Severe Chronic Respiratory Failure and Citrulline

Study Overview
=================
Brief Summary
-----------------
Because of its very high bioavailability and its specific and direct action on protein synthesis, the investigators hypothesize that citrulline supplementation would be an innovative nutritional strategy to improve the peripheral muscle mass and strength in COPD patients with severe chronic respiratory failure. This supplementation would be more effective if the pathology is severe and the chronic systemic inflammation important. The benefits of this supplementation could help the most severe patients break out of the cycle of inactivity and thus optimize their quality of life. The main objective of this study is to evaluate the impact of 45-day nutritional supplementation with Citrulline (10 g / day) on the body composition (lean body mass) in malnourished COPD patients with severe chronic respiratory failure.

Detailed Description
-----------------
Denutrition in patients with COPD (Chronic Obstructive Pulmonary Disease) is characterized by muscle atrophy and loss of strength in the lower extremities. It worsens the symptomatology, exercise intolerance, impaired quality of life and prognosis of patients. Consequence of a protein deficiency associated with systemic inflammation, denutrition is becoming increasingly important in patients with chronic respiratory failure (CRF). L-citrulline is an amino acid having a direct action on muscle protein synthesis. The citrulline supplementation is an effective treatment to fight against muscle loss in aging subjects. Its impact on the functional and nutritional status of COPD patients has not been studied. Our main objective is to determine the impact of supplementation with Citrulline on mass and peripheral muscle strength in COPD with CRF. Our secondary objectives are to identify whether these benefits are dependent on the severity of the disease and if they are associated with increased physical activity, exercise tolerance and an improvement in symptoms and quality of life. This prospective, randomized, controlled, double-blind study will include 60 stable COPD patients (stage 3 and 4), with long-term oxygen therapy and / or non-invasive ventilation, BMI <25 kg.m2 and suspicion of sarcopenia. For 45 days, patients will receive either citrulline (ProteoCIT®, 10mg) or placebo. The severity of COPD will be assessed by spirometry and blood gas data, the BODE index, exacerbations, comorbidities, nutritional status and systemic inflammation (CRPs, Fibrinogens). the investigators will evaluate before and after supplementation: body composition (DEXA), quadriceps strength and grip strength, walking speed, the exercise tolerance (6MWD), dyspnea (MMRC scales, BDI / TDI), quality of life (CAT and VSRQ questionnaires). Physical activity will be assessed by continuous actigraphy. This multicenter study will be conducted in 3 French hospitals: Grenoble, Nancy, Dijon.

Official Title
-----------------
Effects of Oral Citrulline Supplementation in Sarcopenia for Patients With Severe Chronic Respiratory Failure by COPD

Conditions
-----------------
Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
-----------------
* Drug: ProteoCIT®
* Drug: Placebo Oral Tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: COPD Gold III and IV involuntary decrease in weight ≥ 5% in the last 6 months, BMI < 25 kg.m² suspicion of sarcopenia marked by a score higher than 4 on the SARC-F questionnaire clinical stability defined by no exacerbation requiring hospitalization for at least 3 months long-term oxygen therapy (≥ 12h / day) and / or non-invasive ventilation for at least 6 months At least one exacerbation requiring hospitalization in the year before inclusion. Informed consent written Exclusion Criteria: Restrictive or mixed respiratory disease. Long-term systemic corticosteroids (> 6 months per year) Severe and terminal renal failure (creatinine clearance <30ml / min) Patients with severe hypotension, uncontrolled hypertension Contraindication to taking citrulline: anticoagulant and anticancer chemotherapy Osmotic diarrhea Taking food supplements whatever its form. Severe and / or unbalanced progressive disease that may be life-threatening in the medium term, Proven psychiatric pathology (schizophrenia type, dementia, bipolar / severe psychotic disorders, severe depressive syndrome), Cognitive or psychomotor problem that limit the realization and understanding of the different evaluations, Simultaneous participation in another research involving the human person Pregnant, parturient or breastfeeding women deprivation of liberty by judicial or administrative decision, protection by law, under the protection of justice, under guardianship or trusteeship, No affiliation to a social security scheme.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: After signing the informed consent form, the patients will be randomized either in the experimental group (Citrulline (ProteiCIT®): 10 g / day) or in the control group (placebo).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supplementation with Citrulline<br>Patients will receive citrulline (ProteoCIT®) 10 mg by day during 45 days | Drug: ProteoCIT®<br>* 30 patients will be randomized into the group that will receive 10 mg of citrulline and 30 patients will be randomized into the placebo group for 45 days<br>|
| Placebo Comparator: Placebo<br>Patients will receive placebo (one tablet by day) during 45 days | Drug: Placebo Oral Tablet<br>* 30 patients will be randomized into the group that will receive 10 mg of citrulline and 30 patients will be randomized into the placebo group for 45 days<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of a 45-day nutritional supplementation with Citrulline (10 g / day) on body composition (lean body mass) of malnourished patients with COPD and severe chronic respiratory failure | Lean mass (kg.m-2) measured by DEXA | 45 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of a nutritional supplementation with Citrulline on body composition | Regional variations of fat and bone mass measured by DEXA | 45 days | 
| Impact of a nutritional supplementation with Citrulline on muscular force | Grip force, Maximum strength of the quadriceps | 45 days | 
| Impact of a nutritional supplementation with Citrulline on tolerance to effort | 3 min chair test | 45 days | 
| Impact of a nutritional supplementation with Citrulline on BODE stage | BODE score - The BODE score is composed of the following parameters: the body mass index, the post-bronchodilator FEV1 expressed as a percentage of the theoretical values (airflow obstruction), the dyspnoea score measured by the modified scale of the RCM ( Dyspnea) and the distance in meters traveled during a 6-minute walk test (Exercise).Each value of each parmeter corresponds to 1 point (from 0 to 4) and we add everything. The results are: score 0 to 2: mortality 15% at 4 years; and score 7 to 10: 80% mortality at 4 years | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | BMI | 45 days | 
| Impact of a nutritional supplementation with Citrulline on quality of life and dyspnea | Quality of life questionaries: COPD assessement Test (CAT): the participants answers differents questions that make it possible to measure the state of health of the patient. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on physical activity | Actigraphy | 45 days | 
| Impact of a nutritional supplementation with Citrulline on tolerance to effort | Pulmonary function test | 45 days | 
| Impact of a nutritional supplementation with Citrulline on tolerance to effort | Exacerbation number | 45 days | 
| Impact of a nutritional supplementation with Citrulline on tolerance to effort | Comorbidities | 45 days | 
| Impact of a nutritional supplementation with Citrulline on tolerance to effort | Blood gas results | 45 days | 
| Impact of a nutritional supplementation with Citrulline on quality of life and dyspnea | Quality of life questionaries: Visual Simplified respiratory questionary (VSRQ) | 45 days | 
| Impact of a nutritional supplementation with Citrulline on quality of life and dyspnea | Quality of life questionaries: Medical Research Council (mMRC) | 45 days | 
| Impact of a nutritional supplementation with Citrulline on quality of life and dyspnea | Quality of life questionaries: The baseline and Transition Dyspnea Indices (TDI/BDI scale) | 45 days | 
| Impact of a nutritional supplementation with Citrulline on quality of life and dyspnea | Quality of life questionaries: Disability Related to COPD tool (DIRECT) : a self-administered questionnaire designed to evaluate the impact of COPD on the patient's daily activities | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | MNA test : Mini Nutritional Assessment | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | a blood sample will be taken from the participants to measure the effects of citrulline on the inflammation and nutritional status of the patient. C reactive protein (CRPus), inflammation marker | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | Fibrinogen : inflammation marker that will be measured on a blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | Transthyretinemia biological parameter that will measure the nutritional status of the patient.will be mesasured on blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | Albuminemia : biological parameter that will measure the nutritional status of the patient.will be mesasured on blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | glycemia biological parameter that will measure the nutritional status of the patient.will be mesasured on blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | Insulinemia biological parameter that will measure the nutritional status of the patient. will be mesasured on blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | Acid-aminemia biological parameter that will measure the nutritional status of the patient. will be mesasured on blood sample. | 45 days | 
| Impact of a nutritional supplementation with Citrulline on inflammation and nutritional status | 3 MethylHistine / urinary creatinine : this biological parameter will be measure on the urine: biological parameter measured on the urine. which will help to highlight the nutritional status of the patient. | 45 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pulmonary Disease, Chronic Obstructive, Sarcopenia, Citrulline, Body composition, Denutrition