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

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT03887169

Collaborator

(none)

Enrollment

Location

Arm

8.5

Actual Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Alveolar Proteinosis Mutation Ala393Thr of the MARS Gene mutationSer567Leu of the MARS Gene	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	Phase 1/Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

3 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 16, 2019

Actual Primary Completion Date :

Jun 1, 2020

Actual Study Completion Date :

Jun 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Methionine	Drug: Methionine Administration of methionine from D1 to D60 Drug: 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 Diagnostic Test: Thoracic CT scan At D60 Diagnostic Test: Abdominal and liver ultrasound. At D60 Diagnostic Test: Brain MRI In case of abnormal neurological examination

Arm

Intervention/Treatment

Experimental: Methionine

Drug: Methionine

Administration of methionine from D1 to D60

Drug: 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

Diagnostic Test: Thoracic CT scan

At D60

Diagnostic Test: Abdominal and liver ultrasound.

At D60

Diagnostic Test: Brain MRI

In case of abnormal neurological examination

Outcome Measures

Primary Outcome Measures

Tolerance Assessment [From day 0 to day 75]
No adverse event from day 0 to day 75.

Secondary Outcome Measures

Respiratory rate (cycles /min) [At day 0, day 15, day 30, day 45, day 60, day 75]
number of cycles per minute
Oxygen need (L/min) [At day 0, day 15, day 30, day 45, day 60, day 75]
Flow in L/min
Respiratory signs of struggle [At day 0, day 15, day 30, day 45, day 60, day 75]
Presence or absence of signs
Lung lesions [At Day 60]
Lesions appearance on thoracic CT scan, scored form 0 to 4
Lipo-proteinaceous material [At each bronchial-alveolar washes during the 2,5 months]
Fluid examination
Weight [At Day 15, Day 30, Day 45, Day 60, Day 75]
To evaluate Nutritional status
mid upper arm circumference / head circumference rapport [At Day 15, Day 30, Day 45, Day 60, Day 75]
To evaluate Nutritional status
Hepatomegaly [At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75]
liver damage evaluate by physician during clinical examination
cholestasis and hepatic cytolysis [At Day 0, Day 15, Day 30, Day 60, Day 75]
liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin
Hepatomegaly [At Day 0 and Day 60]
liver damage evaluate by echography
C reactive protein [At Day 0, Day 30, Day 60]
Biological parameters to evaluate Systemic inflammation
sedimentation rate [At Day 0, Day 30, Day 60]
Biological parameters to evaluate Systemic inflammation
Immunoglobulin G level [At Day 0, Day 30, Day 60]
Biological parameters to evaluate Systemic inflammation
Haemoglobin level [At Day 0, Day 30, Day 60]
Biological parameters to evaluate inflammatory anaemia
Plasma concentration of methionine [From Day 0 to Day 75]
Variation of the concentration for each patient
Plasma concentration of homocysteine [From Day 0 to Day 75]
Variation of the concentration for each patient

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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