Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.

NCT03887169 | Completed Phase 1

• 2 other identifiers: DC201803382018-004140-28
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to determine the safety and tolerance of an oral administration of methionine in the treatment of pulmonary alveolar proteinosis due to the double mutation Ala393Thr / Ser567Leu in the MARS gene. This disease is very severe and especially leads to chronic respiratory insufficiency. There is no curative treatment for this disease. The MARS gene encodes the methionine tRNA synthetase (MetRS). Mutations in this gene leads to a defect in MetRS function. In cultured mutated yeast, addition of methionine in culture medium restores MetRS function. Therefore, the investigators hypothesized that treatment of patients with methionine could have beneficial effects on the disease.

Conditions

Pulmonary Alveolar Proteinosis; Mutation Ala393Thr of the MARS Gene; mutationSer567Leu of the MARS Gene

Keywords

Pulmonary alveolar proteinosis; MARS gene; methionine

Outcome Measures

Primary Outcomes (1)

• Tolerance Assessment

  No adverse event from day 0 to day 75.

  From day 0 to day 75

Secondary Outcomes (16)

• Respiratory rate (cycles /min)

  At day 0, day 15, day 30, day 45, day 60, day 75

• Oxygen need (L/min)

  At day 0, day 15, day 30, day 45, day 60, day 75

• Respiratory signs of struggle

  At day 0, day 15, day 30, day 45, day 60, day 75

• Lung lesions

  At Day 60

• Lipo-proteinaceous material

  At each bronchial-alveolar washes during the 2,5 months

Study Arms (1)

Methionine

EXPERIMENTAL

Drug: Methionine; Drug: Vitamin B12, B9, B6, C supplementation; Diagnostic Test: Methionine/homocysteine Dosage; Diagnostic Test: Thoracic CT scan; Diagnostic Test: Abdominal and liver ultrasound.; Diagnostic Test: Brain MRI

Interventions

Methionine DRUG

Administration of methionine from D1 to D60

Methionine

Vitamin B12, B9, B6, C supplementation DRUG

In case of hyperhomocysteinemia

Methionine

Methionine/homocysteine Dosage DIAGNOSTIC_TEST

Plasma concentration control of methionine and homocysteine from D0 to D75

Methionine

Thoracic CT scan DIAGNOSTIC_TEST

At D60

Methionine

Abdominal and liver ultrasound. DIAGNOSTIC_TEST

At D60

Methionine

Brain MRI DIAGNOSTIC_TEST

In case of abnormal neurological examination

Methionine

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Minor Patient with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven.
• Patient in need of prolonged hospitalization in Necker for treatment of bronchial-alveolar washes in the context of care.
• Patient for which methionine can be administered orally or by enteral probe (Nasogastric or gastrostomy probe)
• Signed Informed consent form by parents / legal guardian

You may not qualify if:

• Patient with alveolar proteinosis by other mutations of the MARS gene
• Patient with alveolar proteinosis secondary to another etiology or without identified cause
• Refusal to participate in the study
• High blood pressure requiring drug treatment
• Heart failure
• Known hypersensitivity to one of the substances used or potentially used in the study: methionine, vitamins B6, B12, B9 and C
• Pre-Hypermethioninemia (Methioninemia \> + 2 DS of normal for age) whatever the cause

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• URC-CIC Paris Descartes Necker Cochin: collaborator

Study Sites (1)

Hôpital Necker-Enfants Malades

Paris, Île-de-France Region, 75015, France

Location

Related Publications (1)

• Hadchouel A, Drummond D, Pontoizeau C, Aoust L, Hurtado Nedelec MM, El Benna J, Gachelin E, Perisson C, Vigier C, Schiff M, Lacaille F, Molina TJ, Berteloot L, Renolleau S, Ottolenghi C, Treluyer JM, de Blic J, Delacourt C. Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis. Eur Respir J. 2022 Apr 21;59(4):2101554. doi: 10.1183/13993003.01554-2021. Print 2022 Apr.

  PMID: 34503986 RESULT

MeSH Terms

Conditions

Pulmonary Alveolar Proteinosis

Interventions

Methionine; Vitamin B 12

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids, Essential; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Neutral; Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Alice HADCHOUEL, PhD

  Hospital Necker Enfants Malades

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 12, 2019
• First Posted: March 22, 2019
• Study Start: September 16, 2019
• Primary Completion: June 1, 2020
• Study Completion: June 1, 2020
• Last Updated: November 20, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)