellular 5'nucleotidase, which dephosphorylates AMP, or by the hydrolysis of S-adenosylhomcysteine by hydrolase. An alternative pathway of AMP degradations is provided by the cytosolic enzyme AMP deaminase (AMPD), which catalyses the irreversible deamination of AMP to inosine monophosphate and ammonia.
Read more
In humans four AMPD isoforms have been described, named after the source from which they were initially purified; M (muscle), L (liver), E1 and E2 (erythrocyte), encoded by AMPD1, AMPD2 and AMPD3. Approximately 15-20% of Caucasian and African American individuals are heterozygous or homozygous for the 34C>T variant of AMPD1.
We hypothesize that healthy volunteers who have the polymorphism for AMPD1 have a less severe inflammatory response to LPS and show less (severe) organ failure. This hypothesis is based on the expected higher levels of adenosine in patients with the AMPD1 polymorphism. This hypothesis is strengthened by the fact that patients with coronary artery disease and the AMPD1 polymorphism show improved cardiovascular survival (Anderson JL et al. J Am Coll Cardiol 2000; 36: 1248-52) possibly based on higher adenosine levels by reduced AMPD activity. Furthermore the polymorphism predicts improved clinical outcome in patients with heart failure (Loh E et al. Circulation 1999) also based on a hypothetical elevation of adenosine.
We hypothesize that:
The C34T-polymorphism of the enzyme AMP-deaminase leads to a decreased inflammatory respons and thereby a decrease of LPS-induced tissue damage.
A second hypothesis is based on the antagonism of the adenosine receptor, by caffeine;
Antagonism of the adenosine receptor by caffeine leads to an increased LPS-induced inflammatory reaction and an increase in (subclinical) tissue damage?
- Conditions
- Endotoxemia
- Being tested
- AMPD1 polymorphism, Caffeine infusion, placebo
- Keywords
- Endotoxin, Adenosine, Caffeine, AMPD1 polymorphism
- Medical subject headings
- Endotoxemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AMPD1 polymorphismGenetic
Endotoxin 2ng/kg to subjects with a AMPD1 polymorphism
Caffeine infusionDrug
Endotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist.
placeboDrug
Endotoxin 2ng/kg combined with saline infusion (0.9%)
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Endotoxin and AMPD1 polymorphism Receives: Genetic: AMPD1 polymorphism |
| 2 | Experimental | Endotoxin and intervention with caffeine Receives: Drug: Caffeine infusion |
| 3 | Placebo comparator | Endotoxin combined with placebo Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hemodynamics; heart rate variability
Measured: 24 hrs after LPS administration
Markers of Inflammation
Measured: 24 hrs after LPS administration
Cytokines
Measured: 24 hrs after LPS administration
Sensitivity to norepinephrine
Measured: 24 hrs after LPS administration
Endothelial-dependent and independent vasorelaxation
Measured: 24 hrs after LPS administration
Mediators of Vascular reactivity
Measured: 24 hrs after LPS administration
Markers of endothelial damage and circulating endothelial cells
Measured: 24 hrs after LPS administration
Urinary excretion of markers of renal injury
Measured: 24 hrs after LPS administration
Neurologic testing
Measured: 24 hrs after LPS administration
Adenosine and related nucleotide concentrations.
Measured: 24 hrs after LPS administration
Additional blood samples will be drawn for measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways.
Measured: 24 hrs 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 posted8 Aug 2007 (estimated)
- Study startAug 2007
- Primary completionAug 2008
- Study completionAug 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)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 1
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 33 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Investigators
- Peter Pickkers, MD,PhD, Principal investigator, Radboud University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00513110
- Sponsor's protocol ID
- 2007/099
- Other IDs
- CMO 2007/099
- Status last verified
- Aug 2007
- First submitted
- 7 Aug 2007
- Last updated
- 1 Oct 2009
- Results posted
- No
- Data monitoring committee
- No
Publications
Ramakers BP, Riksen NP, van den Broek P, Franke B, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Circulating adenosine increases during human experimental endotoxemia but blockade of its receptor does not influence the immune response and subsequent organ injury. Crit Care. 2011;15(1):R3. doi: 10.1186/cc9400. Epub 2011 Jan 6.
PubMed 21211004van den Boogaard M, Ramakers BP, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, Verbeek MM, Schoonhoven L, van der Hoeven JG, Pickkers P. Endotoxemia-induced inflammation and the effect on the human brain. Crit Care. 2010;14(3):R81. doi: 10.1186/cc9001. Epub 2010 May 5.
PubMed 20444270
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2009. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Possible Therapeutic Role for Adenosine During Inflammation
- ClinicalTrials.gov ID
- NCT00513110
- Acronym / sponsor ID
- 2007/099
- Conditions
- Endotoxemia
- Keywords
- Endotoxin, Adenosine, Caffeine, AMPD1 polymorphism
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (estimated)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- Aug 2007
- Primary completion
- Aug 2008 (actual)
- Study completion
- Aug 2008 (actual)
- First posted
- 8 Aug 2007 (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 adenosine receptor is known for its anti-inflammatory actions and could therefore be a potential target in the treatment of sepsis and septic shock. Stimulation of the adenosine receptor could potentially lead to a decrease in inflammation and tissue damage.
Under normal conditions adenosine is formed either by an intracellular 5'nucleotidase, which dephosphorylates AMP, or by the hydrolysis of S-adenosylhomcysteine by hydrolase. An alternative pathway of AMP degradations is provided by the cytosolic enzyme AMP deaminase (AMPD), which catalyses the irreversible deamination of AMP to inosine monophosphate and ammonia.
In humans four AMPD isoforms have been described, named after the source from which they were initially purified; M (muscle), L (liver), E1 and E2 (erythrocyte), encoded by AMPD1, AMPD2 and AMPD3. Approximately 15-20% of Caucasian and African American individuals are heterozygous or homozygous for the 34C>T variant of AMPD1.
We hypothesize that healthy volunteers who have the polymorphism for AMPD1 have a less severe inflammatory response to LPS and show less (severe) organ failure. This hypothesis is based on the expected higher levels of adenosine in patients with the AMPD1 polymorphism. This hypothesis is strengthened by the fact that patients with coronary artery disease and the AMPD1 polymorphism show improved cardiovascular survival (Anderson JL et al. J Am Coll Cardiol 2000; 36: 1248-52) possibly based on higher adenosine levels by reduced AMPD activity. Furthermore the polymorphism predicts improved clinical outcome in patients with heart failure (Loh E et al. Circulation 1999) also based on a hypothetical elevation of adenosine.
We hypothesize that:
The C34T-polymorphism of the enzyme AMP-deaminase leads to a decreased inflammatory respons and thereby a decrease of LPS-induced tissue damage.
A second hypothesis is based on the antagonism of the adenosine receptor, by caffeine;
Antagonism of the adenosine receptor by caffeine leads to an increased LPS-induced inflammatory reaction and an increase in (subclinical) tissue damage?
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Genetic: AMPD1 polymorphismEndotoxin and AMPD1 polymorphism |
| 2 | Experimental | Drug: Caffeine infusionEndotoxin and intervention with caffeine |
| 3 | Placebo comparator | Drug: placeboEndotoxin combined with placebo |
Who may qualify
- Ages
- 18 to 35 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- Healthy male volunteers
Key exclusion criteria (3 listed)
- Drug-, nicotine-, alcohol abuses
- Tendency towards fainting
- Relevant medical history
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 |
|---|---|---|
| AMPD1 polymorphismEndotoxin 2ng/kg to subjects with a AMPD1 polymorphism | Genetic | 1 |
| Caffeine infusionEndotoxin 2ng/kg combined with caffeine. Caffeine (4mg/kg) is used as an adenosine receptor antagonist. | Drug | 2 |
| placeboEndotoxin 2ng/kg combined with saline infusion (0.9%) | Drug | 3 |
Primary outcome
Hemodynamics; heart rate variability
Time frame: 24 hrs after LPS administration
Markers of Inflammation
Time frame: 24 hrs after LPS administration
Cytokines
Time frame: 24 hrs after LPS administration
Sensitivity to norepinephrine
Time frame: 24 hrs after LPS administration
Endothelial-dependent and independent vasorelaxation
Time frame: 24 hrs after LPS administration
Mediators of Vascular reactivity
Time frame: 24 hrs 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
Neurologic testing
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 measurement of: TLR-expression, Genetics; micro array analyses and determination of intercellular signalling pathways.
Time frame: 24 hrs 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 1 Oct 2009.
- Derived from this study: PubMed 21211004Ramakers BP, Riksen NP, van den Broek P, Franke B, Peters WH, van der Hoeven JG, Smits P, Pickkers P. Circulating adenosine increases during human experimental endotoxemia but blockade of its receptor does not influence the immune response and subsequent organ injury. Crit Care. 2011;15(1):R3. doi: 10.1186/cc9400. Epub 2011 Jan 6.
- Derived from this study: PubMed 20444270van den Boogaard M, Ramakers BP, van Alfen N, van der Werf SP, Fick WF, Hoedemaekers CW, Verbeek MM, Schoonhoven L, van der Hoeven JG, Pickkers P. Endotoxemia-induced inflammation and the effect on the human brain. Crit Care. 2010;14(3):R81. doi: 10.1186/cc9001. Epub 2010 May 5.
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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.
Peter Pickkers, MD,PhD 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 1 study testing AMPD1 polymorphism and Caffeine infusion 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 1 inclusion and 3 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 1 Oct 2009. 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Hemodynamics; heart rate variability (time frame: 24 hrs after LPS administration). The study lists 11 primary outcomes in all. 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 NCT00513110, which also lists 2 linked publications.
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 1 Oct 2009.