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

Pulmonary Alveolar Proteinosis Clinical Trial

— MetPAP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03887169
• Other study ID #: DC20180338
• Secondary ID: 2018-004140-28
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 16, 2019
• Est. completion date: June 1, 2020

Study information

• Verified date: November 2020
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Pulmonary alveolar proteinosis (PAP) is a rare respiratory disorder. Recently, a genetic cause has been identified for a specific form of PAP predominant on La Reunion Island. This form is characterized by a multisystem phenotype including PAP, failure to thrive, hepatic involvement and chronic inflammation. This is a severe disease without any specific treatment and a high rate of mortality related to end-stage respiratory insufficiency. Two recurrent mutations were isolated in the MARS gene that encodes the methionine tRNA synthetase (MetRS). This enzyme catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. Functional studies on mutated yeast show an altered growth and protein synthesis as compared to control yeast. Addition of methionine in culture medium corrects these defects. Complementary experiments on human purified MetRS show altered enzymatic catalytic parameters in mutated forms. Increasing blood concentration of methionine in patients could correct these parameters and potentially improve patients' phenotype in this severe disorder where no curative treatment exists. The main objective of this protocol is to determine the tolerance of a prolonged daily supplementation of methionine in patients presenting a MARS related PAP. The secondary objectives are to determine the efficiency of such treatment on respiratory, hepatic, inflammatory and growth status. To meet the objectives of the study, enrolled patients will receive daily oral or enteral methionine administration at increasing doses, under surveillance of plasma levels of methionine and homocysteine, and possible clinical side effects, until determining the "ideal" dose for each patient. Once daily dosage determined for each patient, this dosage will be continued for a total of 2 months with daily clinical monitoring of tolerance and bi-monthly plasma levels surveillance of methionine and homocysteine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3
• Est. completion date: June 1, 2020
• Est. primary completion date: June 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 18 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

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

Intervention

Drug:
• Methionine
Administration of methionine from D1 to D60
• Vitamin B12, B9, B6, C supplementation
In case of hyperhomocysteinemia

Diagnostic Test:
• Methionine/homocysteine Dosage
Plasma concentration control of methionine and homocysteine from D0 to D75
• Thoracic CT scan
At D60
• Abdominal and liver ultrasound.
At D60
• Brain MRI
In case of abnormal neurological examination

Locations

Country	Name	City	State
France	Hôpital Necker-Enfants Malades	Paris	Ile De France

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Tolerance Assessment	No adverse event from day 0 to day 75.	From day 0 to day 75
Secondary	Respiratory rate (cycles /min)	number of cycles per minute	At day 0, day 15, day 30, day 45, day 60, day 75
Secondary	Oxygen need (L/min)	Flow in L/min	At day 0, day 15, day 30, day 45, day 60, day 75
Secondary	Respiratory signs of struggle	Presence or absence of signs	At day 0, day 15, day 30, day 45, day 60, day 75
Secondary	Lung lesions	Lesions appearance on thoracic CT scan, scored form 0 to 4	At Day 60
Secondary	Lipo-proteinaceous material	Fluid examination	At each bronchial-alveolar washes during the 2,5 months
Secondary	Weight	To evaluate Nutritional status	At Day 15, Day 30, Day 45, Day 60, Day 75
Secondary	mid upper arm circumference / head circumference rapport	To evaluate Nutritional status	At Day 15, Day 30, Day 45, Day 60, Day 75
Secondary	Hepatomegaly	liver damage evaluate by physician during clinical examination	At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75
Secondary	cholestasis and hepatic cytolysis	liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin	At Day 0, Day 15, Day 30, Day 60, Day 75
Secondary	Hepatomegaly	liver damage evaluate by echography	At Day 0 and Day 60
Secondary	C reactive protein	Biological parameters to evaluate Systemic inflammation	At Day 0, Day 30, Day 60
Secondary	sedimentation rate	Biological parameters to evaluate Systemic inflammation	At Day 0, Day 30, Day 60
Secondary	Immunoglobulin G level	Biological parameters to evaluate Systemic inflammation	At Day 0, Day 30, Day 60
Secondary	Haemoglobin level	Biological parameters to evaluate inflammatory anaemia	At Day 0, Day 30, Day 60
Secondary	Plasma concentration of methionine	Variation of the concentration for each patient	From Day 0 to Day 75
Secondary	Plasma concentration of homocysteine	Variation of the concentration for each patient	From Day 0 to Day 75