Clinical trial NCT04701138: Bioavailability of SPMs in Obese Humans
Official title: Bioavailability of Specialized Pro-resolving Mediators in Obese Humans
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Obesity Adult Onset
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: Metagenics, Inc.
name: North Carolina Translational and Clinical Sciences Institute
First posted: 2021-01-08
Enrollment: 24
Sex: ALL
Minimum age (years): 50
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Research Question: Does 4 weeks of supplementation with 'SPM Active' lead to a statistically significant increase in plasma SPM concentration for obese human subjects? Primary Aim 1: To compare plasma SPM concentrations and immunological fitness pre- and post- oral SPM administration in the obese.

* Aim 1a: To quantify plasma SPM concentrations in plasma (pg/mL), serum (pg/mL) and PBMCs before and after 4 weeks of supplementation with 'SPM Active.' The concentration of SPMs in plasma, in addition to other PUFA-derived metabolites that share the same enzymatic pathways as SPMs, will be established at baseline and post-intervention using mass spectrometry-based metabololipidomics.
* Aim 1b: To measure in vitro antibody responses of B cells in PBMC pool with in vitro stimulation and cytokine production before and after 4 weeks of supplementation with 'SPM Active.' In addition, researchers will quantify the relative abundance of differing immune cell populations.

Detailed description: Purpose: Specialized pro-resolving mediators (SPMs) are a superfamily of lipid metabolites, predominantly derived from the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acids (DHA). Previous research has established that obese mice and humans have lower circulating levels of SPMs relative to lean controls. In this study, SPMs will be administered as a dietary supplement to obese human subjects to establish: 1) their bioavailability in plasma, serum and peripheral blood mononuclear cells (PBMCs) and 2) their effects on immune cell abundance and in vitro antibody production. The rationale for focusing on immune cells is that SPMs may be targeting their abundance and phenotype. This study does not intend to make any health or health-related claims.

Participants: A total of 24 (n=12 men + 12 women) obese (BMI 30-40 kg/m2) euglycemic and pre-diabetic subjects (fasting glucose 70-125 mg/dL or HbA1c of 5.7-6.4%) aged 50-65 years will be recruited by Dr. Erik Butler from the UNC Family Medicine Center in Chapel Hill.

Procedures (methods): This is a non-randomized uncontrolled clinical trial. The study will provide the intervention 'SPM Active' provided by Metagenics. All subjects will be advised to take 4 capsules per day (2 capsules with breakfast and 2 capsules with dinner) of 'SPM Active' for 4 weeks total. Each capsule contains 145 mg of SPMs for a total daily dose of 580 mg. Fasting blood will be drawn pre- and post-intervention using phlebotomy available under the direction of Dr. Butler. The scientific approach will rely on mass-spectrometry based metabololipidomics, immunophenotyping with flow cytometry, and anthropomorphic/blood pressure/BMI measurements (anthropometric measures are only intended for use in statistical analysis for confounding variables).

Eligibility criteria: Inclusion Criteria:

* 24 (n=12 male + 12 female) obese (BMI 30-40 kg/m\^2) subjects with age 50-65 years who are euglycemic and pre-diabetic (i.e. fasting glucose 70-125 mg/dL or HbA1c of 5.7-6.4%).
* Only post-menopausal females will be recruited in the female cohort to reduce the confounding effects of estrogen on lipid metabolism during supplementation.

Exclusion Criteria:

* Those with fasting glucose values \> 126 mg/dL or known type 2 diabetes
* Females who are pre-menopausal, pregnant, planning to become pregnant, breastfeeding or lactating
* Subjects consuming n-3 PUFA supplements in the last 3 months prior to enrollment, high consumption of fatty fish (\>2 servings per week), and subjects with active autoimmune disease, liver disease, coagulopathy, hypothyroidism, known allergy to fish or shellfish, inability to give informed consent, or taking anticoagulants (e.g. warfarin and direct-acting anticoagulants), those taking estrogen or testosterone, and anyone taking daily aspirin, NSAIDs, or active asthma medications.
* Subjects receiving immunomodulatory or immunosuppressant therapy (corticosteroids or monoclonal antibodies) in the 4 weeks prior to study enrollment, and subjects with known active malignancy or undergoing treatment for malignancy will be excluded.
* Subjects who test positive for COVID-19 or have tested positive in the past will be excluded. Those who report COVID-19 or flu-like symptoms will be excluded, as well as those that fail to pass COVID-19 screening at baseline.

Primary outcomes:
measure: Mean Pro-inflammatory & Pro-resolving Metabolites
timeFrame: From Baseline (Week 1/Day1) through 28 to 30 days of supplementation
Secondary outcomes:
measure: Mean White Blood Cell Populations
timeFrame: From Baseline (Week 1/Day1) through 28 to 30 days of supplementation
Other outcomes:
measure: Antibody Concentrations in Culture
timeFrame: From Baseline (Week 1/Day1) through 28 to 30 days of supplementation
Locations:
city: Chapel Hill
country: United States
facility: UNC Chapel Hill Family Medicine Center
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Saame R Shaikh, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: UNC Family Medicine
name: Erik Butler, DO
role: STUDY_DIRECTOR
References:
citation: Crouch MJ, Kosaraju R, Guesdon W, Armstrong M, Reisdorph N, Jain R, Fenton J, Shaikh SR. Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody. J Leukoc Biol. 2019 Aug;106(2):241-257. doi: 10.1002/JLB.3HI1017-405RR. Epub 2018 Dec 21.
citation: Kosaraju R, Guesdon W, Crouch MJ, Teague HL, Sullivan EM, Karlsson EA, Schultz-Cherry S, Gowdy K, Bridges LC, Reese LR, Neufer PD, Armstrong M, Reisdorph N, Milner JJ, Beck M, Shaikh SR. B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection. J Immunol. 2017 Jun 15;198(12):4738-4752. doi: 10.4049/jimmunol.1601031. Epub 2017 May 12.
citation: Serhan CN, Levy BD. Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest. 2018 Jul 2;128(7):2657-2669. doi: 10.1172/JCI97943. Epub 2018 May 14.
citation: Lopez-Vicario C, Titos E, Walker ME, Alcaraz-Quiles J, Casulleras M, Duran-Guell M, Flores-Costa R, Perez-Romero N, Forne M, Dalli J, Claria J. Leukocytes from obese individuals exhibit an impaired SPM signature. FASEB J. 2019 Jun;33(6):7072-7083. doi: 10.1096/fj.201802587R. Epub 2019 Mar 6.
citation: Al-Shaer AE, Regan J, Buddenbaum N, Tharwani S, Drawdy C, Behee M, Sergin S, Fenton JI, Maddipati KR, Kane S, Butler E, Shaikh SR. Enriched Marine Oil Supplement Increases Specific Plasma Specialized Pro-Resolving Mediators in Adults with Obesity. J Nutr. 2022 Jul 6;152(7):1783-1791. doi: 10.1093/jn/nxac075.