Clinical trial NCT04616235: Acute Exercise and NK Cell Regulation in Tissue and Circulation After IL-6R Blockade
Official title: Acute Exercise and NK Cell Regulation in Tissue and Circulation After IL-6R Blockade - a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Interleukin-6 Inhibition
Physical Stress
Appetitive Behavior
Keywords: Natural Killer cells
Aerobic exercise
IL-6R blockade
Human
Appetite
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
First posted: 2020-11-04
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The study is a randomized controlled trial studying the acute effect of intense aerobic exercise upon NK (Natural Killer) cell activation and appetite-regulation in human participants with or without concommitant IL-6R receptor blockade (Tocilizumab)

Detailed description: Objectives:

Primary Objective:

* To explore the association between acute exercise, IL-6 blockade and NK regulation in circulation.
* To explore whether exercise activated NK-cells have a unique phenotype using single cell RNA sequencing.

Secondary Objectives:

* To explore the effect of acute aerobic exercise on NK cell number and activity in circulation, muscle and adipose tissue, in healthy young males, in order to indirectly explore exercise as an anti-cancer remedy.
* To assess the kinetics of the NK-cell response and, if possible, chronologically investigate the appearance and whereabouts of the activated NK-cells.

Explorative Objectives

* To establish a reproducible protocol for tracking various immune-cells and their involvement in the acute exercise response in humans
* To investigate novel signal molecules released from muscle during exercise with immunological importance.
* To investigate the possible role of exercise induced IL-6 on subjective feelings of hunger and satiety post exercise and food intake. • To explore the effect of IL-6 receptor blockade on the exercise proteome and metabolome, using mass spectrometry

Methods:

30 healthy recreationally active young males will be included in this acute exercise study in which NK-cell kinetic and regulation will be studied in response to acute aerobic exercise and IL-6R blockade or placebo.

The study consists of 2 visits. At inclusion (visit 1) all subjects will undergo assessment encompassing: baseline medical screening (auscultation, blood pressure, ECG), determination of body composition (DXA), cardiovascular fitness (VO2max) and standard fasting blood-biochemistry which will be analyzed immediately. Visit 2 will consist of a muscle and fat biopsy from the dominant leg and abdominal subcutaneous-fat depot respectively (both under resting conditions), which will then act as reference tissue for the further tissue analysis. Then, a 18G antecubital peripheral venous access will be secured prior to commencing with IL-6R infusion. 2 hours after the infusion procedure the subjects will undergo an acute exercise protocol. Subjects will then be challenged by a high intensity acute aerobic exercise bout, utilizing a bicycle ergometer. Blood samples will be drawn prior to the infusion and exercise, during exercise, as well as immediately, ½, 1, 1½ and 2h post exercise and up 4h post exercise in the appetite regulation substudy. Blood samples will immediately be analyzed for leucocyte count and differentiation as well as plasma biochemistry. In addition, blood samples will be utilized for NK cell isolation with subsequent single cell RNA sequencing, immune cell distribution and killing capacity towards cancer cells. Furthermore, plasma samples will be collected and frozen for later determination of cortisol, prolactin and circulating cytokines, including but not limited to IL-6 and G-CSF. Lastly, in the appetite substudy, insulin, GLP-1 and free fatty acids will be measured.

Tissue samples will be obtained 2h post exercise for optimizing gene-expression analysis. Both muscle and adipose tissue samples will be analyzed for inflammatory and anti-inflammatory markers, NK cell content and phenotyping of these NK cells using markers obtained from single cell sequencing, conducted on the blood-borne NK-cells. Furthermore, immune cell infiltration will be assessed using histology. All tissue samples will be obtained using a Bergström needle under sterile conditions during local anesthesia in order to minimize any sample-related discomfort or infection.

After the tissue sample, an ad libitum meal will be served, the subjects can eat as much can, but are instructed not to overconsume as any leftover food can be taken home. Paracetamol (1.5g) will be given to asses gastric emptying.

All participants will undergo the 2 study visits at the same approximate time of the day (9.00 a.m.) After completion of the study, any left-over material will be transferred to the CFAS biobank.

Subjects: Included subjects will be 30 recreationally active, moderately trained, healthy young males aged 18-40 years. Exclusion criteria are: cardiovascular, rheumatologic and metabolic disease, elite sports or high aerobic training status. Chronic use of nonsteroidal anti-inflammatory drug (NSAID) or other immunosuppressants.

Intervention: Subjects will be randomized to acute exercise, with (n=15) or without (n=15) prior IL-6R blockade. The exercise intervention will consist of a highly taxing ≈45 minutes interval based, aerobic exercise bout, conducted on a stationary bicycle ergometer. After an initial 5-minute warmup at 50-60% of HRmax, subjects will undergo seven, verbally encouraged, 3-minute intervals at above 90% HRmax, interspersed by 3 minutes of low intensity pedaling. Blood samples will be drawn before, during as well as immediately, ½, 1, 1½ and 2h post exercise together with tissue sampling at the 2h time-point.

To assess appetite regulation, further blood samples will be drawn from 2h-4h post exercise.

Statistical considerations: Based on data from our pilot study, we anticipate a ≈ 45 % lower maximal NK cell mobilization in the IL6R inhibition group compared to CON and a 29 % difference in NK cell nadir with the lowest values obtained in the IL6R inhibition group. Assuming a 5%-significance level in two-sided tests, we need to include 9 patients in each group to achieve 90% power for detecting a relative difference of 45 % in the intervention-group. To account for potential dropouts/excluded, due to the somewhat invasive setup, we will include a total of 30 patients (15 per group).

Recruitment: Subjects will be recruited through forsøgsperson.dk or similar sites alongside advertising at relevant sites.

Subjects will contact us at CFAS and will be given the choice whether to receive study information pr. telephone (thereby denying the option of a bystander) or a face to face meeting at CFAS. All this information will be given by the primary investigator. If the subject is interested in hearing more of the study, relevant documents will be emailed. If the subject is interested in joining the study after having received written or oral information, he will have 24h to consider study participation. When the subject has been informed either by telephone or face to face and accepts study participation, he will be invited to visit 1 where written and informed consent will be obtained (or signed and brought from home by the participant).

Risks and adverse reactions: Subjects may experience minor discomfort with regard to blood and tissue samples. The blood volume drawn is negligible and will not be associated with any health risk. All sampling of tissues will be performed under sterile conditions during local anesthesia and will thus be associated with little pain or discomfort and very little risk of infection. During exercise testing, participants may experience shortness of breath.

IL-6R inhibition is generally well tolerated with only few side-effects. The dose of paracetamol is low and is not associated with any risk.

Contact information of the involved medical doctor will be given to participants at study inclusion, so that any adverse event can be reported and solved.

Dissemination of study results: Both positive, negative and inconclusive results will be published in relevant international scientific journals.

Ethical consideration: The project is expected to cause limited risks, side effects and discomfort. All procedures will be performed by experienced physicians and physiologists with relevant safety. Tocilizumab is generally well tolerated and the dose of paracetamol is low. Included subjects may at any time, and without justification, retract their consent of study participation. We believe that the project is important and will contribute with critical new information on the IL-6 modifiable NK-cell response to acute exercise both in circulation and in adipose and muscle tissue (as there is currently very limited knowledge on the latter).

The study is considered a toolbox-study by Lægemiddelstyrelsen, and hence not at pharmaceutical study

Eligibility criteria: Inclusion Criteria:

* recreationally active
* moderately trained
* healthy young males aged 18-40 years
* BMI from 18-30 kg·m2

Exclusion Criteria:

* Cardiovascular disease
* Rheumatologic disease
* Metabolic disease,
* Elite sports or high aerobically training status (VO2max\>60ml O2/min/kg),
* Frequent/chronic use of medications affecting physical performance or inflammation (NSAIDS, DMARDS)

Primary outcomes:
measure: Kinetics and regulation of NK (Natural Killer) cells during and following acute exercise
timeFrame: Up to 1 day
measure: NK cell phenotype in response to acute exercise with or without IL-6R blockade
timeFrame: Up to 1 day
Secondary outcomes:
measure: Change in NK cell count in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in NK cell phenotype in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in NK cell count in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in NK cell phenotype in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in macrophage count in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in macrophage phenotype in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in macrophage count in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in macrophage phenotype in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in T-cell count in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in T-cell phenotype in adipose tissue
timeFrame: 3 hours after intervention
measure: Change in T-cell count in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in T-cell phenotype in muscle tissue
timeFrame: 3 hours after intervention
measure: Change in monocyte count in circulation
timeFrame: Up to 1 day
measure: Change in T-cell count in circulation
timeFrame: Up to 1 day
measure: Change in B-cell count in circulation
timeFrame: Up to 1 day
measure: Change in IL-6 receptor expression on NK-cells in circulation
timeFrame: Up to 1 day
measure: Change in circulating IL-6
timeFrame: Up to 1 day
measure: Change in circulating IL-2
timeFrame: Up to 1 day
measure: Change in circulating IL-1
timeFrame: Up to 1 day
measure: Change in circulating IL-10
timeFrame: Up to 1 day
measure: Change in circulating TNF-alpha
timeFrame: Up to 1 day
measure: Change in circulating G-CSF
timeFrame: Up to 1 day
measure: Change in circulating epinephrine
timeFrame: Up to 1 day
measure: Change in circulating norepinephrine
timeFrame: Up to 1 day
measure: Change in circulating total leucocytes
timeFrame: Up to 1 day
measure: Change in circulating neutrophils
timeFrame: Up to 1 day
measure: Change in circulating reticulocytes
timeFrame: Up to 1 day
measure: Change in circulating eosinophils
timeFrame: Up to 1 day
measure: Change in circulating basofile leucocytes
timeFrame: Up to 1 day
measure: Change in circulating total lymphocytes
timeFrame: Up to 1 day
measure: Change in circulating Prolactin
timeFrame: Up to 1 day
measure: Change in cortisol
timeFrame: Up to 1 day
measure: Change in metamyelocytes
timeFrame: Up to 1 day
measure: Change in ACTH
timeFrame: Up to 1 day
measure: Change in circulating lactate
timeFrame: Up to 1 day
measure: Change in CRP
timeFrame: Up to 1 day
measure: Change in hsCRP
timeFrame: Up to 1 day
measure: Novel myokines during acute exercise
timeFrame: Immediately after acute bout of exercise
measure: VO2max
timeFrame: Baseline
measure: Lean Body mass
timeFrame: Baseline
measure: Fat mass
timeFrame: Baseline
measure: Bone Mineral Density
timeFrame: Baseline
measure: Appetite assessment
timeFrame: 4 hours after intervention
measure: Ad libitum caloric intake
timeFrame: 4 hours after intervention
measure: Gastric emptying
timeFrame: 4 hours after intervention
measure: Change in GLP1
timeFrame: 4 hours after intervention
measure: Change in PYY
timeFrame: 4 hours after intervention
measure: Change in CCK
timeFrame: 4 hours after intervention
measure: Change in Glucose
timeFrame: 4 hours after intervention
measure: Change in Insulin
timeFrame: 4 hours after intervention
measure: Change in C-peptide
timeFrame: 4 hours after intervention
measure: Change in free fatty acids
timeFrame: 4 hours after intervention
measure: Change in acetoacetate
timeFrame: 4 hours after intervention
measure: Change in betahydroxybutyrate
timeFrame: 4 hours after intervention
measure: Change in CRH
timeFrame: 4 hours after intervention
measure: Change in AVP
timeFrame: 4 hours after intervention
Other outcomes:
Locations:
city: Copenhagen Ø
country: Denmark
facility: Center For Physical Activity (CFAS)
Study officials:
affiliation: CFAS (Center For Physical Activity) Rigshospitalet
name: Andreas K Ziegler, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CFAS (Center For Physical Activity) Rigshospitalet
name: Jesper F Christensen, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CFAS (Center For Physical Activity) Rigshospitalet
name: Claus Brandt, PhD
role: PRINCIPAL_INVESTIGATOR
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