Clinical trial NCT03960827: Molecular Transducers of Physical Activity Consortium
Official title: Molecular Transducers of Physical Activity Consortium
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Physical Activity
Keywords: endurance exercise
resistance exercise
physical activity
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Stanford University
name: Broad Institute of MIT and Harvard
name: Duke University
name: Emory University
name: Icahn School of Medicine at Mount Sinai
name: Pacific Northwest National Laboratory
name: University of Michigan
name: Wake Forest University
name: University of Vermont
name: National Institutes of Health (NIH)
name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
name: Mayo Clinic
First posted: 2019-05-23
Enrollment: 1837
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The randomized trial is conducted in accordance with an intent-to-treat (ITT) design.
Primary purpose: OTHER

Brief summary: The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to assess molecular changes that occur in response to physical activity (PA). To achieve this aim, a mechanistic randomized controlled trial (RCT) is conducted, in which adult study participants are randomized to endurance exercise (EE) training, resistance exercise (RE) training, or no exercise Control for a period of approximately 12 weeks. The overarching hypothesis is that there are discoverable molecular transducers that communicate and coordinate the effects of exercise on cells, tissues, and organs, which may initiate processes ultimately leading to the health benefits of exercise. Because this is a mechanistic trial, the main goal is not a single health-related outcome. Rather, the goal is to generate a resource leading to the generation of a map of the molecular responses to exercise that will be used by the Consortium and by the scientific community at large to generate hypotheses for future investigations of the health benefits of PA.

Detailed description: Study assessments are completed before and after the intervention period (exercise or control), and at specific interim time points during the intervention. Assessments include measurements of cardiorespiratory fitness, muscular strength, and body composition (including total body bone mineral content) determined by dual-energy x-ray absorptiometry (DXA). There is also collection of blood, muscle, and adipose tissue biospecimens, monitoring of free-living PA level using wearable devices, and completion of participant reported outcomes and health status by interview and/or questionnaire. An additional group of highly active (HA) individuals currently active in either EE (HAEE) or RE (HARE) are recruited for a single acute exercise testing session of either endurance or resistance exercise and other study assessments. MoTrPAC participants are recruited, trained, and assessed via six adult Clinical Centers (CC), involving 10 clinical sites. As part of the MoTrPAC functions, participant data and biological samples are transferred from the clinical sites to the Consortium Coordinating Center (CCC) Data Management, Analysis and Quality Control Center (DMAQC)and to the Biological Sample Repository, and later analyzed by the Consortium Chemical Analysis Sites (CAS) and the Bioinformatics Center (BIC).

Biological samples collected in this project undergo molecular phenotyping, including metabolomic, lipidomic, proteomic, epigenomic, transcriptomic, and genomic analyses. These assays are done at the MoTrPAC CAS.

Overall coordination of the study and analyses occurs at 4 institutions which make up the CCC and the BIC.

Eligibility criteria: ADULT PARTICIPANT INCLUSION CRITERIA - SEDENTARY PARTICIPANTS

* Willingness to provide informed consent to participate in the MoTrPAC Study
* Must be able to read and speak English well enough to provide informed consent and understand instructions
* Aged ≥18 y
* Body Mass Index (BMI) ≥19 to ≤35 kg/m2
* Sedentary defined as self-reporting no more than 1 day per week, lasting no more than 60 minutes, of regular (structured) EE \[e.g., brisk walking, jogging, running, cycling, elliptical, or swimming activity that results in feelings of increased heart rate, rapid breathing, and/or sweating\] or RE (resulting in muscular fatigue) in the past year

  * Persons bicycling as a mode of transportation to and from work \>1 day/week etc. are not considered sedentary
  * Leisure walkers are included unless they meet the heart rate, breathing, and sweating criteria noted above
  * Willingness to include de-identified individual-level data at low risk of re-identification (e.g.,non-genomic data) in the MoTrPAC open-access database
  * Only one member of a household can participate

ADULT PARTICIPANT INCLUSION CRITERIA - HIGHLY ACTIVE PARTICIPANTS

* Willingness to provide informed consent to participate in the MoTrPAC Study
* Must be able to read and speak English well enough to provide informed consent and understand instructions
* Aged ≥18 y
* BMI ≥19 to ≤35 kg/m2
* Comparator Participants

  * HAEE: defined as ≥240 minutes/week of ET for ≥1 year; this can include running, walking (brisk, power), cycling, elliptical, etc. which (at a minimum) results in increased heart rate, rapid breathing and sweating
  * Must include cycling at least 2 days/week
  * RT in the past year must be limited to ≤2 days/week of upper body RE and ≤2 muscle groups of upper body RE and ≤1 day/week of lower body RE
  * HARE: defined as RT of ≥3 upper and ≥3 lower body muscle groups ≥2 times/week for ≥1 year; using a prescription sufficient to increase strength and muscle mass
  * ET in the past year must be limited to ≤90 minutes/week of vigorous EE, with no limit on cycling days per week
  * Elite or Competitive Athletes: can be included, if they meet HAEE or HARE inclusion criteria
  * Potential participants are informed that use of performance enhancing drugs in the last 6 months is exclusionary
  * Willingness to include de-identified individual-level data at low risk of re-identification (e.g., non-genomic data) in the MoTrPAC open-access database
  * In addition to meeting HAEE or HARE inclusion criteria, all HA participants must meet all other exclusion criteria defined in this protocol

EXCLUSION CRITERIA

ADULT PARTICIPANT EXCLUSION CRITERIA Exclusion criteria are confirmed by self-report (i.e., medical and medication histories reviewed by a clinician), screening tests performed by the MoTrPAC study team at each clinical site, and/or clinician judgement as specified for each criterion.

* Diabetes (self-report and screening tests)

  * Treatment with any hypoglycemic agents (self-report) or A1c \>6.4% (screening test; may reassess once if 6.5-6.7%)
  * Fasting glucose \>125 mg/dL (screening test; may reassess once)
  * Use of hypoglycemic drugs for non-diabetic reasons (self-report)
* Abnormal bleeding or coagulopathy (self-report)

  * History of a bleeding disorder or clotting abnormality
* Thyroid disease (screening test)

  * Thyroid Stimulating Hormone (TSH) value \>5.9 IU/mL
  * Individuals with hypothyroidism may be referred to their primary care provider (PCP) for evaluation and retested; any medication change must be stable for ≥3 months prior to retesting
  * Individuals with hyperthyroidism are excluded, including those with normal TSH on pharmacologic treatment
* Pulmonary (self-report)

  * Clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD)
* Metabolic bone disease (self-report)

  * History of non-traumatic fracture from a standing height or less
  * Current pharmacologic treatment for low bone mass or osteoporosis, other than calcium, vitamin D, or estrogen
* Estrogens, progestins (self-report)

  * Supplemental, replacement or therapeutic use of estrogens or progestins within the last 6 months, other than birth control or to control menopausal symptoms
* Pregnancy (screening test) and pregnancy-related conditions (self-report)

  * Pregnant - pregnancy test performed on day of DXA scan in women of child-bearing potential
  * Post-partum during the last 12 months
  * Lactating during the last 12 months
  * Planning to become pregnant during the participation period
* Elevated blood pressure readings (screening test)

  * Resting Systolic Blood Pressure (SBP) ≥150 mmHg or Resting Diastolic Blood Pressure (DBP) ≥95 mmHg
  * Reassessment of BP during screening will be allowed to ensure rested values are repeatable
* Cardiovascular (self-report, screening test, and clinician judgement)

  * Congestive heart failure, coronary artery disease, significant valvular disease, congenital heart disease, serious arrhythmia, stroke, or symptomatic peripheral artery disease (self-report, screening test)
  * Specific criteria used to determine whether a volunteer can undergo the screening CPET follow the American Heart Association (AHA) Criteria \[54\]
  * Inability to complete the CPET
  * Reassessment of the CPET may be allowed under some circumstances (e.g., test was not a maximal effort)
* Abnormal blood lipid profile (screening test)

  * Fasting triglycerides \>500 mg/dL
  * Low-density lipoprotein cholesterol (LDL-C) \>190mg/dL
* Cancer (self-report)

  * History of cancer treatment (other than non-melanoma skin cancer) and not "cancer-free" for at least 2 years
  * Anti-hormonal therapy (e.g., for breast or prostate cancer) within the last 6 months
* Chronic active or latent infection (self-report)

  * Active or latent infections requiring chronic antibiotic or anti-viral treatment
  * Chronic active infection whether on chronic antimicrobials or not
  * Human Immunodeficiency Virus
  * Active hepatitis B or C undergoing antiviral therapy
  * Individuals successfully treated for hepatitis C and virologically negative for at least 6 months are not excluded
* Liver enzyme tests (Alanine transaminase, Aspartate transaminase) (screening test)

  * \>2 times the laboratory upper limit of normal
  * Reassessment during screening may be allowed under some conditions (e.g., recent use of acetaminophen)
  * Individuals may be referred to their PCP for evaluation; any medication change must be stable for ≥3 months prior to retesting
* Chronic renal insufficiency (screening test)

  * Estimated glomerular filtration rate \<60 mL/min/1.73 m2 from serum creatinine (mg/dL) by the Chronic Kidney Disease Epidemiology Collaboration equation
  * Reassessment may be allowed under some conditions (e.g., questionable hydration status or other acute renal insult)
* Hematocrit (screening test)

  * Hematocrit \>3 points outside of the local normal laboratory ranges for women and men
  * Reassessment may be allowed under certain conditions
  * Individuals may be referred to their PCP for evaluation; any medication change must be stable for ≥3 months prior to retesting
  * Individuals with known thalassemia trait may be included (despite having \>3 points outside of the local normal laboratory ranges), upon approval from their PCP or a hematologist
* Blood donation (self-report)

  * Whole blood donation in the last 3 months or plans for blood donation during the entire protocol period
  * Platelet or plasma donation in the last week or plans for platelet or plasma donation during the entire protocol period
* Autoimmune disorders (self-report)

  * Individuals receiving any active treatment (including monoclonal antibodies) within the last 6 months
* Alcohol consumption (self-report)

  * More than 7 drinks per week for women
  * More than 14 drinks per week for men
  * History of binge drinking (≥5 drinks for males or ≥4 drinks for females in a 2-hour period more than once per month)
* Tobacco (self-report)

  * Current smokers: any tobacco or e-cigarette/e-nicotine products
  * Former smokers:
  * Stopped smoking \<10 years at time of screening for those with a ≥20 pack-year smoking history
  * Stopped smoking \<5 years at time of screening for those with a \<20 pack-year smoking history
* Marijuana (self-report)

  * Self-reported use ≥3 days/week in any form
* Shift workers (self-report)

  * Night shift work in the last 6 months
  * Planning night shift work during the study period
* Cognitive status (screening)

  * Unable to give consent to participate in and safely complete the protocol, as based on the judgement of the local investigator
* Psychiatric illness (self-report and screening test)

  * Hospitalization for any psychiatric condition within one year (self-report)
  * Center for Epidemiological Studies-Depression Scale (CESD) score ≥16 \[55\] (screening test)
* Weight change (self-report)

  * Weight change (intentional or not) over the last 6 months of \>5% of body weight
  * Plan to lose or gain weight during the study
* Lidocaine or other local anesthetic (self-report)

  * Known allergy to lidocaine or other local anesthetic
* COVID-19 infection

  * Hospitalization for COVID-19 infection in the past 12 months
  * Individuals who tested positive for COVID-19 but were not hospitalized must be symptom-free at least 14 days
* Other (clinician judgement)

  * Genetic metabolic disorders that could effect metabolomic results (e.g.,phenylketonuria)
  * Any other cardiovascular, pulmonary, orthopedic, neurologic, psychiatric. metabolic, or other conditions that, in the opinion of the local clinician, would preclude participation and successful completion of the protocol
  * Any other illnesses that, in the opinion of the local clinician, would negatively impact or mitigate participation in and completion of the protocol

EXCLUSIONS FOR MEDICATION USE

* Continuous use for 7 days or more of a new drug (prescription or over-the-counter; additional guidance in the MOP) in the last 3 months; eye and ear drops are allowed regardless of when they were started
* Dose change for any chronic-use drug in the last 3 months; changes in eye and ear drops are allowed
* Cardiovascular

  * Beta blockers and centrally acting anti-hypertensive drugs
  * Anticoagulants
  * Antiarrhythmic drugs
  * Antiplatelet drugs (other than aspirin ≤100 mg/day)
* Psychiatric drugs

  * Chronic use of medium or long-acting sedatives and hypnotics including all benzodiazepines; (short-acting non-benzodiazepine sedative-hypnotics are allowed)
  * Mood stabilizers
  * Antiepileptic drugs
  * Stimulants, Attention-Deficit/Hyperactivity Disorder (ADHD) drugs
  * Anti-psychotic drugs
* Pulmonary, inflammation

  * Chronic oral steroids; inhaled steroids are allowed
  * Burst/taper oral steroids more than once in the last 12 months; inhaled steroids are allowed
  * B2-agonists
  * allowed if on stable dose at least 3 months
* Genitourinary

  * 5-alpha reductase inhibitors
  * Daily phosphodiesterase type 5 inhibitor use
* Hormonal

  * Androgenic anabolic steroids
  * Anti-estrogens, anti-androgens
  * Estrogens and/or progestins used for reasons other than birth control or menopause
  * Growth hormone, insulin like growth factor-I, growth hormone releasing hormone
  * Any drugs used to treat diabetes mellitus or to lower blood glucose
  * Metformin for any indication
  * Any drugs used specifically to induce weight loss
  * Any drugs used specifically to induce muscle growth/hypertrophy or augment exercise-induced muscle hypertrophy
* Pain/inflammation

  * Narcotics and narcotic receptor agonists
  * Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen
  * Muscle relaxants ≥3 days per week
  * Oral/sublingual cannabidiol or similar in any formulation
* Other

  * Chronic systemic antimicrobials (antibiotic, antiviral, antifungal, antiparasite, etc) for any reason
  * High-potency topical steroids if ≥10% of surface area using rule of 9s
  * Continuous/chronic use of antibiotics or other anti-infectives for treatment or prevention
  * Monoclonal antibodies
  * Anti-rejection medications/immune suppressants
* Any other medications that, in the opinion of local clinicians, would negatively impact or mitigate full participation and completion

Primary outcomes:
measure: Cardiopulmonary Exercise Test (CPET) VO2 Peak
timeFrame: Baseline; Week 12
measure: Isometric Knee Peak Torque by Group
timeFrame: Baseline; Week 12
Secondary outcomes:
measure: HDL-C
timeFrame: Baseline; Week 12
measure: LDL-C
timeFrame: Baseline; Week 12
measure: Triglycerides
timeFrame: Baseline; Week 12
measure: HbA1C
timeFrame: Baseline; Week 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado Denver
state: Colorado
city: Orlando
country: United States
facility: Florida Hospital / Advent Health
state: Florida
city: Muncie
country: United States
facility: Ball State University
state: Indiana
city: Baton Rouge
country: United States
facility: Pennington Biomedical Research Center
state: Louisiana
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Galveston
country: United States
facility: University of Texas Medical Branch - Galveston
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center, San Antonio
state: Texas
Study officials:
affiliation: Wake Forest University Health Sciences
name: Mike E Miller, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: MoTrPAC Study Group; Jakicic JM, Kohrt WM, Houmard JA, Miller ME, Radom-Aizik S, Rasmussen BB, Ravussin E, Serra M, Stowe CL, Trappe S, Abouassi H, Adkins JN, Alekel DL, Ashley E, Bamman MM, Bergman BC, Bessesen DH, Broskey NT, Buford TW, Burant CF, Chen H, Christle JW, Clish CB, Coen PM, Collier D, Collins KA, Cooper DM, Cortes T, Cutter GR, Dubis G, Fernandez FM, Firnhaber J, Forman DE, Gaul DA, Gay N, Gerszten RE, Goodpaster BH, Gritsenko MA, Haddad F, Huffman KM, Ilkayeva O, Jankowski CM, Jin C, Johannsen NM, Johnson J, Kelly L, Kershaw E, Kraus WE, Laughlin M, Lester B, Lindholm ME, Lowe A, Lu CJ, McGowan J, Melanson EL, Montgomery S, Moore SG, Moreau KL, Muehlbauer M, Musi N, Nair VD, Newgard CB, Newman AB, Nicklas B, Nindl BC, Ormond K, Piehowski PD, Qian WJ, Rankinen T, Rejeski WJ, Robbins J, Rogers RJ, Rooney JL, Rushing S, Sanford JA, Schauer IE, Schwartz RS, Sealfon SC, Slentz C, Sloan R, Smith KS, Snyder M, Spahn J, Sparks LM, Stefanovic-Racic M, Tanner CJ, Thalacker-Mercer A, Tracy R, Trappe TA, Volpi E, Walsh MJ, Wheeler MT, Willis L. Molecular Transducers of Physical Activity Consortium (MoTrPAC): human studies design and protocol. J Appl Physiol (1985). 2024 Sep 1;137(3):473-493. doi: 10.1152/japplphysiol.00102.2024. Epub 2024 Apr 18.