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Physiological and Psychological Effects of Testosterone During Severe Energy Deficit and Recovery (OPS)

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ClinicalTrials.gov Identifier: NCT02734238
Recruitment Status : Completed
First Posted : April 12, 2016
Results First Posted : January 2, 2019
Last Update Posted : January 16, 2019
Sponsor:
Collaborators:
United States Army Research Institute of Environmental Medicine
MyoSyntax
Defence Research and Development Canada
United States Department of Defense
Information provided by (Responsible Party):
Jennifer C. Rood, Pennington Biomedical Research Center

Tracking Information
First Submitted Date  ICMJE March 31, 2016
First Posted Date  ICMJE April 12, 2016
Results First Submitted Date  ICMJE December 10, 2018
Results First Posted Date  ICMJE January 2, 2019
Last Update Posted Date January 16, 2019
Actual Study Start Date  ICMJE April 2016
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 3, 2019)
Body Composition at the End of Each Study Phase [ Time Frame: end of each study phase: Day 11 for Phase 1, Day 39 for Phase 2, up to Day 85 for Phase 3 ]
Height was measured using a stadiometer. Weight was measured using a calibrated digital scale. Body composition was determined using dual-energy X-ray absorptiometry. These data were used to calculate fat-free body mass, fat mass, and total body tissue mass.
Original Primary Outcome Measures  ICMJE
 (submitted: April 5, 2016)
Change in Total Body Mass [ Time Frame: baseline; days 11, 28, 39, 53; and through study completion, up to day 85 ]
Height will be measured using a stadiometer. Weight will be measured using a calibrated digital scale. Body composition will be determined using dual-energy X-ray absorptiometry. These data will be used to calculate lean body mass, fat mass, bone mineral content, bone mineral density, and total body tissue mass.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2016)
  • Change in Skeletal Muscle Mass [ Time Frame: Days 11, 39, and 53; and upon return to initial body weight, up to day 85 ]
    Participants will provide a fasting urine sample prior to ingesting a single, 60 mg dose (capsule) of creatine (methyl-d3) on days 11, 39, 53, and at study completion (return to initial body weight, up to day 85). Fasting urine samples will be collected 48 and 72 hours after each creatine pill ingestion.
  • Change in Body Water Enrichment [ Time Frame: from baseline through day 42 ]
    Participants will consume heavy water (70%) from day 0 through day 42. Body water enrichment will be determined from blood collected on days 14, 28, and 42 and saliva samples collected on days 3, 7, 11, 15, 19, 23, 27, 31, 35 and 39.
  • Change in Muscle Protein Synthesis Rates [ Time Frame: Days 14, 28, 42 ]
    Muscle biopsy samples of the vastus lateralis will be collected while participants are under local anesthesia (1% lidocaine) using a 5-mm Bergstrom needle with manual suction on days 14, 28, and 42. Participants will undergo three muscle biopsy procedures taken from the same incision (pre-exercise, 60-min and 360-min post-exercise) on days 14 and 42. One muscle biopsy will be performed on day 28 on the same leg sampled on day 14, with the incision ~7 cm apart from the incision made on day 14. Up to 250 mg of tissue will be collected with each procedure. Participants will be fasted for pre-exercise and 60-min post-exercise biopsies. A segment of each muscle biopsy sample will be used for muscle proteomics and molecular analyses.
  • Determination of Proteome Dynamics [ Time Frame: Days 14, 28, 42 ]
    Muscle samples will be analyzed to calculate peptide elemental composition and isotopomer patterns.
  • Change in Muscle Fiber Type (fast/slow) [ Time Frame: days 14 and 42 ]
    The proportion of muscle fiber types (type II/fast-twitch/strength and type I/slow-twitch/endurance) will be measured at day 14 and again at day 42 for both treatment groups.
  • Change in Muscle Cross-Sectional Area [ Time Frame: days 14 and 42 ]
    Cross-sectional area for each muscle fiber type (type II/fast-twitch/strength and type I/slow-twitch/endurance) will be measured at day 14 and again at day 42 for each subject to identify muscle wasting based on fiber type. Expression changes will be measured to link wasting with specific cell signaling.
  • Cell-Specific Response In Vitro to Anabolic Agents [ Time Frame: days 14 and 42 ]
    Expression changes in response to anabolic exposure in vitro will be measured from muscle precursor cells from muscle biopsy segments obtained on days 14 and 42, pre and 360-min post exercise.
  • Inflammatory Profiles in Blood Derived Cells and Muscle Tissue Derived Leukocytes [ Time Frame: days 14 and 42 ]
    Blood and muscle derived monocyte/macrophage and T cell subsets will be measured. Cell subsets in blood and muscle will be compared with serum inflammatory factors measured.
