Targeted Nutrient Supplement in COPD (NUTRECOVER-trial)

Study Overview
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Brief Summary
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The overall objective is to investigate the efficacy of targeted nutrient supplementation on daily physical activity level as well as generic health status in patients with COPD. Additionally the investigators aim to investigate the relative effect of targeted nutrient supplementation on the recovery after hospitalization for a COPD exacerbation. The secondary objective is to investigate the effect of targeted nutrient supplementation on mental health, physical performance, blood markers, patient related outcomes and gut health. Additionally, a secondary objective is to compare the gut microbiome composition of patients with COPD compared to healthy controls.

Detailed Description
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Rationale: Impaired physical and mental health are common features in COPD adversely affecting disease course and quality of life. Furthermore, nutritional status is often impaired due to dietary and plasma nutrient deficiencies, decreased muscle oxidative metabolism and impaired intestinal permeability. The investigators hypothesize that targeted nutrient supplementation can lead to gut-muscle-brain axis-mediated amelioration of physical, cognitive and mental health domains, resulting in a healthier lifestyle, in patients with COPD. Study design: Randomized, placebo-controlled, double-blind trial. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The nutrient supplement is hypothesized to have beneficial effects on general health because it applies physical and mental health domains. The healthy lifestyle counselling aims to improve medical adherence, to address a healthier lifestyle and to manage weight loss which would contribute to improved general health. Risks and inconveniences are limited to the time investment associated with taking the supplements and measuring days. During the test-days various non-invasive measurements as well as minor invasive blood sampling will be performed. The investigators expect no risk of the nutrient supplementation. Healthy controls will only attend a subgroup of baseline measurements which are limited to non-invasive measurements and one minor invasive blood sampling. Healthy controls will not receive the nutritional supplement.

Official Title
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The Effect of Targeted Nutrient Supplementation on Physical Activity and Healthy Related Quality of Life in COPD

Conditions
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Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
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* Dietary Supplement: Targeted nutrient supplementation (Long-drink)
* Dietary Supplement: Placebo supplement
* Behavioral: Counselling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria COPD Patients: COPD patients with moderate to very severe disease stage according to GOLD criteria (i.e. GOLD stage II-IV); Medically stable. Exclusion Criteria COPD Patients: Age <18 years; Allergy or intolerance to components of the study product; Not willing or not able to quit vitamin D or fatty acid supplement intake; Investigator's uncertainty about the willingness or ability of the patient to comply with the protocol requirements (e.g. leg amputation) or patients suffering from other acute or unstable chronic diseases that will compromise the study outcome (e.g. active cancer requiring treatment); Participation in any other study involving investigational or marketed products concomitantly or within four weeks prior to entry into the study; Patients with terminal illness; Recent hospital admission (<4 weeks prior to the start of the study); Temporary oral steroid or antibiotics use due to a COPD exacerbation in the last 4 weeks; Lung malignancy in the previous 5 years; Diagnosis of dementia or neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's chorea, frontotemporal dementia) in the medical records; Recent diagnosis of cerebral conditions (<1 year e.g. cerebral infarction, hemorrhage, brain tumors, transient ischemic attack) in the medical records; Any medical condition that significantly interferes with digestion and/or gastrointestinal function (e.g. short bowel syndrome, inflammatory bowel disease, gastric ulcers, gastritis, (gastro)-enteritis, GI-cancer) as judged by the investigator. Inclusion Criteria Healthy Controls Forced expiratory volume in 1 second/Forced vital capacity > 0.7; Medically stable. Exclusion Criteria Healthy Controls Age <18 years; Investigator's uncertainty about the willingness or ability of the patient to comply with the protocol requirements (e.g. leg amputation) or patients suffering from other acute or unstable chronic diseases that will compromise the study outcome (e.g. active cancer requiring treatment); Participation in any other study involving investigational or marketed products concomitantly or within four weeks prior to entry into the study; Patients with terminal illness; Recent hospital admission (<4 weeks prior to the start of the study); Temporary antibiotics use in the last 4 weeks; Lung malignancy in the previous 5 years; Diagnosis of dementia or neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, Huntington's chorea, frontotemporal dementia) in the medical records; Recent diagnosis of cerebral conditions (<1 year e.g. cerebral infarction, hemorrhage, brain tumors, transient ischemic attack) in the medical records; Any medical condition that significantly interferes with digestion and/or gastrointestinal function (e.g. short bowel syndrome, inflammatory bowel disease, gastric ulcers, gastritis, (gastro)-enteritis, GI-cancer) as judged by the investigator. Diagnosis of any chronic lung disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Next to the 166 COPD patients that receive the nutritional supplement, a subgroup of 30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will not be included in the intervention arm.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group Long-drink<br>83 COPD patients will receive: Targeted nutrient supplementation (Long-drink) once daily Counselling once monthly | Dietary Supplement: Targeted nutrient supplementation (Long-drink)<br>* Once daily for at least 12 months<br>* Other names: Food supplement;Behavioral: Counselling<br>* Counselling on healthy lifestyle (in particular physical activity, smoking cessation) and weight management by motivational interviewing<br>* Other names: Motivational interviewing;|
| Placebo Comparator: Group Placebo<br>83 COPD patients will receive: Isocaloric placebo supplement once daily Counselling once monthly | Dietary Supplement: Placebo supplement<br>* Once daily for at least 12 months<br>* Other names: Non-active supplement;Behavioral: Counselling<br>* Counselling on healthy lifestyle (in particular physical activity, smoking cessation) and weight management by motivational interviewing<br>* Other names: Motivational interviewing;|
| No Intervention: Healthy control group<br>30 healthy controls will be included for baseline comparison of the microbiome composition. These healthy controls will only perform a subset of baseline measurements and will not be included in the intervention. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in physical activity level assessed by measuring step count with accelerometry | Subjects will wear an activPAL accelerometer for 1 week to assess physical activity. | 0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later | 
| Change in generic health status measured by EuroQol-5 dimensions (EQ-5D) | The EQ-5D is a generic classification system used to characterize current health states of patients. It consists of 5 domains (mobility; self-care; usual activity; pain/discomfort; anxiety/depression) and a visual analogue scale (EQ-VAS). The domains have a scale from 1-3 and the VAS-scale from 0-100 in which higher values represent a better outcome. | 0, 3, and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognitive function measured by the Neuropsychological test automated battery (CANTAB) | The investigators will use the Motor Screening Task, Reaction Time Task, Paired Associates Learning, Delayed Matching-to-Sample, Spatial Working Memory and Stop Signal Task. The higher the score on these tasks, the better the cognitive function. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in Depression Anxiety Stress Scale 21 (DASS-21) | The DASS-21 measures 3 related states of depression, anxiety and stress. The DASS-21 consists of 21 negative emotional symptoms and subjects will be asked to extent to which have experienced each symptom over the past week, on a 4-point severity/frequency scale. The total score will range from 0-66 in which a higher score means more susceptibility to depression. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in Hospital and Anxiety Scale (HADS) | The HADS will allow the investigators to measure domain-specific quality of life. This is a 14-item instrument designed to detect the presence and severity of mild degrees of mood disorder, anxiety and depression in hospital and community setting and outside. Per scale (anxiety and depression) a maximum of 21 points can be scored, in which a higher score means worse outcome. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in Cohen's Perceived Stress Scale (PSS) | The PSS is a measure of the degree to which situations in one's life are appraised as stressful. Individual scores on the PSS can range from 0 to 40 with higher scores indicating higher perceived stress. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in blood pressure after the socially evaluated cold pressure test | The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Blood pressure will be measured before and after the test. | 0-12 months. | 
| Change in cortisol in the saliva after the socially evaluated cold pressure test | The SECPT asks the participant to immerse their right hand up to and including the writs into ice water for a maximum of 3 minutes. Cortisol in the saliva will be measured before and after the test. | 0-12 months. | 
| Change in hair cortisol | Cortisol level in hair is a biomarker of chronic stress. | 0 and 12-14 months and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in lower extremity performance by the short physical performance battery (SPPB) | Three manoeuvres will be performed: the balance test, the gait speed test and the chair stand test. Each individual can score 0-12 points in which a higher score means a better physical performance. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in muscle strength by measuring handgrip strength | Handgrip strength is measured in the dominant hand using a hydraulic grip strength dynamometer. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in respiratory muscle strength by measuring the inspiratory and expiratory mouth pressure | The mouth pressure will be measured using the MicroRPM monitor. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in exercise performance by measuring the 6 minute walking distance | Subjects will be instructed to walk as fast as possible for 6 minutes. The distance walked during these 6 minutes will be measured. | 0-12 months. | 
| Change in body composition by performing Dual energy X-ray absorptiometry (DEXA-scan) | Using the DEXA-scan three compartments of the body composition (lean mass, fat mass, bone mass) will be measured. | 0-12 months. | 
| Change in weight | Weight will be measured in kg. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in height | Height will be measured in cm. | 0-12 months | 
| Change in blood markers of systemic inflammation | Markers include high-sensitive C-reactive protein, procalcitonin, interleukin-6, interleukin-8 and leucocyte levels. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in blood markers of nutritional status | Markers include vitamin E, vitamin D, poly unsaturated fatty acids, amino acids (tryptophan), and homocysteine. | 0-3 months; 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in blood markers of gut-muscle-brain cross-talk | Markers include tryptophan, kynurenine and kynurenic acid. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in fatigue by using the checklist individual strength (CIS) | The CIS is a 20-item self-report questionnaire that measures several aspects of fatigue: fatigue severity, concentration, motivation and physical activity. Individual scores can range from 20-140 in which higher scores mean fatigue problems. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in pain using the Visual Analogue Scale (VAS) | Pain will be assessed by the VAS range from 0-100, in which a higher score means more pain experience. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in sleep quality by the Pittsburgh Sleep Quality Index (PSQI) | The PSQI is a self-report questionnaire to assess sleep quality. It consists of 19 individual items, creating 7 components that produce one global score (0-21, in which higher scores indicate worse sleep quality). | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in intestinal fatty acid binding protein (blood) in rest | IFABP is a marker for intestinal integrity. | 0-12 months; and in case of hospitalization for COPD exacerbation within one week after discharge and 4 weeks later. | 
| Change in intestinal fatty acid binding protein (blood) after the 6MWT | IFABP is a marker for intestinal integrity. | 0-12 months. | 
| Change in gut microbiome composition (optional) | Several analysis will be performed after completion of the study. The exact markers of the microbiome will be determined. | 0, 3 and 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, nutrient supplementation, Physical activity, Health related quality of life