Cardiovascular DiseasesNCT05682456
High-fat Challenge Induced Trained Innate Immunity (SHAKE Study)
A study testing High-fat shake and Reference shake in people with Cardiovascular Diseases, run by Radboud University Medical Center at 1 site in Netherlands.
Trial summary
The goal of this randomized controlled cross-over trial is to investigate whether a single high-fat challenge can induce trained innate immunity in healthy volunteers. The main question it aims to answer is: Can a single high-fat challenge induce a persistent pro-inflammatory and pro-atherogenic monocyte phenotype, as… Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Cardiovascular Diseases
- What is being tested?
- High-fat shake and Reference shake
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 16 participants
- Where
- 1 siteNetherlands
- Study dates
- 6 May 2019to 15 Oct 2021
- 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 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- LDL cholesterol < 3.5 mmol/l, fasting triglycerides < 2 mmol/l
- No previous cardiovascular events
Who cannot join
- Smoking within the year before study entry
- Diagnosed with any long-term medical condition that can interfere with the study (i.e.
- gallbladder disease, renal failure, cardiovascular disease, diabetes, rheumatoid arthritis etc.)
- Medication (with the exception of oral contraceptives) or supplement use (i.e. omega3)
- BMI < 18 or > 27 kg/m2
- Previous vaccination within 3 months prior to study entry
Show all 11Show fewer
- Current infection or clinically significant infections within 1 month before study entry (defined as fever > 38.5°C)
- Allergic to cow milk/dairy products
- Pregnancy/lactation
- Abuse of drugs or alcohol
- Vegetarian diet
Trial locations and contacts
1 site in 1 country.
About this study
Official title: High-fat Challenge Induced Trained Innate Immunity
The goal of this randomized controlled cross-over trial is to investigate whether a single high-fat challenge can induce trained innate immunity in healthy volunteers. The main question it aims to answer is: Can a single high-fat challenge induce a persistent pro-inflammatory and pro-atherogenic monocyte phenotype, as detected by an augmented cytokine production capacity? To study this, participants will receive an oral high-fat and reference shake in a cross-over design and blood will be drawn before and at 1, 2, 4, 6, 24, and 72 hours after the shakes.
Read the detailed description
Rationale: Atherosclerosis is characterized by a persistent inflammation of the arterial wall.
Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. It has recently been shown that not only immune cells of the adaptive immune system, but innate immune cells as well are able to adopt a long-term pro-inflammatory phenotype upon stimulation. This nonspecific memory of innate immune cells is mediated by epigenetic and metabolic reprogramming and is termed "trained innate immunity." Previous findings from our lab have shown that not only bacterial components such as LPS, but also pro-atherogenic particles such as oxidized LDL can induce trained immunity in monocytes. Interestingly, this memory-effect of trained immunity indicates that even temporary triggers could induce the persistent inflammation in atherosclerosis.
Triglyceride-rich lipoproteins (TRL) have been identified as an important independent risk factor for atherosclerosis. Moreover, elevated plasma levels of these lipoproteins are associated with increased pro-inflammatory markers. TRLs, however, are characterized by alternating plasma levels, with brief elevations following (fat containing) meals. Notably, a high-fat meal not only contributes to the transient increase of TRL plasma levels, but also induces a brief elevation in LPS levels by briefly increasing the permeability of the gut.
We now aim to investigate whether a single high-fat meal can induce trained innate immunity, since this concept might explain how brief postprandial effects can translate into a long-term pro-inflammatory and pro-atherogenic monocyte phenotype.
Objective: The primary objective is to determine whether a high-fat meal can induce a persistent pro-inflammatory monocyte phenotype, characterized by an increased cytokine production capacity upon ex vivo stimulation. Secondary objectives are metabolic and epigenetic reprogramming of monocytes at these time points as well as the capacity of serum, isolated before and 1-6h after an oral fat load, to induce an increased cytokine production in healthy human monocytes.
Study design: Randomized cross-over high-fat challenge intervention study.
Study population: Healthy human volunteers, aged between 18 and 40 years.
Intervention: A single high-fat challenge (milkshake containing 95g of fat) and 'control' shake (comparable to an average breakfast).
Main study parameters/endpoints: Blood will be drawn at t=0h (before) and at t=1h, t=2h, t=4h, t=6h, t=24 and t=72h after an oral fat load and at the same time points after a 'control' shake. The primary endpoint is the monocyte TNFα production upon ex vivo stimulation with LPS at the 72h time point. Additional secondary endpoints are the production of other cytokines and chemokines upon ex vivo stimulation at t=0h, t=4h, t=24h and t=72h, the monocytes' inflammatory phenotype as assessed by flowcytometry analysis and serum induced persistent cytokine production capacity.
