Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit (STROMA-ICU)

April 30, 2021 updated by: Massachusetts General Hospital

Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit (STROMA-ICU)

Acute muscle wasting occurs early and rapidly during the first week of critical illness and contributes substantially to weakness acquired in the ICU. Muscle wasting and subsequent weakness is associated with delayed liberation from mechanical ventilation, prolonged hospital length of stay, long-term functional disability, and worse quality of life. Moreover, low muscle volume as well as ICU-acquired weakness increases the risk of mortality in critically ill patients. Although several factors likely accelerate skeletal muscle wasting during critical illness (e.g., immobility, inflammation, multi-organ failure), the understanding of the underlying mechanisms remains limited and is reflected in the lack of effective interventions to prevent the loss of muscle mass in ICU patients. To-date, there is no known safe and effective pharmacological or nutritional intervention to attenuate the acute loss of muscle mass in ICU patients.

Leucine is an amino acid widely regarded for its anabolic effects on muscle metabolism. However, the concentrations required to maximize its anti-proteolytic effects are far greater than the concentrations required to maximally stimulate protein synthesis. This has resulted in the search for leucine metabolites that may also be potent mediators of anabolic processes in skeletal muscle; one such compound is β-hydroxy-β-methylbutyrate (HMB). HMB is thought to primarily facilitate protein synthesis through stimulation of mammalian target of rapamycin (mTOR), a protein kinase responsive to mechanical, hormonal, and nutritional stimuli that plays a central role in the control of cell growth. Randomized, controlled trials to assess the effect of HMB supplementation on clinical outcomes in patients with chronic diseases are limited, and even fewer studies have assessed its effects on skeletal muscle metabolism during critical illness. Furthermore, despite compelling preclinical evidence, the exact mechanisms underlying the effect of HMB supplementation during acute catabolic stress in humans is not well defined. Therefore, the investigators goal is to study the impact of early HMB supplementation on skeletal muscle mass in ICU patients and to explore the mechanisms by which HMB may exert its effects on skeletal muscle metabolism during critical illness.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Acute muscle wasting occurs early and rapidly during the first week of critical illness and contributes substantially to weakness acquired in the ICU. Muscle wasting and subsequent weakness is associated with delayed liberation from mechanical ventilation, prolonged hospital length of stay (LOS), long-term functional disability, and worse quality of life. Moreover, low muscle volume and ICU-acquired weakness increases the risk of mortality in critically ill patients. Although several factors likely accelerate skeletal muscle wasting during critical illness (e.g., immobility, muscle unloading, inflammation, multi-organ failure), the understanding of the underlying mechanisms remains limited and is reflected in the lack of effective interventions to prevent the loss of muscle mass in ICU patients.

Muscle mass is maintained through balanced protein breakdown and synthesis . As such, for wasting to occur, catabolic pathways must be increased relative to anabolic processes. In general, nutritional status is an important factor for maintaining skeletal muscle homeostasis. However, adequate caloric delivery is often challenging in ICU patients and recent data suggest that high protein delivery in early critical illness may adversely impact muscle protein synthesis. Moreover, randomized, placebo-controlled, clinical trials (RCTs) in ICU patients do not support the use of aggressive early macronutrient delivery. Such findings emphasize the need for targeted therapies to enhance anabolic pathways, which may improve clinical outcomes in critically ill patients.

The amino acid leucine is widely regarded for its anabolic effects on muscle metabolism, but the concentrations required to maximize its anti-proteolytic effects are far greater than the concentrations required to maximally stimulate protein synthesis. This has resulted in the search for leucine metabolites that may also be potent mediators of anabolic processes in skeletal muscle -- one such compound is β-hydroxy-β-methylbutyrate (HMB).

HMB is thought to primarily facilitate protein synthesis through stimulation of mammalian target of rapamycin (mTOR), a protein kinase responsive to mechanical, hormonal, and nutritional stimuli that plays a central role in the control of cell growth. Indeed, preclinical studies demonstrate that HMB supplementation increases phosphorylation of mTOR as well as its downstream targets. Preclinical data also suggest that HMB supplementation results in an increase in skeletal muscle insulin-like growth factor 1(IGF-1) levels, which may further stimulate mTOR. In addition, HMB may influence systemic levels of myostatin, a key negative regulator of mature skeletal muscle growth. Myostatin has been shown to reduce muscle protein synthesis by inhibiting mTOR signaling and by increasing proteolytic mechanisms. Recent preclinical data suggest that HMB may reduce myostatin levels and attenuate skeletal muscle atrophy. Furthermore, preclinical data has shown that HMB also stimulates the release of irisin, a newly discovered myokine, which up-regulates IGF-1 and inhibits myostatin.

On the other hand, skeletal muscle proteolysis is thought to occur primarily through the ubiquitin-proteasome system, which is an energy-dependent proteolytic system that degrades intracellular proteins. The activity of this pathway is thought to be regulated through expression of nuclear factor kappa B (NF-κB), which is significantly increased in conditions such as fasting, immobilization, bed rest, and in various disease states. In preclinical studies, HMB has been shown to decrease proteasome expression and reduce activity of this pathway during catabolic states. Furthermore, caspase proteases (in particular, caspase protease-3 and caspase protease-9) are thought to induce skeletal muscle proteolysis through apoptosis of myonuclei. Preclinical data suggest that in catabolic states, HMB attenuates the up-regulation of caspases, which in turn, reduces myonuclear apoptosis and reduces skeletal muscle protein degradation.

Randomized controlled trials (RCTs) that have assessed the effect of HMB supplementation on clinical outcomes in patients with chronic diseases are limited, and even fewer studies have assessed its effects on skeletal muscle metabolism during critical illness. Furthermore, despite compelling preclinical evidence, the exact mechanisms underlying the effect of HMB supplementation during acute catabolic stress in humans is not well defined.

Therefore, the investigators goal is to study the impact of early HMB supplementation on skeletal muscle mass in surgical ICU patients and to explore the mechanisms by which HMB may exert beneficial effects on skeletal muscle metabolism during the course of critical illness.

Study Type

Interventional

Phase

  • Phase 2
  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. 18 years or older
  2. English-speaking
  3. Expected to require at least 72 hours of ICU care
  4. Able to provide written/verbal consent or have a suitable healthcare proxy
  5. Able to ultrasound the diaphragm and quadriceps muscles in a consistent location for 7 days
  6. Ability to take study drug orally vs. an indwelling nasogastric, orogastric, gastric, or gastrojejunostomy tube

Exclusion Criteria:

  1. Pregnant or peri-partum female
  2. Baseline hemoglobin less than 8g/dL
  3. Not expected to survive beyond 72 hours
  4. Unable to provide a written/verbal consent or an available healthcare proxy
  5. Enrolled in another study which may interfere with the current study
  6. Prior ICU admission with 1 year of current admission or more than 7 days of hospital admission before transfer to the ICU
  7. Strict "nil per os" (NPO) status
  8. High output through naso/orogastric tube
  9. Clinically significant bowel obstruction
  10. Active cancer (except for actinic keratosis, squamous cell carcinoma, and basal cell carcinoma confined to the skin)
  11. Palliative care status
  12. Known or anticipated history of difficult blood draws
  13. History of elevated low density lipoprotein (LDL) and not on a stable treatment regimen
  14. Blood urea nitrogen (BUN): creatinine >20 without an underlying cause
  15. History of hypoglycemia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo + Vital HP
GROUP 1 will receive Placebo (within 24 hours of ICU admission) and Vital HP ® (while on tube feeds). Vital HP® is on the Massachusetts General hospital formulary, but it is often restricted to patients with malabsorption due to its higher cost compared to other standard enteral nutrition formulas.
Dietary supplement: Placebo
The placebo is cornstarch and will be mixed in with Vital HP. The solution will look identical to the intervention arm.
Dietary supplement: Vital HP®
Vital HP® is a form of enteral nutrition a part of the Massachusetts General enteral formulary
Experimental: B-hydroxy-B-methylbutyrate (HMB) + Vital HP
GROUP 2 will receive beta-hydroxy-beta-methylbutyrate (within 24 hours of ICU admission) and Vital HP ® (while on tube feeds). Vital HP® is on the Massachusetts General hospital formulary, but it is often restricted to patients with malabsorption due to its higher cost compared to other standard enteral nutrition formulas. The investigators will limit HMB dosing to 3g/day since this is the most widely studied dose.
Dietary supplement: Vital HP®
Vital HP® is a form of enteral nutrition a part of the Massachusetts General enteral formulary
Dietary supplement: beta-hydroxy-beta-methylbutyrate
HMB is a leucine metabolite that may also be a potent mediator of anabolic processes in skeletal muscle; subjects will not receive >3g of HMB/ day.
Other Names:
  • HMB

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in muscle thickness (diaphragm) at 14 days after ICU admission.
Time Frame: Day 14 of ICU admission or through study completion, an average of 1 month
Change in muscle thickness will be assessed via ultrasound (base line and 14 days)
Day 14 of ICU admission or through study completion, an average of 1 month
Change in muscle thickness (quadriceps at 14 days after ICU admission.
Time Frame: Day 14 of ICU admission or through study completion, an average of 1 month
Change in muscle thickness will be assessed via ultrasound (baseline and 14 days)
Day 14 of ICU admission or through study completion, an average of 1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intensive care unit length of stay
Time Frame: Time of admission to the ICU until the time of discharge from the intensive care unit, up to 100 weeks
Time of admission to the ICU until the time of discharge from the intensive care unit, up to 100 weeks
Hospital Length of Stay
Time Frame: Time of discharge from the ICU until hospital discharge, up to 100 weeks
Time of discharge from the ICU until hospital discharge, up to 100 weeks
30-day ventilator free days
Time Frame: number of days during ICU admission not requiring invasive mechanical ventilation support, or until study completion, up to 100 weeks
number of days not requiring invasive mechanical ventilation support
number of days during ICU admission not requiring invasive mechanical ventilation support, or until study completion, up to 100 weeks
Discharge destination (home vs. non-home)
Time Frame: time of discharge until 90 days after discharge
Assess where patients as discharged to
time of discharge until 90 days after discharge
30-day readmission
Time Frame: From the time of hospital discharge until 30-days after hospitalization
Assess readmission rates in both groups
From the time of hospital discharge until 30-days after hospitalization
30-day all-cause mortality
Time Frame: From the time of hospital discharge until 30 days after hospitalization
Assess 30 day all cause mortality in both groups
From the time of hospital discharge until 30 days after hospitalization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Investigators

  • Principal Investigator: Sadeq A. Quraishi, MD,MHA,MMSc, Massachusetts General Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2017

Primary Completion (Anticipated)

January 1, 2019

Study Completion (Anticipated)

January 1, 2019

Study Registration Dates

First Submitted

May 5, 2016

First Submitted That Met QC Criteria

May 13, 2016

First Posted (Estimate)

May 16, 2016

Study Record Updates

Last Update Posted (Actual)

May 5, 2021

Last Update Submitted That Met QC Criteria

April 30, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2016p001044

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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