  • Determination of Muscular Strength [ Time Frame: days 13, 41, 55 and upon return to initial body weight, up to day 85 ]
    Muscular strength will be measured with isometric and isokinetic knee extension tests on days 13, 41, 55, and upon return to initial body weight, up to day 85. A familiarization session will take place on day 0. Isometric quadriceps strength, maximal power and muscular endurance will be quantified using an isokinetic dynamometer (Biodex Medical Systems, Shirley, New York). Isometric muscle strength will be measured at 75° knee flexion. This procedure will be performed three times, each separated by a 30 sec rest period. Maximal muscle strength (maximal voluntary contraction) will be determined from six maximal knee extensions at a fixed speed of 60° per second, while muscular endurance capability will be quantified during 20 repeated maximal knee extensions with movement speed fixed at 180° per second. Unilateral testing will be done on the dominant leg.
  • Determination of Energy Expenditure [ Time Frame: days 11, 39 and 53 ]
    Energy expenditure will be measured for a 24-hour period in a metabolic chamber. Energy expenditure will be calculated by indirect calorimetry corrected for urinary nitrogen excretion and respiratory quotient. Energy expenditure will be calculated for the 24-hour period and also partitioned between rest, exercise and sleep.
  • Determination of Substrate Oxidation [ Time Frame: days 11, 39 and 53 ]
    Substrate oxidation will be measured for a 24-hour period in a metabolic chamber. Substrate oxidation will be calculated for the 24-hour period and also partitioned between rest, exercise and sleep. Substrate oxidation (carbohydrate, fat, and protein) will be calculated using standard equations.
  • Change in Minnesota Multiphasic Personality Inventory Scores [ Time Frame: days 5 and 40 ]
    A psychological assessment will be administered via computer software.
  • Change in Aggression Impulses [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will rank statements on the 29-item Buss-Perry Aggression Questionnaire.
  • Change in Mood States [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will complete the Profile of Mood States Questionnaire, a 65-item inventory of subjective mood states that is sensitive to a wide variety of nutritional manipulations, environmental factors, sleep loss and subclinical doses of various drugs.
  • Change in Perceived Hunger and Fullness [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will mark on the Satiety Labeled Intensity Magnitude questionnaire their subjective feelings of hunger and fullness.
  • Change in Willingness to Take Risks [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will take the Balloon Analogue Risk Task via computer software to measure willingness to take risks versus "play it safe." It requires the participant to fill a simulated balloon with air. Points are given for maintaining the flow of air and keeping the volume of the balloon as full as possible. The more expanded the balloon gets, the more points are earned. However, all points are lost if the balloon is over-inflated and pops. The object of this task is to earn as many points as possible by keeping the balloon inflated without popping.
  • Change in Cooperation [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Subjects will participate in the Ultimatum Game, a test of negotiation and cooperation between two people.
  • Change in Ability to Infer Intentions of Others [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will be administered the Reading the Mind in the Eyes Test via computer software.
  • Change in Vigilance [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will be administered the Scanning Visual Vigilance Task via computer software.
  • Change in Visual Reaction Time [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will be administered the Psychomotor Vigilance Test via computer software.
  • Change in Short-Term Spatial Memory and Pattern Recognition Skills [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will take the Matching to Sample test via computer software.
  • Change in Language-Based Logical Reasoning [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will take a test adapted from the Baddeley Grammatical Reasoning Test administered via computer software.
  • Change in Rating of Perceived Exertion [ Time Frame: days 15, 20, 22, 27, 29, 34, 36, and 41 ]
    The Borg Rating of Perceived Exertion Scale will be administered during each exercise test session. The scale will be presented on a video monitor and participants will give a verbal response that will be recorded by an experimenter.
  • Change in Working Memory Load [ Time Frame: days 13, 15, 20, 22, 27, 29, 34, 36, 41, 54 and upon return to initial body weight, up to day 85 ]
    Participants will be asked to monitor the identity or location of a series of verbal stimuli (letters) and to indicate when the currently presented stimulus is the same as the one presented "n" trials back (e.g. 0, 1, 2, or 3).
  • Change in Sleep Cycle [ Time Frame: continuously from baseline until return to initial body weight, up to day 85 ]
    Actigraphic measures of sleep will be collected throughout the study using wrist-worn monitors.
