Casein Protein and Leucine Supplementation in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
=================
Brief Summary
-----------------
Weight loss commonly occurs in patients with COPD, negatively influencing their quality of life, treatment response and survival. Loss of muscle protein is generally a central component of this weight loss and independently increases mortality. This study will provide relevant clinical information in regards to the anabolic properties of specific dietary substrates and their co-active anabolic effects. Hypotheses: 1) That supplementation of a hydrolyzed casein-based protein meal with the addition of carbohydrates is more anabolic than a hydrolyzed casein-based protein meal without carbohydrates in COPD patients and healthy older adults; 2) That leucine addition to a hydrolyzed casein-based protein meal only enhances the protein anabolic response in COPD patients and healthy older adults when carbohydrates are not added to the protein meal; 3) That COPD patients have a more efficient protein anabolic response to a hydrolyzed casein-based protein meal than healthy older adults. A fifth study day was added to measure protein requirements of included individuals to be able to interpret their response to the other interventions on the other study days, and to test the hypothesis that subjects with lower protein requirements respond less to intervention with leucine and/or carbohydrates. For the 5th additional test day we will first approach the 10 COPD and 10 healthy subjects who already completed the first 4 study days (and signed the re-contact form) to come back for this extra test day. We will (pre-)screen these subjects by phone for eligibility and check for changes in their recent medical history (with help of the (pre-)screening questionnaires in CRF). If all inclusion criteria are still met, these subjects will be asked to provide a written re-consent. If necessary, we will recruit new subjects who will complete only one of the four test days (i.e. the test day on which the hydrolyzed casein-based protein meal with carbohydrates is provided) and the additional 5th study day.

Detailed Description
-----------------
The study involves 5 study days. The duration of the first 4 study days is approximately 6.5 hours per day and the duration of the 5th study day is approximately 8 hours. On each of the first 4 study days the effect a casein protein meal with or without leucine and carbohydrates will be examined. On the fifth study day the effect of 4 different levels of casein protein and carbohydrate intake by sip feeding (every 20 minutes) is examined. Also, subjects will receive a mixture of amino acids (little parts of protein) which are a little bit heavier than normal, called stable isotopes. This is the so-called stable isotope method to investigate protein behavior in the body (protein kinetics). Altogether about 75 ml of blood will be drawn per study day to assess outcome measures.

Official Title
-----------------
Casein Protein and Leucine Supplementation to Induce Anabolism in COPD Patients and Healthy Elderly

Conditions
-----------------
COPD

Intervention / Treatment
-----------------
* Dietary Supplement: Hydrolyzed casein protein
* Dietary Supplement: Hydrolyzed casein protein + carbohydrates
* Dietary Supplement: Hydrolyzed casein protein + leucine
* Dietary Supplement: Hydrolyzed casein protein + carbohydrates + leucine
* Dietary Supplement: 4 levels of hydrolyzed casein protein + carbohydrates


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria COPD subjects: Ability to walk, sit down and stand up independently Age 45 years or older Ability to lie in supine or elevated position for 5.5 hours Diagnosis of moderate to very severe chronic airflow limitation and compliant to the following criteria: Forced Expiratory Volume(FEV1)/Forced Vital Capacity (FVC) < 0.70 and FEV1 < 70% of reference FEV1 Clinically stable condition and not suffering from a respiratory tract infection or exacerbation of their disease (defined as a combination of increased cough, sputum purulence, shortness of breath, systemic symptoms such as fever, and a decrease in FEV1 > 10% compared with values when clinically stable in the preceding year) at least 4 weeks prior to the first test day Shortness of breath on exertion Willingness and ability to comply with the protocol, including: Adhering to fasting state from 10 pm ± 2h onwards the day prior to each study visit Inclusion criteria healthy control subjects: Healthy male or female according to the investigator's or appointed staff's judgment Ability to walk, sit down and stand up independently Age 45 years or older Ability to lay in supine or elevated position for 5.5 hours No diagnosis of chronic airflow limitation and compliant to the following criteria: FEV1/FVC > 0.70 and FEV1 ≥ 80% of reference FEV1 Willingness and ability to comply with the protocol, including: Adhering to fasting state from 10 pm ± 2h onwards the day prior to each study visit Exclusion Criteria all subjects: Any condition that may interfere with the definition 'healthy subject' according to the investigator's judgment (for healthy control group only) Established diagnosis of malignancy Established diagnosis of Insulin Dependent Diabetes Mellitus History of untreated metabolic diseases including hepatic or renal disorder Presence of acute illness or metabolically unstable chronic illness Recent myocardial infarction (less than 1 year) Any other condition according to the PI or nurse that was found during the screening visit, that would interfere with the study or safety of the patient BMI of < 18.5 or ≥ 35 kg/m2 Dietary or lifestyle characteristics: Use of protein or amino acid containing nutritional supplements within 5 days of first test day Current alcohol or drug abuse Indications related to interaction with study products: Known allergy to milk or milk products Use of long-term oral corticosteroids or short course of oral corticosteroids 4 weeks preceding first test day Failure to give informed consent or Investigator's uncertainty about the willingness or ability of the subject to comply with the protocol requirements (Possible) pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study day 1<br>Hydrolyzed casein protein. On each study day participants receive one out of 4 protein meals (interventions). The 4 interventions are given in a randomized order. | Dietary Supplement: Hydrolyzed casein protein<br>* Amount provided is based on the fat-free mass of subject<br>* Other names: PeptoPro;|
| Experimental: Study day 2<br>Hydrolyzed casein protein + carbohydrates. On each study day participants receive one out of 4 protein meals (interventions). The 4 interventions are given in a randomized order. | Dietary Supplement: Hydrolyzed casein protein + carbohydrates<br>* Amount provided is based on the fat-free mass of subject<br>* Other names: PeptoPro + maltodextrin;|
| Experimental: Study day 3<br>Hydrolyzed casein protein + leucine. On each study day participants receive one out of 4 protein meals (interventions). The 4 interventions are given in a randomized order. | Dietary Supplement: Hydrolyzed casein protein + leucine<br>* Amount provided is based on the fat-free mass of subject. Leucine (40% of essential amino acid content)<br>* Other names: PeptoPro + leucine;|
| Experimental: Study day 4<br>Hydrolyzed casein protein + carbohydrates + leucine. On each study day participants receive one out of 4 protein meals (interventions). The 4 interventions are given in a randomized order. | Dietary Supplement: Hydrolyzed casein protein + carbohydrates + leucine<br>* Amount provided is based on the fat-free mass of subject. Leucine (40% of essential amino acid content)<br>* Other names: PeptoPro + maltodextrin + leucine;|
| Experimental: Study Day 5<br>4 levels of hydrolyzed casein protein + carbohydrates | Dietary Supplement: 4 levels of hydrolyzed casein protein + carbohydrates<br>* Amount provided is based on the fat-free mass of subject. The 4 levels are: 0, 0.02, 0.05, 0.15 g casein protein/kg fat free mass/hr. The ratio between protein and carbohydrates is fixed.<br>* Other names: 4 levels of PeptoPro + maltodextrin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Net whole-body protein synthesis | Change in net whole-body protein synthesis (whole-body protein synthesis - whole-body protein breakdown) | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Net whole-body protein synthesis with different levels of protein intake (Fifth Study Day) | Change in net whole-body protein synthesis (whole-body protein synthesis - whole-body protein breakdown) with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole-body protein synthesis | Change in whole-body protein synthesis | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Whole-body protein breakdown | Change in whole-body protein breakdown | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Splanchnic extraction | The amount of amino acids in the protein meal extracted by the splanchnic tissues after intake | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Body composition | Difference in muscle mass, fat mass and bone density between COPD patients and healthy older adults | 1 day | 
| Skeletal and respiratory muscle strength | Difference in handgrip strength and fatigue and maximum inspiratory and expiratory pressure between COPD patients and healthy older adults | 1 day | 
| Inflammatory mediators | C-reactive protein, interleukines | 90 min before protein meal | 
| Hormones | Area under the plasma concentration versus time curve (AUC) of insulin | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Glucose | Peak plasma concentration (Cmax) of glucose | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Amino acid concentrations | Peak plasma concentration (Cmax) of amino acids | 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240 min post-protein meal | 
| Whole-body protein synthesis with different levels of protein intake (Fifth Study Day) | Change in whole-body protein synthesis with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 
| Whole-body protein breakdown with different levels of protein intake (Fifth Study Day) | Change in whole-body protein breakdown with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 
| Splanchnic extraction with different levels of protein intake (Fifth Study Day) | The amount of amino acids in the protein meal extracted by the splanchnic tissues after intake of 4 different levels of protein (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 
| Hormones with different levels of protein intake (Fifth Study Day) | Area under the plasma concentration versus time curve (AUC) of insulin with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 
| Glucose with different levels of protein intake (Fifth Study Day) | Peak plasma concentration (Cmax) of glucose with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 
| Amino acid concentrations with different levels of protein intake (Fifth Study Day) | Peak plasma concentration (Cmax) of amino acids with 4 different levels of protein intake (duration of each level: 2 hours) as sip feeding (every 20 minutes) | before each sip feeding in the second hour of a level of protein intake ( at 120, 140 and 160 min) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD, Protein synthesis, Protein breakdown, Muscle wasting, Leucine, Hydrolyzed, Casein protein, Carbohydrates