search
Back to results

Vitamin D for Muscle Metabolic Function in Cancer Cachexia

Primary Purpose

Cancer Cachexia, Vitamin D Deficiency

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Vitamin D
Placebo
Sponsored by
David Travis Thomas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Cancer Cachexia focused on measuring vitamin D, muscle, metabolism, cancer cachexia

Eligibility Criteria

45 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients must have histologically or cytologically confirmed stage II-IV lung cancer and be planned for definitive non-surgical therapy.

Patients may have a history of prior malignancy.

Mild cancer cachexia, defined by the miniCASCO score of 0-25 points

Vitamin D insufficiency, defined as 25(OH)D < 32 ng/ml

Aged 45 to 75 years. Stratified randomization by age

ECOG performance status ≤ 2 (see Appendix A).

Life expectancy of greater than 3 months

Patients must have normal renal and liver function as defined below:

AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

Able to swallow thin liquids

No uncontrolled illness including, but not limited to, any of the following:

  • Ongoing or active serious infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Uncontrolled cardiac arrhythmia
  • Uncontrolled hypertension
  • Psychiatric illness or social situation that would preclude compliance with study requirements

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

Patients with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with treated brain metastasis are eligible for this trial, providing they have completed treatment at least one day prior to registration.

History of allergic reactions to whey or milk proteins.

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Patients with a history of calcium oxalate nephrolithiasis are excluded.

Patients with a significant history of malabsorption (e.g. celiac sprue, short bowel syndrome, IBD or other, as determined by the treating physician) are excluded.

Patients will not be eligible if actively receiving treatment for vitamin D deficiency and have had recent (3 month) history of vitamin D supplementation (>1000 IU) or calcium supplementation (>800mg).

The following exclusion criteria will avoid the possibility of preexisting muscle impairment: history of congenital myopathies; neurologic disorder involving sequelae of spinal derangement; disk disease or vascular disease; tremor and rigidity.

Patients will also be excluded if they report lower extremity (LE) surgery or injury to the LE in the past 3 months or a past medical history of primary hyperparathyroidism; or rhabdomyolysis.

Additional exclusion criteria include participation in a scheduled resistance exercise program 1 month;

  • metal implants or other contraindications for the MRI;
  • diabetes,
  • advanced renal disease,
  • uncontrolled hypertension;
  • a vitamin D status (25(OH)D) of > 32ng/mL.

Sites / Locations

  • Markey Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Control (Ctl)

Vitamin D

Arm Description

Standard of Care resistance exercise and timed protein supplementation with placebo capsule daily for 12 weeks

Standard of Care resistance exercise and timed protein supplementation with 5,000IU vitamin D supplementation daily for 12 weeks

Outcomes

Primary Outcome Measures

Non-invasive quantification of muscle lipid distribution
MRI/MRS
Local muscle oxygen consumption
Near Infrared Spectroscopy + Diffuse Correlation Spectroscopy measures will be combined to assess changes in local muscle tissue oxygen consumption (VO2 measure)
Muscle Mass
MRI
Muscle Strength
Maximal voluntary contractions and 1-Repetition Maximum will be aggregated to to provide a comprehensive assessment of muscle strength

Secondary Outcome Measures

Mitochondrial Function in Muscle Fibers in Fresh Muscle Fibers ex vivo
Determine the differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl by measure live tissue oxygen consumption rate. Respiration measures will be combined to assess mitochondrial function Mitochondrial respiration will be measured by the XF96 Seahorse extracellular flux analyzer
Mitochondrial Function in Muscle Fibers in Fresh Muscle Fibers ex vivo
Determine the differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl by measure live tissue oxygen consumption rate. Fatty acid oxidation measures will be combined to assess mitochondrial function Fatty acid oxidation will be estimated by monitoring the OCR of cells with no exogenous glucose or glutamine (Gln) ± a specific fatty acid oxidation (FAO) inhibitor, etomoxir (40 µM)
Stable Isotope-Resolved Metabolomics to describe Fatty Acid Metabolism in relationship to other fuel substrates in Fresh Muscle Fibers ex vivo
Determine the relative importance of vitamin D on lipid, amino acid and energy metabolism involving glucose, glutamine, and β-oxidation in intact muscle fibers. We will culture with 13C8-octanoate, 13C6-glucose, or 13C5-Gln and measure metabolite isotopomer distributions to accomplish this goal.
Utilize cell culture experimentation to understand anabolic signaling in response to vitamin D with or without fiber stretch.
Identify mechanisms whereby vitamin D and RE regulate anabolic signaling in primary human myotube cultures. Changes in signaling pathways associated with hypertrophy, including Akt, mTOR, MAPK, and AMPK, will be measured by phospho-western blot to determine response to calcitriol, palmitate, and stretch treatment in myotubes.
Utilize cell culture experimentation to measure mitochondrial activity in response to vitamin D with or without fiber stretch.
To understand how vitamin D and RE regulate mitochondrial activity in primary human myotube cultures, the investigators will measure extracellular acidification rate (ECAR) in response to calcitriol supplementation. This will be assessed through the addition of CPT-1 inhibitor etomoxir (40 µM) and the ATP-synthase inhibitor oligomycin
Utilize cell culture experimentation to measure mitochondrial activity in response to vitamin D with or without fiber stretch.
Identify mechanisms whereby vitamin D and RE regulate mitochondrial activity in primary human myotube cultures. The investigators will measure the concentration of ATP in myotubes in response to calcitriol supplementation.

Full Information

First Posted
March 20, 2017
Last Updated
October 12, 2020
Sponsor
David Travis Thomas
search

1. Study Identification

Unique Protocol Identification Number
NCT03144128
Brief Title
Vitamin D for Muscle Metabolic Function in Cancer Cachexia
Official Title
The Contribution of Vitamin D to Muscle Metabolic Function in Cancer Cachexia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
May 23, 2018 (Actual)
Primary Completion Date
September 13, 2018 (Actual)
Study Completion Date
September 13, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
David Travis Thomas

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The proposed study is aimed at examining mitochondrial function as a potential target of action of vitamin D on muscle metabolism, size, and strength in preventing the progression of cachexia. This is the first clinical trial designed to understand the effects of vitamin D on muscle metabolic dynamics driving dysfunction in cachectic muscle. Our preliminary data suggest that vitamin D promotes lipid partitioning and muscle metabolic function, which the investigators hypothesize, will mitigate cachexia via improved muscle health and quality that translates into reduced fatigue, and improved patient resilience to multimodal cancer therapy.
Detailed Description
Vitamin D repletion is linked to improved muscle mitochondrial function, lipid deposition and preservation; however, while vitamin D insufficiency is common in cancer, the mechanistic effects of vitamin D on muscle metabolic health in cancer patients have not been studied. This is important to address because cancer cachexia is characterized by marked muscle wasting, anabolic resistance, ectopic fat infiltration, mitochondrial dysfunction and contributes to decreased survival. With novel strategies to address this knowledge gap, the investigators will use a combination of advanced metabolic analytical approaches with complementary model systems in cell culture and human subjects to understand the biochemical and physiological mechanisms underlying cancer cachexia in relation to the role of vitamin D in conjunction with resistance exercise (RE). By combining analyses of muscle size and local tissue hemodynamics in vivo, metabolomics analyses of muscle tissue and isolated mitochondria, and changes in anabolic cell signaling, lipid metabolism and oxidative capacity of primary muscle cells in vitro, the investigators will identify mechanisms underlying muscle response to vitamin D repletion. Our previous findings, together with data that exercise improves muscle vitamin D storage and retrieval, suggest that vitamin D repletion synergizes with RE to improve muscle metabolic function and protein synthesis. Our overall objective is to examine mitochondrial function and anabolic resistance as potential targets of action of vitamin D on muscle metabolism, size and strength in preventing the progression of cachexia. The aims of this study are to: 1) non-invasively quantify lipid redistribution, local muscle tissue metabolism and muscle mass and strength of cancer patients before and after 12 weeks of double blinded vitamin D repletion with exercise and protein supplementation (VitD) compared to exercise and protein supplementation only (Ctl); 2) determine differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl; and 3) identify mechanisms whereby vitamin D and exercise regulate muscle anabolic signaling and mitochondrial activity in primary human myotube cultures. Our central hypothesis is that vitamin D promotes muscle lipid availability for β-oxidation in response to exercise, thereby preventing lipotoxicity in the muscle and potentially improving anabolic sensitivity in muscle during cancer cachexia. The impact of this project, the first nutrition and exercise study designed as an inexpensive intervention, is to understand the effect of vitamin D on the metabolic and anabolic dynamics which underpin dysfunction in cachectic muscle. If vitamin D promotes lipid partitioning, muscle metabolic function and/or anabolic sensitivity, these adaptations will ultimately improve cancer therapy by combating cancer cachexia. Further, diffuse optical spectroscopy techniques have the potential to identify the minimum effective intervention dose for optimizing metabolic health leading to more practical and individualized lifestyle prescriptions to reduce health care costs.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cancer Cachexia, Vitamin D Deficiency
Keywords
vitamin D, muscle, metabolism, cancer cachexia

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
Prospective, double-blinded randomized controlled clinical trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
All subjects receive exercise and protein supplementation. Participants, Investigators, Care Providers, and outcome assessors will be blinded to vitamin D vs. placebo capsule allocation
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Control (Ctl)
Arm Type
Placebo Comparator
Arm Description
Standard of Care resistance exercise and timed protein supplementation with placebo capsule daily for 12 weeks
Arm Title
Vitamin D
Arm Type
Experimental
Arm Description
Standard of Care resistance exercise and timed protein supplementation with 5,000IU vitamin D supplementation daily for 12 weeks
Intervention Type
Dietary Supplement
Intervention Name(s)
Vitamin D
Intervention Description
5,000IU vitamin D given daily for 12 weeks
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
Placebo capsules given daily for 12 weeks
Primary Outcome Measure Information:
Title
Non-invasive quantification of muscle lipid distribution
Description
MRI/MRS
Time Frame
Change between Week 0 and Week 12
Title
Local muscle oxygen consumption
Description
Near Infrared Spectroscopy + Diffuse Correlation Spectroscopy measures will be combined to assess changes in local muscle tissue oxygen consumption (VO2 measure)
Time Frame
Change between Week 0 and Week 12
Title
Muscle Mass
Description
MRI
Time Frame
Change between Week 0 and Week 12
Title
Muscle Strength
Description
Maximal voluntary contractions and 1-Repetition Maximum will be aggregated to to provide a comprehensive assessment of muscle strength
Time Frame
Change between Week 0, Week 6, Week 12
Secondary Outcome Measure Information:
Title
Mitochondrial Function in Muscle Fibers in Fresh Muscle Fibers ex vivo
Description
Determine the differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl by measure live tissue oxygen consumption rate. Respiration measures will be combined to assess mitochondrial function Mitochondrial respiration will be measured by the XF96 Seahorse extracellular flux analyzer
Time Frame
Experiments will be conducted from tissue collected at week 12 study biopsy
Title
Mitochondrial Function in Muscle Fibers in Fresh Muscle Fibers ex vivo
Description
Determine the differences in muscle mitochondrial function in live tissue biopsied from human gastrocnemius from VitD compared to Ctl by measure live tissue oxygen consumption rate. Fatty acid oxidation measures will be combined to assess mitochondrial function Fatty acid oxidation will be estimated by monitoring the OCR of cells with no exogenous glucose or glutamine (Gln) ± a specific fatty acid oxidation (FAO) inhibitor, etomoxir (40 µM)
Time Frame
Experiments will be conducted from tissue collected at week 12 study biopsy
Title
Stable Isotope-Resolved Metabolomics to describe Fatty Acid Metabolism in relationship to other fuel substrates in Fresh Muscle Fibers ex vivo
Description
Determine the relative importance of vitamin D on lipid, amino acid and energy metabolism involving glucose, glutamine, and β-oxidation in intact muscle fibers. We will culture with 13C8-octanoate, 13C6-glucose, or 13C5-Gln and measure metabolite isotopomer distributions to accomplish this goal.
Time Frame
Experiments will be conducted from live tissue collected at week 12 study biopsy
Title
Utilize cell culture experimentation to understand anabolic signaling in response to vitamin D with or without fiber stretch.
Description
Identify mechanisms whereby vitamin D and RE regulate anabolic signaling in primary human myotube cultures. Changes in signaling pathways associated with hypertrophy, including Akt, mTOR, MAPK, and AMPK, will be measured by phospho-western blot to determine response to calcitriol, palmitate, and stretch treatment in myotubes.
Time Frame
Experiments will be conducted from tissue collected at week 12 study biopsy
Title
Utilize cell culture experimentation to measure mitochondrial activity in response to vitamin D with or without fiber stretch.
Description
To understand how vitamin D and RE regulate mitochondrial activity in primary human myotube cultures, the investigators will measure extracellular acidification rate (ECAR) in response to calcitriol supplementation. This will be assessed through the addition of CPT-1 inhibitor etomoxir (40 µM) and the ATP-synthase inhibitor oligomycin
Time Frame
Experiments will be conducted from tissue collected at week 12 study biopsy
Title
Utilize cell culture experimentation to measure mitochondrial activity in response to vitamin D with or without fiber stretch.
Description
Identify mechanisms whereby vitamin D and RE regulate mitochondrial activity in primary human myotube cultures. The investigators will measure the concentration of ATP in myotubes in response to calcitriol supplementation.
Time Frame
Experiments will be conducted from tissue collected at week 12 study biopsy

10. Eligibility

Sex
All
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients must have histologically or cytologically confirmed stage II-IV lung cancer and be planned for definitive non-surgical therapy. Patients may have a history of prior malignancy. Mild cancer cachexia, defined by the miniCASCO score of 0-25 points Vitamin D insufficiency, defined as 25(OH)D < 32 ng/ml Aged 45 to 75 years. Stratified randomization by age ECOG performance status ≤ 2 (see Appendix A). Life expectancy of greater than 3 months Patients must have normal renal and liver function as defined below: AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Able to swallow thin liquids No uncontrolled illness including, but not limited to, any of the following: Ongoing or active serious infection Symptomatic congestive heart failure Unstable angina pectoris Uncontrolled cardiac arrhythmia Uncontrolled hypertension Psychiatric illness or social situation that would preclude compliance with study requirements Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients with untreated brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with treated brain metastasis are eligible for this trial, providing they have completed treatment at least one day prior to registration. History of allergic reactions to whey or milk proteins. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients with a history of calcium oxalate nephrolithiasis are excluded. Patients with a significant history of malabsorption (e.g. celiac sprue, short bowel syndrome, IBD or other, as determined by the treating physician) are excluded. Patients will not be eligible if actively receiving treatment for vitamin D deficiency and have had recent (3 month) history of vitamin D supplementation (>1000 IU) or calcium supplementation (>800mg). The following exclusion criteria will avoid the possibility of preexisting muscle impairment: history of congenital myopathies; neurologic disorder involving sequelae of spinal derangement; disk disease or vascular disease; tremor and rigidity. Patients will also be excluded if they report lower extremity (LE) surgery or injury to the LE in the past 3 months or a past medical history of primary hyperparathyroidism; or rhabdomyolysis. Additional exclusion criteria include participation in a scheduled resistance exercise program 1 month; metal implants or other contraindications for the MRI; diabetes, advanced renal disease, uncontrolled hypertension; a vitamin D status (25(OH)D) of > 32ng/mL.
Facility Information:
Facility Name
Markey Cancer Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Vitamin D for Muscle Metabolic Function in Cancer Cachexia

We'll reach out to this number within 24 hrs