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

• ClinicalTrials.gov Identifier: NCT02773771
• Recruitment Status: Unknown
• First Posted: May 16, 2016
• Last Update Posted: November 23, 2016
• Sponsor: Massachusetts General Hospital
• Information provided by (Responsible Party): Sadeq A. Quraishi, Massachusetts General Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Muscle Atrophy	Dietary Supplement: beta-hydroxy-beta-methylbutyrate; Dietary Supplement: Placebo; Dietary Supplement: Vital HP®	Phase 2; Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Strategies to Reduce Organic Muscle Atrophy in the Intensive Care Unit (STROMA-ICU)
• Study Start Date: January 2017
• Estimated Primary Completion Date: January 2019
• Estimated Study Completion Date: January 2019

Arms and Interventions

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: 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 Name: HMB; Dietary Supplement: Vital HP®; Vital HP® is a form of enteral nutrition a part of the Massachusetts General enteral formulary

Outcome Measures

Primary Outcome Measures :

1. 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)
2. 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)

Secondary Outcome Measures :

1. 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 ]
2. Hospital Length of Stay [ Time Frame: Time of discharge from the ICU until hospital discharge, up to 100 weeks ]
3. 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
4. Discharge destination (home vs. non-home) [ Time Frame: time of discharge until 90 days after discharge ]
   Assess where patients as discharged to
5. 30-day readmission [ Time Frame: From the time of hospital discharge until 30-days after hospitalization ]
   Assess readmission rates in both groups
6. 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Sadeq A. Quraishi, MD, MHA, MMSc; 617-726-3030; SQURAISHI@mgh.harvard.edu

Contact: Tiffany M Otero, BS; 617-726-3030; totero@partners.org

Sponsors and Collaborators

Massachusetts General Hospital

Investigators

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

More Information

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• Responsible Party: Sadeq A. Quraishi, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT02773771
• Other Study ID Numbers: 2016D002272
• First Posted: May 16, 2016
• Last Update Posted: November 23, 2016
• Last Verified: November 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Sadeq A. Quraishi, Massachusetts General Hospital:

Muscle Atrophy; Critical Illness; Ultrasound; beta-hydroxy-beta-methylbutyrate; ICU

Additional relevant MeSH terms:

Muscular Atrophy; Atrophy; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases