Effects of Pre-Run Nutritional Supplements During a Fixed-Pace 5 km Treadmill Run

NCT07854223 | Recruiting

• 1 other identifier: STUDY00000697
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine how three commonly used pre-run nutritional supplements-caffeine, L-citrulline, and an exogenous ketone supplement-affect physiological and perceptual responses during a fixed-pace 5 km treadmill run in healthy, physically active runners. Participants will complete one screening and baseline visit followed by four experimental visits in a randomized order. At each experimental visit, participants will receive caffeine, L-citrulline, an exogenous ketone supplement, or placebo before completing a fixed-pace 5 km treadmill run. Each participant will receive all four conditions and will therefore serve as their own control. The study will evaluate measures including running economy, heart-rate responses, oxygen consumption, respiratory measures, blood lactate and ketone concentrations, perceived exertion, gastrointestinal symptoms, fatigue, energy, and focus. A randomly selected subgroup will also wear a continuous glucose monitor to explore glucose responses during the experimental visits. The study will also assess the feasibility and tolerability of completing repeated treadmill trials under the four supplement conditions.

Conditions

Exercise Physiology; Nutritional Supplementation

Keywords

Running Economy; Heart Rate Drift; Caffeine; L-Citrulline; Exogenous Ketones; Beta-Hydroxybutyrate; 5 km Running; Endurance Exercise; Nutritional Supplements; Indirect Calorimetry; Blood Lactate; Blood Ketones; Continuous Glucose Monitoring

Outcome Measures

Primary Outcomes (2)

• Running Economy (VO₂) During the Fixed-Pace 5 km Treadmill Run

  Running economy will be assessed using oxygen consumption (VO₂) measured by indirect calorimetry during standardized portions of the fixed-pace 5 km treadmill run. Within-participant running-economy responses will be compared across the caffeine, L-citrulline, exogenous ketone, and placebo conditions.

  During the fixed-pace 5 km treadmill run at each of the four experimental visits, approximately 45 minutes after supplement/placebo ingestion.

• Heart-Rate Drift During the Fixed-Pace 5 km Treadmill Run

  Heart-rate drift will be assessed from continuous heart-rate monitoring as the change in heart rate over the course of the fixed-pace 5 km treadmill run. Within-participant heart-rate drift will be compared across the caffeine, L-citrulline, exogenous ketone, and placebo conditions.

  Throughout the fixed-pace 5 km treadmill run at each of the four experimental visits, approximately 45 minutes after supplement/placebo ingestion.

Secondary Outcomes (13)

• Mean Oxygen Consumption (VO₂) During the Fixed-Pace 5 km Treadmill Run

  During the fixed-pace 5 km treadmill run at each of the four experimental visits, beginning approximately 45 minutes after supplement/placebo ingestion.

• Mean Carbon Dioxide Production (VCO₂) During the Fixed-Pace 5 km Treadmill Run

  During the fixed-pace 5 km treadmill run at each of the four experimental visits, beginning approximately 45 minutes after supplement/placebo ingestion.

• Ventilation

  During the fixed-pace 5 km treadmill run at each of the four experimental visits.

• Respiratory Exchange Ratio

  During the fixed-pace 5 km treadmill run at each of the four experimental visits.

• 1-Minute Heart-Rate Recovery After the Fixed-Pace 5 km Treadmill Run

  From exercise cessation to 60 seconds after completion of the fixed-pace 5 km treadmill run at each of the four experimental visits.

Other Outcomes (3)

• Interstitial Glucose Response During the Experimental-Visit Window in the CGM Subgroup

  From pre-supplement baseline through completion of the immediate post-exercise assessments at each experimental visit.

• Completion of All Four Experimental Visits

  Across each participant's approximately 4-6 weeks of study participation.

• Participants Experiencing Adverse Events

  From the first study visit through completion of the final study visit, approximately 4-6 weeks per participant.

Study Arms (4)

Sequence 1: Caffeine-L-Citrulline-Placebo-Ketone

EXPERIMENTAL

Participants assigned to this randomized crossover sequence will receive caffeine, followed by L-citrulline, placebo, and exogenous ketone across four experimental visits. Each intervention will be administered 45 minutes before a fixed-pace 5 km treadmill run. Experimental visits will be separated by a minimum washout/recovery period of four days.

Dietary Supplement: Caffeine; Dietary Supplement: L-Citrulline; Dietary Supplement: Exogenous Ketone (Beta-Hydroxybutyrate); Other: placebo beverage

Sequence 2: L-Citrulline-Ketone-Caffeine-Placebo

EXPERIMENTAL

Participants assigned to this randomized crossover sequence will receive L-citrulline, followed by exogenous ketone, caffeine, and placebo across four experimental visits. Each intervention will be administered 45 minutes before a fixed-pace 5 km treadmill run. Experimental visits will be separated by a minimum washout/recovery period of four days.

Dietary Supplement: Caffeine; Dietary Supplement: L-Citrulline; Dietary Supplement: Exogenous Ketone (Beta-Hydroxybutyrate); Other: placebo beverage

Sequence 3: Ketone-Placebo-L-Citrulline-Caffeine

EXPERIMENTAL

Participants assigned to this randomized crossover sequence will receive exogenous ketone, followed by placebo, L-citrulline, and caffeine across four experimental visits. Each intervention will be administered 45 minutes before a fixed-pace 5 km treadmill run. Experimental visits will be separated by a minimum washout/recovery period of four days.

Dietary Supplement: Caffeine; Dietary Supplement: L-Citrulline; Dietary Supplement: Exogenous Ketone (Beta-Hydroxybutyrate); Other: placebo beverage

Sequence 4: Placebo-Caffeine-Ketone-L-Citrulline

EXPERIMENTAL

Participants assigned to this randomized crossover sequence will receive placebo, followed by caffeine, exogenous ketone, and L-citrulline across four experimental visits. Each intervention will be administered 45 minutes before a fixed-pace 5 km treadmill run. Experimental visits will be separated by a minimum washout/recovery period of four days.

Dietary Supplement: Caffeine; Dietary Supplement: L-Citrulline; Dietary Supplement: Exogenous Ketone (Beta-Hydroxybutyrate); Other: placebo beverage

Interventions

Caffeine DIETARY_SUPPLEMENT

Caffeine will be administered at exactly 4 mg/kg body weight. The individualized dose will be calculated using body weight measured at the baseline visit. The commercially manufactured capsule contents will be weighed by trained study staff using a calibrated analytical balance to obtain the protocol-specified dose. Caffeine will be dispensed in the standardized study beverage and consumed 45 minutes before the fixed-pace 5 km treadmill run.

Sequence 1: Caffeine-L-Citrulline-Placebo-Ketone; Sequence 2: L-Citrulline-Ketone-Caffeine-Placebo; Sequence 3: Ketone-Placebo-L-Citrulline-Caffeine; Sequence 4: Placebo-Caffeine-Ketone-L-Citrulline

L-Citrulline DIETARY_SUPPLEMENT

L-citrulline will be administered at exactly 7.0 g. The commercially manufactured pure L-citrulline powder will be weighed using a calibrated analytical balance, dispensed in the standardized study beverage, and consumed 45 minutes before the fixed-pace 5 km treadmill run.

Sequence 1: Caffeine-L-Citrulline-Placebo-Ketone; Sequence 2: L-Citrulline-Ketone-Caffeine-Placebo; Sequence 3: Ketone-Placebo-L-Citrulline-Caffeine; Sequence 4: Placebo-Caffeine-Ketone-L-Citrulline

Exogenous Ketone (Beta-Hydroxybutyrate) DIETARY_SUPPLEMENT

The exogenous ketone condition will consist of one 15 g serving of Nutricost Ketone BHB Salt 4-in-1 Powder, providing 11.5 g beta-hydroxybutyrate (BHB) as calcium, magnesium, sodium, and potassium BHB salts. The supplement will be dispensed in the standardized study beverage and consumed 45 minutes before the fixed-pace 5 km treadmill run.

Sequence 1: Caffeine-L-Citrulline-Placebo-Ketone; Sequence 2: L-Citrulline-Ketone-Caffeine-Placebo; Sequence 3: Ketone-Placebo-L-Citrulline-Caffeine; Sequence 4: Placebo-Caffeine-Ketone-L-Citrulline

placebo beverage OTHER

The placebo will be a study-prepared beverage containing water, food-grade lime flavoring, and stevia, with no active study supplement. It will use the same standardized final volume as the active conditions and will be consumed 45 minutes before the fixed-pace 5 km treadmill run.

Sequence 1: Caffeine-L-Citrulline-Placebo-Ketone; Sequence 2: L-Citrulline-Ketone-Caffeine-Placebo; Sequence 3: Ketone-Placebo-L-Citrulline-Caffeine; Sequence 4: Placebo-Caffeine-Ketone-L-Citrulline

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-35 years
• Healthy adult
• Able to provide written informed consent
• Regularly engaged in running-based aerobic training at least 3 times per week for at least 30 minutes per session during the past 3 months
• Able to complete a 5 km run in under 30 minutes
• Able and willing to comply with treadmill testing, fingerstick testing, dietary standardization, supplement restrictions, and pre-visit instructions
• Participants randomly selected for the continuous glucose monitoring subgroup must also be willing to undergo Dexcom Stelo continuous glucose monitor placement and wear

You may not qualify if:

• Known cardiovascular, metabolic, pulmonary, or neurological disease that may increase the risk associated with exercise testing or materially influence study outcomes
• Uncontrolled hypertension or another cardiovascular condition that, in the investigator's judgment, makes vigorous treadmill exercise unsafe
• Diagnosed type 1 or type 2 diabetes mellitus or another known metabolic disease that may materially influence study outcomes
• Pregnant, breastfeeding, or planning pregnancy during the study period
• Current use of nitrate medications or phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil, tadalafil, or vardenafil
• Known sensitivity or allergy to caffeine, L-citrulline, exogenous ketone/BHB salt products, or any study beverage ingredient
• Current use of stimulant medications or other medications that may significantly influence cardiovascular, blood pressure, or metabolic responses to exercise, as determined by the investigator
• Musculoskeletal injury or condition that limits safe treadmill running
• Smoking or regular use of nicotine products
• Recent illness, surgery, or hospitalization that, in the opinion of the investigators, may interfere with safe participation or study outcomes
• Unable or unwilling to comply with study procedures or pre-visit standardization requirements

Sponsors & Collaborators

• St. Louis University: lead

Study Sites (1)

Saint Louis University, Allied Health Building

St Louis, Missouri, 63104, United States

RECRUITING

MeSH Terms

Interventions

Caffeine; Citrulline; 3-Hydroxybutyric Acid

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Amino Acids, Diamino; Amino Acids; Amino Acids, Peptides, and Proteins; Hydroxybutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Ketone Bodies; Ketones; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Hossein Rafiei

  St. Louis University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hossein Rafiei, PhD, RD, ACSM-CPT

CONTACT

314-977-8675; hossein.rafiei@health.slu.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Participants will be blinded to the assigned supplement condition at each experimental visit. Study beverages will use the same standardized vehicle and final volume, with identical or similar opaque containers used to support participant blinding when feasible. Complete taste matching cannot be guaranteed because the active supplements have different inherent tastes.
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Model Details: Participants will be randomized in a 1:1:1:1 ratio to one of four treatment sequences using a four-period, four-treatment Williams square design (ABDC, BCAD, CDBA, DACB), where A = caffeine, B = L-citrulline, C = exogenous ketone, and D = placebo. This counterbalanced design balances treatment assignment across study periods and first-order carryover. Each participant will receive all four conditions and serve as their own control. Experimental visits will be separated by a minimum washout/recovery period of four days.

Study Record Dates

• First Submitted: September 26, 2026
• First Posted: October 2, 2026
• Study Start: October 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): August 1, 2027
• Last Updated: October 2, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)