- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02602977
the Influence of Remote Ischemic Preconditioning on Inflammation During Human Endotoxemia (RISPENDO)
the Influence of Remote Ischemic Preconditioning on Inflammation During Human Endotoxemia, a Pilot Proof-of-principle Study
Study Overview
Status
Conditions
Detailed Description
Although the immune system is essential to survival, a variety of diseases originate from inappropriate or excessive activation of the immune response. Examples include a wide range of auto-inflammatory disease, infectious diseases such as sepsis, but also after major surgery like cardiac artery bypass grafting, after radiation therapy in the treatment of cancer, or following organ transplantation. In these instances, attenuation of the immune response could be beneficial.
The concept of ischemic preconditioning (IPC) was first described in the 1980's. Murry and colleagues showed a protective effect of preconditioning the heart with 4 cycles of 5-minute long ischemia on the extent of myocardial infarction in dog hearts. Follow-up animal studies showed the same protective effects on the heart by introducing the cycles of ischemia to distant, or 'remote', organs like the kidney or the gut. Furthermore, this principle of 'remote ischemic preconditioning' (RIPC) was also shown to be effective in humans when using a tourniquet to temporary cut off blood supply to one of the limbs, either an arm or a leg. As such, RIPC has been identified as a cheap and easy method of protecting patients undergoing elective CABG surgery from perioperative myocardial ischemic damage. In recent studies, two different timeframes in which RIPC exerts its protective effects have been identified. The classical or 'early window of protection' protects in the 1-2 hour after the RIPC stimulus while a 'second window of protection' is evident 12-24 hours after RIPC and lasts for 48-72 hours. Multiple-dose RIPC may be of additional value, as 7 daily doses of RIPC in humans resulted in protection of endothelial dysfunction, with both the local and remote beneficial effects lasting for up to 8 days after the last RIPC dose. This could be due to additive or synergistic effects of combining the first and second windows of protection.
The mechanisms behind the observed protective effects are however still subject of investigation. Several have been put forward, of which attenuation of the inflammatory response is a major candidate.
For instance, recent animal work has shown that RIPC results in downregulation of pro-inflammatory cytokines such as TNF-α and IL-6 and upregulation of anti-inflammatory cytokines such as IL-10. In support of the latter, the cardioprotective effects of RIPC were absent in IL-10 knockout mice or in wild-type mice treated with a monoclonal antibody against the IL-10 receptor. Hypoxia-inducible factor (HIF) has been shown to be a major contributor to this RIPC-induced IL-10 response.
Adenosine appears to be a major determinant of the anti-inflammatory and tissue-protective effects of RIPC. In a in vivo forearm model, adenosine and ischemic preconditioning both resulted in the same reduction in ischemia-reperfusion injury. Also, administration of exogenous adenosine can mimic the protective effects of IPC, and antagonizing the adenosine receptor with caffeine blocks the protective effects of RIPC and augments the anti-inflammatory IL-10 response to lipopolysaccharide (LPS). Interestingly, one of the pathways in which ischemia-reperfusion can increase adenosine levels is through upregulation of CD73, which is dependent on the aforementioned HIF.
Another possible mechanism behind the anti-inflammatory effects of RIPC is release of Toll-like receptor (TLR) ligands, which in turn induce an endotoxin tolerance-like state. Endotoxin tolerance is a refractory state of the immune system after challenge with the TLR4 ligand LPS, characterized by diminished cytokine production upon a subsequent LPS challenge. However, induction of endotoxin tolerance was found to occur not only after LPS challenge but also using other TLR(4)-ligands, so-called 'cross-tolerance'. A possible candidate to induce tolerance in RIPC is heat shock protein 70 (HSP70), as extracellular HSP70 has been shown to induce tolerance to LPS in monocytes in vitro. Furthermore, in rats receiving ischemic preconditioning of the lower extremity, HSP70 expression was increased in the spinal cord and myocardium, and HSP70 upregulation was found in cardiomyocytes after RIPC in infants undergoing cardiac surgery. However, other, yet unidentified TLR ligands could also be involved.
From the abovementioned studies, it appears that RIPC exerts significant effects on the immune response. However, this has not yet been demonstrated in the setting of systemic inflammation in humans in vivo. Furthermore, the mechanisms behind the putative anti-inflammatory effects and possible additive or synergistic effects of repeated RIPC (thereby combining both the first and second windows of protection) are unknown as well. This study aims to investigate the effects of (repeated) ischemic preconditioning during human endotoxemia, a standardized controlled model of inflammation.
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
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Nijmegen, Netherlands, 6525 GA
- Radboud University Medical Centre, Intensive Care
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Written informed consent to participate in this trial
- Male subjects aged 18 to 35 years inclusive
- Healthy as determined by medical history, physical examination, vital signs, 12-lead electrocardiogram and clinical laboratory parameters
Exclusion Criteria:
- Use of any medication
- Smoking
- Use of recreational drugs within 21 days prior to endotoxemia experiment day
- Use of caffeine or alcohol within 1 day prior to endotoxemia experiment day
- Previous participation in a trial where LPS was administered
- Surgery or trauma with significant blood loss or blood donation within 3 months prior to endotoxemia experiment day
- Participation in another clinical trial within 3 months prior to endotoxemia experiment day
- History, signs, or symptoms of cardiovascular disease
- History of frequent vaso-vagal collapse or of orthostatic hypotension
- History of atrial or ventricular arrhythmia
- Hypertension (RR systolic >160 or RR diastolic >90)
- Hypotension (RR systolic <100 or RR diastolic <50)
- Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block
- Renal impairment: plasma creatinine >120 µmol/L
- Liver function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L
- History of asthma
- Obvious disease associated with immune deficiency
- CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxemia day
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: multiple-dose RIPC
Multiple-dose Remote Ischemic Preconditioning.
A group of 10 subjects that will receive 4 cycles of remote ischemic preconditioning of the upper limb per day in the 7 consecutive days before the endotoxemia experiment.
The last dose will be applied 40 minutes before LPS administration.
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A blood-pressure cuff with handheld rubber inflation balloon and manometer is placed on the non-dominant arm of the subject. The cuff will be placed proximally from the elbow with the most proximal part of the cuff placed in the armpit. The cuff will be inflated to 250 mmHg after which a 5 minute countdown is started. After 5 minutes the pressure is released and the 5 minute countdown for reperfusion is started. This concludes one cycle out of a total of four. 1 "RIPC-dose" consists of 4 cycles of 5 minute ischemia followed by 5 minute reperfusion as described above. Multiple-dose RIPC consists of a daily dose of 1 RIPC as described above for 7 consecutive days.
Other Names:
To achieve a controlled inflammatory state, 30 subjects (multiple-dose RIPC group [n=10], single-dose RIPC group [n=10] and control group [n=10]) will receive LPS intravenously.
The LPS at a dose of 2 ng/kg iv will be injected in 1 minute.
Other Names:
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Experimental: single-dose RIPC
Single-dose Remote Ischemic Preconditioning.
A group of 10 subjects that will receive a single RIPC dose, starting 40 minutes before LPS administration.
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To achieve a controlled inflammatory state, 30 subjects (multiple-dose RIPC group [n=10], single-dose RIPC group [n=10] and control group [n=10]) will receive LPS intravenously.
The LPS at a dose of 2 ng/kg iv will be injected in 1 minute.
Other Names:
A blood-pressure cuff with handheld rubber inflation balloon and manometer is placed on the non-dominant arm of the subject. The cuff will be placed proximally from the elbow with the most proximal part of the cuff placed in the armpit. The cuff will be inflated to 250 mmHg after which a 5 minute countdown is started. After 5 minutes the pressure is released and the 5 minute countdown for reperfusion is started. This concludes one cycle out of a total of four. 1 "RIPC-dose" consists of 4 cycles of 5 minute ischemia followed by 5 minute reperfusion as described above. Single-dose RIPC consists of 1 dose of RIPC as described above
Other Names:
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Active Comparator: control group
Only LPS infusion.
A group of 10 subjects that will be administered LPS without RIPC.
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To achieve a controlled inflammatory state, 30 subjects (multiple-dose RIPC group [n=10], single-dose RIPC group [n=10] and control group [n=10]) will receive LPS intravenously.
The LPS at a dose of 2 ng/kg iv will be injected in 1 minute.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma TNF-α concentration following LPS administration
Time Frame: 1 day
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The primary study parameter is the difference in circulating TNF-α concentration over time between the multiple-dose (7 days) RIPC group and the control group.
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1 day
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
circulating cytokines (including but not limited to IL-6, IL-10, IL-1RA)
Time Frame: 1 day
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1 day
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body temperature
Time Frame: 1 day
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1 day
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Hemodynamic parameters
Time Frame: 1 day
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blood pressure, heart frequency, respiratory frequency
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1 day
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subjective symptom scores
Time Frame: 1 day
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The subject is asked to score the severity of experienced symptoms every 30 minutes throughout the experiment.
Symptom are scored on a scale ranging from 0, (symptom not present) to 5 (worst ever experienced).
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1 day
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kidney injury markers in urine - TIMP2*IGFBP7
Time Frame: 1 day
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TIMP2*IGFBP7 (expressed in ng/ml^2) is a combined marker that is measured using the NephroCheck Test (Astute Medical, San Diego, CA, USA).
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1 day
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Collaborators and Investigators
Investigators
- Principal Investigator: Jelle Zwaag, MSc, Radboud University Medical Center
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- RISPENDO
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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