Safety and Tolerability of a Nutritional Formula Designed to Aid in Maintenance of Muscle During Periods of Caloric Restriction in Adults (Redefine)

An Adaptive, Randomized, Double-Blind, Placebo-Controlled Clinical Trial Assessing the Safety and Tolerability of Redefine, a Multi-Ingredient Nutritional Formulation Designed to Aid Lean Mass Preservation in Subjects Undergoing Caloric Restriction

Muscle loss during caloric restriction is a significant concern for metabolic health and physical function, yet there is limited evidence on interventions that simultaneously target multiple contributing pathways. This study investigates a multi-component formulation targeting these complementary pathways to address critical gaps in strategies for preserving lean mass during energy restriction. The primary goal of this study is to demonstrate the safety and tolerability of the product Redefine when used as an adjunct to a well-established caloric restriction regimen. Caloric restriction is known to result in unintended loss of skeletal muscle mass, which may negatively impact physical function and metabolic health. This study seeks to evaluate whether supplementation with Redefine may help preserve muscle mass and support the maintenance of healthy muscle function during caloric restriction. Secondarily, this study aims to explore whether Redefine supplementation may confer favorable changes in body composition in subjects participating in a caloric restriction regimen. This product consists of HMB, postbiotics and botanicals.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity & Overweight
• Intervention / Treatment: Dietary supplement: Redefine; Dietary supplement: Placebo

Detailed Description

Caloric restriction is a cornerstone of weight loss and metabolic health interventions; however, it is consistently associated with unintended reductions in lean body mass. Clinical evidence indicates that pharmacologic-induced caloric restriction involving GLP-1 receptor agonists (GLP-1RAs) consistently produces substantial weight loss (~10-15% of baseline body weight). This is consistently accompanied by reductions in lean mass as well, similar to the changes seen in diet-induced weight loss. A review of the effect of semaglutide on lean mass in clinical trials indicates that, while weight loss is primarily due to reductions in fat mass, lean mass can account for up to 40% of total weight loss. In the SURMOUNT-1 study, of the tirzepatide-associated body weight lost, 75% was fat mass and 25% was lean mass. This raises concerns as the lean mass loss can account for a clinically meaningful portion of total weight reduction, highlighting the need for strategies to support muscle preservation during semaglutide-induced weight loss.

Loss of skeletal muscle is clinically relevant, as it negatively impacts physical function, resting energy expenditure, metabolic flexibility, and long-term weight maintenance. During sustained energy deficits, skeletal muscle protein balance shifts toward net catabolism due to suppressed anabolic signaling, reduced dietary protein and amino acid availability, and increased activation of proteolytic pathways. Reductions in insulin and insulin-like growth factor-1 (IGF-1), along with increased activity of the ubiquitin-proteasome and autophagy-lysosome systems, contribute to accelerated muscle protein breakdown during caloric restriction.

Appetite suppression whether behaviorally induced or pharmacologically mediated can further exacerbate inadequate protein and micronutrient intake, increasing vulnerability to muscle loss. Importantly, lean mass loss observed in these contexts is largely attributable to reduced caloric and protein intake rather than to the specific method used to achieve energy restriction, underscoring the relevance of muscle-preserving strategies across weight-loss approaches.

Beyond foundational macronutrient strategies, specific dietary ingredients have been shown to directly influence muscle protein metabolism. Beta-hydroxy-beta-methylbutyrate (HMB) has been shown in clinical studies and meta-analyses to help preserve or modestly increase lean body mass by reducing muscle protein breakdown and supporting protein synthesis . HMB is a metabolite of the branched-chain amino acid leucine and has been extensively studied for its ability to support skeletal muscle preservation under catabolic conditions, including caloric restriction, aging, and physical inactivity. Mechanistic studies indicate that HMB attenuates muscle protein breakdown by modulating proteolytic pathways, including the ubiquitin-proteasome system, while also supporting anabolic signaling pathways involved in muscle protein synthesis. Metanalyses suggest that HMB supplementation can reduce lean mass loss during periods of negative energy balance, making it a mechanistically appropriate intervention for individuals undergoing caloric restriction.

Emerging evidence highlights the gut-muscle axis as a key contributor to lean mass regulation during metabolic stress. Caloric restriction can alter gut microbiota composition, increase intestinal permeability, and impair nutrient absorption, potentially elevating inflammatory mediators that promote muscle catabolism. Akkermansia muciniphila, a gut microbial species consistently linked to metabolic health, has been shown to be reduced in individuals with sarcopenia and low muscle mass. Preclinical and early clinical studies indicate that Akkermansia-based interventions may help preserve muscle mass and function by enhancing gut barrier integrity, reducing inflammation, and modulating anabolic-catabolic signaling in muscle.

Botanical dietary interventions can influence muscle preservation pathways by optimizing nutrient absorption and metabolic efficiency. Citrus bioflavonoids (e.g., hesperidin, naringin etc.), have been shown in preclinical and clinical studies to modulate key pathways in metabolic health, including antioxidant and anti-inflammatory signaling, improved lipid and glucose metabolism, and enhanced insulin sensitivity. Mechanistic evidence indicates these flavonoids can inhibit pro-inflammatory cytokines, reduce oxidative stress, influence lipid synthesis/oxidation, and interact with incretin and metabolic regulators. Dandelion and artichoke extracts support liver function by enhancing bile secretion, lipid metabolism, and nutrient absorption. Improved liver efficiency increases the availability of amino acids and vitamins essential for muscle protein synthesis, indirectly helping to preserve lean mass during caloric restriction. Dandelion and artichoke extracts have been shown to activate AMPK, a cellular energy sensor that enhances mitochondrial function and cellular metabolism.

Muscle loss during caloric restriction is a significant concern for metabolic health and physical function, yet there is limited evidence on interventions that simultaneously target multiple contributing pathways. this study will evaluate whether a targeted nutritional intervention including HMB, Akkermansia muciniphila, and selected botanical bioactives can preserve lean mass during GLP-1-induced caloric restriction. The objective is to optimize the quality of weight loss by supporting fat mass reduction while minimizing muscle loss to improve metabolic and functional outcomes.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bhargavi Manda, PhD; Phone Number: 801-341-7984; Email: bhargavi@natr.com
• Study Contact Backup: Name: Wei Gao, PhD; Phone Number: 801-341-7903; Email: weig@natr.com

Study Locations

• United States
  • Utah
    • Lehi, Utah, United States, 84048
      • Breakthrough Medical
      • Contact: Rustin Gibbs; Phone Number: 801-921-6340; Email: rustin@fightweightgain.com
      • Contact: Cherlyn Gibbs; Phone Number: 801-921-6340; Email: cheryln@fightweightgain.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has been receiving a GLP-1 receptor agonist (semaglutide) treatment for weight loss, and is titrated to start receiving a weekly dose of 1 mg semaglutide (Inclusive)
• Body Mass Index (BMI): At study enrollment (participants that have achieved 1 mg titration), 25.0-34.9 (kg/m2) while receiving a GLP-1 receptor agonist (semaglutide) (inclusive)
• Willing to give written informed consent to participate in the Study

Exclusion Criteria:

Medical History and Concurrent Diseases:

• A serious, unstable illness including cardiac, hepatic, renal, gastrointestinal, respiratory, endocrinologic, neurologic, immunologic/rheumatological, or oncological/hematologic disease.
• Allergies related to ingredients in Study products
• Known infection with HIV, TB or Hepatitis B or C.
• POCBP: Not using effective contraception.

Medications/Supplements:

• Discontinuation of semaglutide treatment.
• Discontinuation of semaglutide treatment may be necessary in some cases. However, during the titration phase, GLP-1-related symptoms often do not require treatment discontinuation or reinitiation.
• Diabetes medications
• Currently taking any nutritional supplements judged by the study coordinator to negate or camouflage the effects of the Study Products. See below for a brief list of explicitly allowed supplements.
• Explicitly allowed supplements: Fish Oil, Multivitamin, Magnesium, Vitamin D, Vitamin C
• Use of Narcotics during the last 30 days
• Use of Anticoagulants during last 30 days
• Use of Corticosteroids during the last 30 days

Other Exclusionary Criteria:

• Use of controlled substances on a recreational basis during the last 30 days.
• Consumption of more than 1 alcoholic beverage per day (One beverage is a 5-ounce glass of wine, 12 ounces of beer, or one ounce of hard liquor)
• Inability to comply with Study and/or follow-up visits.
• Any concurrent condition (including clinically significant abnormalities in medical history, physical examination, or laboratory evaluations) which, in the opinion of the PI, would preclude safe participation in this study or interfere with compliance.
• Any sound medical, psychiatric and/or social reason which, in the opinion of the PI, would preclude safe participation in this Study or interfere with compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Redefine for 60 days; Participants consume Redefine daily for 60 days	Dietary supplement: Redefine; Redefine, a nutritional formulation composed of beta-hydroxy-beta-methylbutyrate (HMB), an Akkermansia-derived postbiotic, and herbal extracts.
Placebo Comparator: Placebo for 60 days; Participants consume Placebo daily for 60 days	Dietary supplement: Placebo; Placebo is formulated from a blend of flavors, colorants, and excipients that closely resemble Redefine
Experimental: Redefine for 90 days; Participants consume Redefine daily for 90 days	Dietary supplement: Redefine; Redefine, a nutritional formulation composed of beta-hydroxy-beta-methylbutyrate (HMB), an Akkermansia-derived postbiotic, and herbal extracts.
Placebo Comparator: Placebo for 90 days; Participants consume Placebo daily for 90 days	Dietary supplement: Placebo; Placebo is formulated from a blend of flavors, colorants, and excipients that closely resemble Redefine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with supplementation-related adverse events (AEs) as assessed by Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0).	Data collection from weekly surveys and at individual study visits (Baseline, Day-60 and Day-90) will be used to assess participants for supplementation program-related adverse events. Subjects with ongoing AEs may be followed until resolution at the discretion of the PI.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in body composition with Redefine compared to placebo	Body composition analyses including lean muscle mass and fat mass will be measured using DEXA at all visits (baseline, day-60 and day-90).	90 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Grip Strength with Redefine compared to Placebo	Grip strength will be measured using a Dynamometer at all visits (baseline, day-60 and day-90)	90 days
Changes in self-perceived health with Redefine compared to placebo	Self-perceived health will be assessed using the 36-item Short Form Survey (part of the RAND Medical Outcomes Study: Measures of Quality of Life Core Survey (MOS) from RAND Health Care) at all visits (baseline, day-60 and day-90). Raw item responses are recoded and linearly transformed to a 0-100 scale according to standard scoring procedures. Each domain is scored from 0 to 100, with higher scores indicating better perceived health status.	90 days

Collaborators and Investigators

• Sponsor: Nature's Sunshine Products, Inc.
• Investigators: Principal Investigator: Joseph Lamb, MD, Natures Sunshine

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: February 25, 2026
• First Submitted That Met QC Criteria: February 25, 2026
• First Posted (Actual): March 4, 2026

Study Record Updates

• Last Update Posted (Actual): March 5, 2026
• Last Update Submitted That Met QC Criteria: March 3, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Overweight; Obesity
• Other Study ID Numbers: NSP-CT-024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No