  • Change in Risk-Taking Propensity [ Time Frame: days 5, 36, and 55 ]
    Participants will perform the life-cash version of the Gambling Task to assess the propensity for high-risk, high-reward decisions, with differing reward domains (life and cash, respectively). In repeated trials of a simple game, participants are asked to click buttons to choose between a high-risk, high-reward outcome and a low-risk, low-reward outcome. The test will be administered while the participant is inside a magnetic resonance imaging (MRI) scanner. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Retaliatory Aggression Against a Provoking Adversary [ Time Frame: days 5, 36, and 55 ]
    The participant engages in a simple game with an opponent; after each round of the game, the winner of the round is allowed to apply electrical stimulus to the opponent and is instructed to set the intensity of the applied pain (modulated by the number of electrical stimuli applied to the arm) to a value of his choosing. The test will be administered while the participant is inside an MRI scanner. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Inhibitory Control Function [ Time Frame: days 9, 37, and 56 ]
    The Multiple Source Interference Task will be administered while the participant is inside an MRI scanner. Each trial shows the participant a string of three numbers including digits 1 to 3, and requires the participant to use a 3-button response box to identify which of the three numbers appears only once in the string. There are two sources of interference: the two other distracting numbers in the string and positioning of the probe number that is discordant with the position of the corresponding button on the response box. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Working Memory in Continuous Performance Task [ Time Frame: days 9, 37, and 56 ]
    The AX continuous performance task requires individuals to click a response button when they observe an X that has been followed by an A in a stream of characters displayed on the screen. The test will be administered while the participant is inside an MRI scanner. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Attentional and Inhibitory Control [ Time Frame: days 12, 38, and 57 ]
    Participants will perform the Attention Network Task, in which they are presented with a line of arrows and required to click a lefthand or righthand button depending on whether the center arrow points to the left or right, respectively. The participant is required to suppress multiple distracting spatial cues to provide this correct response. The test will be administered while the participant is inside an MRI scanner. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Emotional Reactivity [ Time Frame: days 12, 38, and 57 ]
    Participants are presented with a series of trials in which a probe image of a human face shown in the center of the screen must be identified to a face shown either on the left or right side of the screen. The test will be administered while the participant is inside an MRI scanner. A beltlike respiratory monitor will be affixed around the waist and a pulse oximeter will be clipped onto a finger or toe for physiological monitoring. Headphones are placed over the ears to remove MRI scanner noise and deliver audio stimuli during the task.
  • Change in Endocrine Mediators of Appetite [ Time Frame: days 7 and 43 and upon return to initial body weight, up to day 85 ]
    A fasted blood sample will be taken 15 minutes prior to a breakfast meal. Additional samples will be taken at 30, 60, 120, and 180 minutes after the meal on days 7 and 43 and at end of study. Samples also will be taken at 215, 245, 305, and 365 minutes after the meal on day 43. Serum will be analyzed for leptin and insulin, serum for glucose, and plasma for acyl ghrelin and des-acyl ghrelin. Additional samples will be collected and archived for future tests.
  • Change in Gut Microbiome Composition [ Time Frame: days 11-14, days 25-28, days 39-42, and upon return to initial body weight, up to day 85 ]
    A single fecal sample will be collected at each of 4 time points in the course of the study. Samples will be processed for analysis of gut microbiome composition.
  • Change in Gastrointestinal Permeability [ Time Frame: days 11 and 39 and upon return to initial body weight, up to day 85 ]
    Participants will consume 2 g sucralose and 4 g mannitol dissolved in 180 mL water. Mannitol and sucralose are sugar substitutes commonly used as sweeteners in a variety of food products. Participants will then collect a urine sample 24 hours after sugar substitute ingestion. The sucralose:mannitol ratio in the 24hr urine collection will provide measures of whole gut permeability.
  • Change in Eating Attitudes [ Time Frame: baseline, days 14 and 42, and upon return to initial body weight, up to day 85 ]
    Participants in a fasted state will complete the Food Cravings Questionnaire-trait and Food Cravings Inventory 2 to measure the frequency of cravings for specific types of foods.
  • Change in Eating Behaviors [ Time Frame: baseline, days 14 and 42, and upon return to initial body weight, up to day 85 ]
    Participants in a fasted state will complete the Three Factor Eating Questionnaire to measure hunger, dietary restraint and disinhibition.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Physiological and Psychological Effects of Testosterone During Severe Energy Deficit and Recovery
Official Title  ICMJE Physiological and Psychological Effects of Testosterone During Severe Energy Deficit and Recovery: a Randomized, Placebo Controlled Trial
Brief Summary The objective of this study is to determine whether maintaining a eugonadal state, during severe, sustained energy deficit, attenuates physiological decrements, particularly the loss of lean body mass.
Detailed Description This study will enroll up to 60 physically active men in a 3-phase randomized, placebo-controlled trial. After completing a 14-day (free-living, phase 1), energy-adequate, diet-acclimation phase (protein, 1.6 g∙kg-1∙d-1; fat 30% total energy intake, with remaining energy derived from carbohydrate), participants will be randomized to one of two experimental groups and undergo a 28-day (live-in, phase 2), 55% energy deficit phase: energy deficit alone (DEF) or energy deficit + exogenous testosterone (DEF+TEST). Recovery (free-living, phase 3) will be assessed after completing phase 2 to determine when body mass has been recovered within ± 2.5% of initial body mass (duration will vary, 42-day maximum for phase 3). This study will delineate the contribution of testosterone declines from the physical and mental demands encountered by Warfighters during military training and combat operations on complex markers of physiological and psychological status, addressing a direct, consistently observed, gap in knowledge.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Caloric Restriction
  • Exercise
Intervention  ICMJE
  • Drug: Sesame Oil
    200 mg sesame oil by intramuscular injection weekly on days 15, 21, 28, and 35
  • Drug: testosterone enanthate
    200 mg testosterone enanthate by intramuscular injection weekly on days 15, 21, 28, and 35
Study Arms  ICMJE
  • Placebo Comparator: Energy Deficit
    Participants randomly assigned to the control condition will be subject to exercise-induced energy expenditure resulting in a 55% energy deficit and will be administered sesame oil placebo injections during phase 2 of the trial.
    Intervention: Drug: Sesame Oil
  • Experimental: Energy Deficit + Testosterone
    Participants randomly assigned to the intervention condition will be subject to exercise-induced energy expenditure resulting in a 55% energy deficit and will be administered testosterone enanthate injections during phase 2 of the trial.
    Intervention: Drug: testosterone enanthate
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 18, 2017)
53
Original Estimated Enrollment  ICMJE
 (submitted: April 5, 2016)
60
Actual Study Completion Date  ICMJE December 2017
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Physically active (at least 2 days per week aerobic and/or resistance exercise)
  • Not taking any prescription medications and/or willing to refrain from all medication use prior to and throughout the entire study period, unless provided/approved by the study physician
  • Willing to refrain from alcohol, smoking, e-cigarettes, or use of any nicotine product, caffeine, and dietary supplement use throughout the entire study period

    • At the discretion of the study physician, wash-out period for medications, supplements, and over-the-counter medications is ≥ 1 to 4 weeks
    • Wash-out period for caffeine and alcohol is ≥ 7 days
  • Willing to live on the Pennington Biomedical Research Center inpatient unit for 28 consecutive days
  • Willing to have a urine drug screening
  • Meets age-specific U.S. Army body composition standards according to Army Regulation 600-9, which includes estimates of percent body fat based on height, weight, and circumference measures (neck and waist)
  • Total testosterone concentration is within the normal physiological range, total testosterone (300-1,000 ng/dL).

Exclusion Criteria:

  • Musculoskeletal injuries that compromise exercise capability
  • Diagnosed cardiometabolic disorders (i.e., hypertension, hyperlipidemia, kidney disease, diabetes, etc.)
  • Allergies or intolerance to foods, vegetarian practices, or history of complications with lidocaine
  • Anabolic steroid, human growth hormone, or nutritional testosterone precursor-like supplement use within the past 6 months
  • Will not refrain from smoking (any nicotine product), alcohol, caffeine, or any other dietary supplement during the study
  • Any use of antibiotics, except topical antibiotics, within 3 months of study participation
  • Colonoscopy within 3 months of study participation
  • Chronic use of laxatives, stool softeners, antacids, or anti-diarrheal medications (≥ once a week)
  • History of gastrointestinal disease (e.g., celiac, irritable bowel syndrome, colitis, Crohn's disease)
  • Restrained eater (the Three-Factor Eating Questionnaire) as assessed by the study's psychological and behavioral assessment staff
  • Adults unable to consent
  • Women
  • Prisoners
  • Metal implants, claustrophobia, head size incompatible with MRI equipment, etc.
  • Sedentary or engages in <2 days of physical activity per week (aerobic and/or resistance training)
  • Exceeds age-specific U.S. Army body composition standards according to Army Regulation 600-9
  • Previous history of kidney stones unless otherwise approved by the medical investigator
  • Systolic blood pressure > 150 or diastolic blood pressure > 95 mmHg
  • Previous history of breast or prostate cancer
  • Previous history of Chronic Obstructive Pulmonary Disease or Obstructive Sleep Apnea
  • Findings of lab results of prostate-specific antigen > 3ng/ml, Hematocrit > 50%, or positive urine drug screening
  • Based on the investigative team's clinical judgment, a subject may not be appropriate for participation in the study
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 39 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02734238
Other Study ID Numbers  ICMJE PBRC 2015-063
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jennifer C. Rood, Pennington Biomedical Research Center
Study Sponsor  ICMJE Pennington Biomedical Research Center
Collaborators  ICMJE
  • United States Army Research Institute of Environmental Medicine
  • MyoSyntax
  • Defence Research and Development Canada
  • United States Department of Defense
Investigators  ICMJE
Principal Investigator: Jennifer C Rood, Ph.D. Pennington Biomedical Research Center
PRS Account Pennington Biomedical Research Center
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP