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The Granheim COPD Study - Vitamin D and Strength Training

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ClinicalTrials.gov Identifier: NCT02598830
Recruitment Status : Completed
First Posted : November 6, 2015
Last Update Posted : December 12, 2018
Sponsor:
Collaborators:
Sykehuset Innlandet HF
Lillehammer Hospital for Rheumatic Diseases
University of Bergen
University of Copenhagen
Norwegian School of Sport Sciences
Information provided by (Responsible Party):
Inland Norway University of Applied Sciences

Tracking Information
First Submitted Date  ICMJE November 5, 2015
First Posted Date  ICMJE November 6, 2015
Last Update Posted Date December 12, 2018
Actual Study Start Date  ICMJE November 2015
Actual Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
  • Muscle size [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Muscle cell cross-sectional area measured in biopsies from m. vastus lateralis using immunohistochemistry
  • Muscle phenotype [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Muscle fiber type composition measured in biopsies from m. vastus lateralis using immunohistochemistry
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2015)
  • Thigh muscle cross-sectional area [ Time Frame: wk0, wk14, wk30 ]
    Changes in muscle cross-sectional area of each thigh, measured using Ultrasound/Magnetic Resonance Imaging/immunohistochemistry
  • One-legged maximal dynamic strength [ Time Frame: wk0, wk14, wk17, wk23, wk30 ]
    Changes in the ability of muscles of each leg to exert maximal force during a dynamic movement
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
  • Lung function [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Lung function measured using spirometry
  • One-legged cycling [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Performance indicies measured during an incremental one-legged cycling test
  • Hormones in blood [ Time Frame: Changes over the course of the intervention (week 0 to 28) ]
    Levels of hormones in blood
  • Cytokines in blood [ Time Frame: Changes over the course of the intervention (week 0 to 28) ]
    Levels of cytokines in blood
  • Steroids in skeletal muscle [ Time Frame: Changes over the course of the intervention (week 0 to 28) ]
    Levels of steroids in m. vastus lateralis
  • Androgen-converting enzymes in skeletal muscle [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Levels of androgen-converting enzymes in m. vastus lateralis
  • Gene expression in skeletal muscle [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in m. vastus lateralis, measured both as single genes and at the level of the transcriptome
  • Gene expression in skeletal muscle [ Time Frame: Changes from before to after familiarization to strength training (week 15 to week 17) ]
    RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in m. vastus lateralis, measured both as single genes and at the level of the transcriptome
  • Protein abundances in skeletal muscle [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Levels of proteins and their modification status (e.g. phosphorylation) in m. vastus lateralis, measured at the level of single proteins and at the level of the proteome
  • Protein abundances in skeletal muscle [ Time Frame: Changes from before to after familiarization to strength training (week 15 to week 17) ]
    Levels of proteins and their modification status (e.g. phosphorylation) in m. vastus lateralis, measured at the level of single proteins and at the level of the proteome
  • Vitamin D in blood [ Time Frame: Changes over the course of the intervention (week 0 to 28) ]
    Levels of vitamin D in blood
  • Step test [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Performance and performance indicies measured during a 6 minutes step test
  • Pasient-reported outcome measures, generic [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Pasient-related outcome measures assessed using the generic survey SF-36
  • Pasient-reported outcome measures, COPD-specific [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    COPD-specific pasient-reported outcome assessed using COPD assessment test
  • Body mass composition [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Body mass composition measured using Dual-energy X-ray absorptiometry (DXA)
  • Bilateral upper body maximal strength [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    The ability of muscles of the upper body to exert maximal force during dynamic movements
  • Grip strength [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Isometric hand grip strength
  • Sit-to-stand test [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Performance and performance indicies measured during a sit-to-stand test
  • Unilateral lower body maximal muscle strength [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    The ability of muscles of the lower body to exert maximal force during dynamic movements
  • Unilateral lower body muscle endurance [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    The ability of muscles of the lower body to perform repeated dynamic contractions at a specified submaximal load to exhaustion
  • Bilateral upper body muscle endurance [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    The ability of muscles of the upper body to perform repeated dynamic contractions at a specified submaximal load to exhaustion
  • Unilateral lower body isokinetic muscle strength [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    The ability of muscles of the lower body to exert maximal force during isokinetic movements
  • Daily life activity level [ Time Frame: Changes from before to after the intervention (week 0 to week 28) ]
    Daily life activity level measured using accelerometer
  • Muscle cell biological traits [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Muscle cell biological traits, including numbers of myonuclei, satelitte cells and capillaries, measured in biopsies from m. vastus lateralis using immunohistochemistry
  • Muscle mitochondrial quantities [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Mitochondrial quantities measured in biopsies from m. vastus lateralis
  • Muscle mitochondrial functions [ Time Frame: Changes from before to after the strength training intervention (week 19 to week 28) ]
    Mitochondrial functions measured in biopsies from m. vastus lateralis
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2015)
  • Lung function [ Time Frame: wk0, wk14, wk30 ]
    Changes in lung function measured using spirometry
  • Inflammatory status in induced sputum [ Time Frame: wk0, wk14, wk30 ]
    Changes in inflammatory/infection status and gene expression in induced sputum from lungs
  • One-legged cycling [ Time Frame: wk14, wk30 ]
    Changes in performance indicies measured during an incremental one-legged cycling test
  • Two-legged cycling [ Time Frame: wk0, wk14, wk30 ]
    Changes in performance indicies measured during an incremental two-legged cycling test
  • One-legged maximal isometric strength [ Time Frame: wk0, wk14, wk17, wk24, wk30 ]
    Changes in the ability of muscles of each leg to exert maximal isometric force
  • One-legged time to maximal force development [ Time Frame: wk0, wk14, wk17, wk24, wk30 ]
    Changes in the rate at which muscles of each leg can develop maximal force, measured isometrically and dynamically
  • One-legged muscular endurance [ Time Frame: wk0, wk14, wk17, wk24, wk30 ]
    Changes in the ability of muscles of each leg to perform repeated dynamic contractions at submaximal loads (50% of 1 repetition maximum)
  • Anabolic hormones in blood [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in levels of anabolic hormones in blood
  • Cytokines in blood [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in levels of cytokines in blood
  • Cytokines in skeletal muscle [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in levels of cytokines in musculus vastus lateralis
  • Steroids in skeletal muscle [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in levels of steroids in musculus vastus lateralis
  • Androgen-converting enzymes in skeletal muscle [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in levels of androgen-converting enzymes in musculus vastus lateralis
  • Gene expression in skeletal muscle [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in RNA (mRNA, microRNA, rRNA) abundances in musculus vastus lateralis, measured both as single genes and whole-transcriptome
  • Protein abundances in skeletal muscle [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in protein abundances and protein modification status (such as phosphorylation) in musculus vastus lateralis, measured at the level of single proteins
  • Vitamin D in blood [ Time Frame: wk0, wk2, wk10, wk14, wk23, wk30 ]
    Changes in levels of 25(OH)D in blood
  • Muscle fiber composition [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in muscle fiber composition in musculus vastus lateralis in a 2X to 2A direction, measured using immunohistochemistry, SDS-PAGE and mRNA profiling
  • Muscle fiber characteristics [ Time Frame: wk0, wk14, wk17, wk30 ]
    Changes in muscle fiber characteristics such as myonuclei number, satellite cell abundances and capillary density in musculus vastus lateralis, measured using immunohistochemistry
  • Incremental shuttle walk test [ Time Frame: wk0, wk14, wk30 ]
    Changes in performance and performance indicies measured during a incremental shuttle walk test
  • Pasient-reported outcome measures, generic [ Time Frame: wk0, wk14, wk30 ]
    Changes in pasient-related outcome measures assessed using the generic survey SF-36
  • Pasient-reported outcome measures, COPD-specific [ Time Frame: wk0, wk14, wk30 ]
    Changes in COPD-specific pasient-reported outcome measures using two different surveys (COPD assessment test and VQ11)
  • Daily life activity [ Time Frame: wk0, wk14, wk31 ]
    Changes in 4d daily life activity patterns measured using accelerometer
  • Body mass composition [ Time Frame: wk0, w1k4, wk30 ]
    Changes in body mass composition measured using Dual-energy X-ray absorptiometry (DXA)
  • Bilateral upper body maximal dynamic strength [ Time Frame: wk0, wk14, wk17, wk24, wk30 ]
    Changes in the ability of muscles of the upper body to exert maximal force during dynamic movements
  • Grip strength [ Time Frame: wk0, wk14, wk17, wk24, wk30 ]
    Changes in isometric hand grip strength
Current Other Pre-specified Outcome Measures
 (submitted: September 7, 2017)
  • Training diary [ Time Frame: Measured over the course of the strength training familiarization period and the strength training intervention (week 15 to week 28) ]
    Training diary containing information about type of training, duration of training and training intensity
  • Dietary registration [ Time Frame: Registred at one time point during the strength training intervention (~week 23, registred over four days) ]
    Detailed registration of food intake
  • Self-reported information on lifestyle-related aspects [ Time Frame: Measured over the course of the intervention (week 0 to week 28) ]
    Disease, symptoms, injury, vitamin D-intake, time spent outdoors, solarium, training background, smoking, etc
Original Other Pre-specified Outcome Measures
 (submitted: November 5, 2015)
  • Training diary [ Time Frame: wk0-wk31 ]
    Diary containing information on type of training, duration and intensity performed
  • Sun exposure diary [ Time Frame: wk0-wk31 ]
    Diary containing information on exposure to solarium or sun in countries south of Norway
  • Vitamin D-intake diary [ Time Frame: wk0-wk31 ]
    Diary containing information on approximate intake of vitamin D from sources other than the study-specific supplement, including ingestion of fish, seafood and vitamin D-supplement
  • Dietary registration [ Time Frame: w0, w24 ]
    Detailed registration of food intake: recall interviews (multiple; wks 0 and 24) and registration of dietary habits (wk24)
 
Descriptive Information
Brief Title  ICMJE The Granheim COPD Study - Vitamin D and Strength Training
Official Title  ICMJE The Granheim COPD Study: Effects of Vitamin D3-supplementation on the Efficacy of Strength Training in COPD Patients and Healthy Controls - a Double-blinded RCT
Brief Summary This study evaluates the effect of vitamin D supplementation on outcomes of 10 weeks progressive strength training in 100 ageing subjects (>45 years of age). Participants will be recruited into two similarly sized strata; one containing COPD patients and one containing healthy subjects of similar age. In each stratum, half the participants will receive vitamin D supplementation and half the participants will receive placebo
Detailed Description

Physical activity is a potent way of relieving some of the adverse morbidities associated with COPD, such as muscle atrophy and reduced muscle quality. It is thus problematic that 20-30% of patients fail to elicit positive adaptations to training. This oddity has been ascribed inherent muscular properties, with potential links to comorbidities such as vitamin D and testosterone deficiency and the nature of the training program. In the present project, a double-blinded RCT will be performed to disclose the functional and biological efficacy of vitamin D supplementation (with concomitant ingestion of 1000 mg Ca2+) on the outcomes of 10 wks strength training in 100 aging individuals with or without COPD. The strength training intervention will be preceded by 3 weeks of progressive introduction to training protocols.

50 COPD patients and 50 healthy subjects will be allocated into two strata and separately randomized into two equally sized supplementation groups; (1) vitamin D3 and (2) placebo. The planned 50:50 ratio between COPD patients and healthy individuals may change, depending on the access to COPD patients. All subjects will perform lower-limb strength-training protocols in a contralateral manner: (leg 1) high-resistance (10 RM) and (leg 2) low-resistance (30 RM). Such a one-limb-at-a-time protocol ensures training that is unconfined by the cardiorespiratory limitations inherent to these patients, and allow comparison of the two training modalities in a manner unconfined by individual variation in exercise adaptability. A pilot study investigating the possible central pulmonary capacity limitation to two-legged strength training exercise in COPD patients will be performed. In this pilot study, we will compare exercise performance involving large and small muscle mass. In addition, all subjects will perform a selection of bilateral upper body exercises (10 RM), ensuring adequate hormonal responses and compliance to the study. The study is likely to revitalize guidelines for rehabilitation of COPD patients, and to provide vital information regarding the role of vitamin D in adaptations to strength training.

For outcome measures specific to COPD pasients, final analyses will be performed on data from the COPD population only. For other outcome measures, final analyses will be performed on data merged from COPD patients and healthy subjects. An important rationale behind implementing healthy control subjects is to increase the statistical power of outcome measures unrelated to COPD epidemiology, which are of general relevance to physiological adaptation to strength training. In a related set of analyses, we will perform between-groups comparisons, including multivariate analyses. We will also compare the efficacy of high- and low-resistance strength training in COPD patients and healthy control subjects. The two training modalities are expected to result in similar muscular adaptations.

In general, baseline vitamin D levels in blood, measured as 25(OH)D, is anticipated to be a determinant of the efficacy of the strength training intervention. In response to vitamin D3 supplementation, individuals with low baseline levels of 25(OH)D are expected to display more pronounced changes in biological active vitamin D, leading to more pronounced changes in functional and biological outcome measures in response to strength training. In contrast, supplementation may not lead to further elevation of blood 25(OH)D levels in individuals with high baseline levels, essentially meaning that vitamin D3 ingestion will be leveled out by or exceeded by the elimination of vitamin D derivatives. In these individuals, vitamin D3 ingestion will not have an additive effect on functional and biological outcome measures in response to strength training. To assess individual variation in vitamin D responses, data on functional and biological variables will be divided into quartiles based on baseline 25(OH)D-levels, whereupon comparisons will be made between low-end and high-end quartiles. Individual variation in responses to vitamin D supplementation and strength training will also be assessed using a mixed model approach.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • Dietary Supplement: Vitamin D3
    Vitamin D3 dissolved in olive oil, encapsuled
    Other Name: cholecalciferol
  • Dietary Supplement: Placebo
    Olive oil, encapsuled
Study Arms  ICMJE
  • Experimental: Vitamin D3+str.training, COPD & Healthy

    Vitamin D3 capsules for 30 weeks:

    • weeks 1-2: 10000 IU/day (equivalent to 250 ug), accompanied by 1000 mg Ca2+
    • weeks 3-30: 2000 IU/day (equivalent to 50 ug), accompanied by 1000 mg Ca2+

    Progressive unilateral strength training of the legs for 3+10 weeks (weeks 15-28); leg 1 = high-load training, leg 2 = low-load training, allocated to left and right foot in a randomized manner:

    • weeks 15-17, familiarization period
    • week 18, test period
    • weeks 19-28, intervention period
    • weeks 29-30, test period
    Intervention: Dietary Supplement: Vitamin D3
  • Placebo Comparator: Placebo+str.training, COPD & Healthy

    Placebo capsules for 30 weeks (the number of capsules ingested each day match those of the vitamin D3 group)

    Progressive unilateral strength training of the legs for 3+10 weeks (weeks 15-28); leg 1 = high-load training, leg 2 = low-load training, allocated to left and right foot in a randomized manner:

    • weeks 15-17, familiarization period
    • week 18, test period
    • weeks 19-28, intervention period
    • weeks 29-30, test period
    Intervention: Dietary Supplement: Placebo
Publications * Molmen KS, Hammarstrom D, Falch GS, Grundtvig M, Koll L, Hanestadhaugen M, Khan Y, Ahmad R, Malerbakken B, Rodolen TJ, Lien R, Ronnestad BR, Raastad T, Ellefsen S. Chronic obstructive pulmonary disease does not impair responses to resistance training. J Transl Med. 2021 Jul 6;19(1):292. doi: 10.1186/s12967-021-02969-1.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 11, 2018)
97
Original Estimated Enrollment  ICMJE
 (submitted: November 5, 2015)
130
Actual Study Completion Date  ICMJE June 2018
Actual Primary Completion Date June 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

COPD group

Inclusion Criteria:

  • Stable COPD at GOLD stage II or III, FEV1/FVC < 0.7 and FEV1 <80% and >30% of predicted
  • >45 years of age

Exclusion Criteria:

  • Unstable cardiovascular disease
  • Chronic granulomatous
  • Known active malignant disease within last 5 years
  • Physically disabling muscloskeletal diseases
  • Peroral use of steroids within last 2 months
  • Serious psychiatric comorbidity
  • Less than 4 weeks since last return t o habit ual condit ion from exacerbation
  • Failing to understand Norwegian literary or verbally
  • Medical record diagnosis of asthma
  • More than one bout of strength training per week during the last 6 months leading up to the project

Healthy control group

Inclusion Criteria:

- >45 years of age

Exclusion Criteria:

  • COPD
  • Unstable cardiovascular disease
  • Chronic granulomatous
  • Known active malignant disease within last 5 years
  • Physically disabling muscloskeletal diseases
  • Peroral use of steroids within last 2 months
  • Serious psychiatric comorbidity
  • Failing to understand Norwegian literary or verbally
  • Medical record diagnosis of asthma
  • More than one bout of strength training per week during the last 6 months leading up to the project
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02598830
Other Study ID Numbers  ICMJE Trainsome 2014#004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified data will be made available to the academic community through the general biobank "The Trainsome - effects of exercise and environment on human cells" (REK-2013/2045, Regional Comitees for Medical and Health Research Ethics South East). Data will be available on request and will be restricted to scientists and/or projects with a sound scientific purpose and rationale.
Current Responsible Party Inland Norway University of Applied Sciences
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Inland Norway University of Applied Sciences
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Sykehuset Innlandet HF
  • Lillehammer Hospital for Rheumatic Diseases
  • University of Bergen
  • University of Copenhagen
  • Norwegian School of Sport Sciences
Investigators  ICMJE
Principal Investigator: Knut Sindre Mølmen, MSc Inland Norway University of Applied Sciences
PRS Account Inland Norway University of Applied Sciences
Verification Date December 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP