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.

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.

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.

Double blind study: treatment (experimental group) vs placebo (control group).