- Conditions
- Cardiovascular Diseases
- Being tested
- High-fat shake, Reference shake
- Medical subject headings
- Cardiovascular Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-fat shakeDietary supplement
The high-fat shake consisted of 53% (w/v) fresh cream, 3% (w/v) sugar and 44% (w/v) water
Reference shakeDietary supplement
The reference shake consisted of 43% (w/v) full cream milk, 48% (w/v) full cream yoghurt, 4% (w/v) lemonade, 4% (w/v) fantomalt (Nutricia B.V., the Netherlands) and 1% (w/v) wheat fiber
| Study group | Role | What they receive |
|---|---|---|
| High-fat shake | Experimental | Not described Receives: Dietary Supplement: High-fat shake |
| Reference shake | Active comparator | Not described Receives: Dietary Supplement: Reference shake |
What is being measured
The primary outcome is the main question the study is designed to answer.
Monocyte TNFα production upon ex vivo stimulation with LPS
Measured: 72 hours
Secondary outcomes (4)
The monocyte production of TNFa, IL-6, IL-1beta, IL-10 upon ex vivo stimulation with LPS, Pam3Cys or Candida Albicans.
Measured: 0 hour, 4 hours, 24 hours and 72 hours
The monocyte's inflammatory phenotype as assessed by flowcytometry analysis (i.e. membrane expression of markers including but not limited to CD14, CD16, CD11b, CCR2)
Measured: 0 hour, 4 hours, 24 hours and 72 hours
Postprandial serum-induced TNFa and IL-6 production of healthy human monocytes upon stimulation with LPS or Pam3Cys 6 days later.
Serum isolated before and after consumption of a high-fat meal is used in in vitro studies. In these studies isolated monocytes of healthy human donors are exposed to pooled fasting (t=0h) or fed serum (t=2h, 4h, or 6h) obtained from the study participants. The TNFa and IL-6 production of these cells is measured after stimulation with LPS and Pam3Cys 6 days later. Subsequently, it is studied whether a possible increase in TNFa or IL-6 production can be prevented by co-incubation with pharmacological inhibitors (e.g. TLR4 antagonists/inhibitors)
Measured: 0 hour, 2 hours, 4 hours , 6 hours
Plasma triglyceride, glucose, free fatty acid and insulin concentrations
The baseline (t=0h) and postprandial concentrations (at t=1h, 2h, 4h and 6h) of circulating triglycerides, glucose, free fatty acids and insulin are measured in the study participants after consumption of both the high-fat and control shake.
Measured: 0 hour, 1 hour, 2 hours, 4 hours , 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jan 2023
- Study start6 May 2019
- Primary completion9 Jan 2020
- Study completion15 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cardiovascular 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
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- Radboud University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Niels Riksen, MD, PhD, Principal investigator, Vascular Internal Medicine, Radboudumc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05682456
- Sponsor's protocol ID
- 107808
- Other IDs
- NTR7612
- Status last verified
- Dec 2022
- First submitted
- 16 Dec 2022
- Last updated
- 12 Jan 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 12 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- High-fat Challenge Induced Trained Innate Immunity
- ClinicalTrials.gov ID
- NCT05682456
- Acronym / sponsor ID
- 107808
- Conditions
- Cardiovascular Diseases
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- Radboud University Medical CenterUniversity, hospital or other
- Study start
- 6 May 2019 (actual)
- Primary completion
- 9 Jan 2020 (actual)
- Study completion
- 15 Oct 2021 (actual)
- First posted
- 12 Jan 2023 (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 goal of this randomized controlled cross-over trial is to investigate whether a single high-fat challenge can induce trained innate immunity in healthy volunteers. The main question it aims to answer is: Can a single high-fat challenge induce a persistent pro-inflammatory and pro-atherogenic monocyte phenotype, as detected by an augmented cytokine production capacity? To study this, participants will receive an oral high-fat and reference shake in a cross-over design and blood will be drawn before and at 1, 2, 4, 6, 24, and 72 hours after the shakes.
Detailed description
Rationale: Atherosclerosis is characterized by a persistent inflammation of the arterial wall.
Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. It has recently been shown that not only immune cells of the adaptive immune system, but innate immune cells as well are able to adopt a long-term pro-inflammatory phenotype upon stimulation. This nonspecific memory of innate immune cells is mediated by epigenetic and metabolic reprogramming and is termed "trained innate immunity." Previous findings from our lab have shown that not only bacterial components such as LPS, but also pro-atherogenic particles such as oxidized LDL can induce trained immunity in monocytes. Interestingly, this memory-effect of trained immunity indicates that even temporary triggers could induce the persistent inflammation in atherosclerosis.
Triglyceride-rich lipoproteins (TRL) have been identified as an important independent risk factor for atherosclerosis. Moreover, elevated plasma levels of these lipoproteins are associated with increased pro-inflammatory markers. TRLs, however, are characterized by alternating plasma levels, with brief elevations following (fat containing) meals. Notably, a high-fat meal not only contributes to the transient increase of TRL plasma levels, but also induces a brief elevation in LPS levels by briefly increasing the permeability of the gut.
We now aim to investigate whether a single high-fat meal can induce trained innate immunity, since this concept might explain how brief postprandial effects can translate into a long-term pro-inflammatory and pro-atherogenic monocyte phenotype.
Objective: The primary objective is to determine whether a high-fat meal can induce a persistent pro-inflammatory monocyte phenotype, characterized by an increased cytokine production capacity upon ex vivo stimulation. Secondary objectives are metabolic and epigenetic reprogramming of monocytes at these time points as well as the capacity of serum, isolated before and 1-6h after an oral fat load, to induce an increased cytokine production in healthy human monocytes.
Study design: Randomized cross-over high-fat challenge intervention study.
Study population: Healthy human volunteers, aged between 18 and 40 years.
Intervention: A single high-fat challenge (milkshake containing 95g of fat) and 'control' shake (comparable to an average breakfast).
Main study parameters/endpoints: Blood will be drawn at t=0h (before) and at t=1h, t=2h, t=4h, t=6h, t=24 and t=72h after an oral fat load and at the same time points after a 'control' shake. The primary endpoint is the monocyte TNFα production upon ex vivo stimulation with LPS at the 72h time point. Additional secondary endpoints are the production of other cytokines and chemokines upon ex vivo stimulation at t=0h, t=4h, t=24h and t=72h, the monocytes' inflammatory phenotype as assessed by flowcytometry analysis and serum induced persistent cytokine production capacity.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| High-fat shake | Experimental | Dietary Supplement: High-fat shake |
| Reference shake | Active comparator | Dietary Supplement: Reference shake |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- LDL cholesterol < 3.5 mmol/l, fasting triglycerides < 2 mmol/l
- No previous cardiovascular events
Key exclusion criteria (11 listed)
- Smoking within the year before study entry
- Diagnosed with any long-term medical condition that can interfere with the study (i.e.
- gallbladder disease, renal failure, cardiovascular disease, diabetes, rheumatoid arthritis etc.)
- Medication (with the exception of oral contraceptives) or supplement use (i.e. omega3)
- BMI < 18 or > 27 kg/m2
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 |
|---|---|---|
| High-fat shakeThe high-fat shake consisted of 53% (w/v) fresh cream, 3% (w/v) sugar and 44% (w/v) water | Dietary supplement | High-fat shake |
| Reference shakeThe reference shake consisted of 43% (w/v) full cream milk, 48% (w/v) full cream yoghurt, 4% (w/v) lemonade, 4% (w/v) fantomalt (Nutricia B.V., the Netherlands) and 1% (w/v) wheat fiber | Dietary supplement | Reference shake |
Primary outcome
Monocyte TNFα production upon ex vivo stimulation with LPS
Time frame: 72 hours
4 secondary outcomes
The monocyte production of TNFa, IL-6, IL-1beta, IL-10 upon ex vivo stimulation with LPS, Pam3Cys or Candida Albicans.
Time frame: 0 hour, 4 hours, 24 hours and 72 hours
The monocyte's inflammatory phenotype as assessed by flowcytometry analysis (i.e. membrane expression of markers including but not limited to CD14, CD16, CD11b, CCR2)
Time frame: 0 hour, 4 hours, 24 hours and 72 hours
Postprandial serum-induced TNFa and IL-6 production of healthy human monocytes upon stimulation with LPS or Pam3Cys 6 days later.
Time frame: 0 hour, 2 hours, 4 hours , 6 hours
Plasma triglyceride, glucose, free fatty acid and insulin concentrations
Time frame: 0 hour, 1 hour, 2 hours, 4 hours , 6 hours
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 12 Jan 2023.
- Individual participant dataSharing planned: Undecided
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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.
Niels Riksen, MD, PhD principal investigator
Vascular Internal Medicine, Radboudumc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High-fat shake and Reference shake in people with Cardiovascular Diseases, 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 2 inclusion and 11 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 12 Jan 2023. 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. 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?
Monocyte TNFα production upon ex vivo stimulation with LPS (time frame: 72 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 Jan 2023.