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

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ClinicalTrials.gov Identifier: NCT03887169
Recruitment Status : Completed
First Posted : March 22, 2019
Last Update Posted : November 9, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

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Study Type : Interventional  (Clinical Trial)
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 : September 16, 2019
Actual Primary Completion Date : June 1, 2020
Actual Study Completion Date : June 1, 2020

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Tolerance Assessment [ Time Frame: From day 0 to day 75 ]
    No adverse event from day 0 to day 75.


Secondary Outcome Measures :
  1. Respiratory rate (cycles /min) [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]
    number of cycles per minute

  2. Oxygen need (L/min) [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]
    Flow in L/min

  3. Respiratory signs of struggle [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]
    Presence or absence of signs

  4. Lung lesions [ Time Frame: At Day 60 ]
    Lesions appearance on thoracic CT scan, scored form 0 to 4

  5. Lipo-proteinaceous material [ Time Frame: At each bronchial-alveolar washes during the 2,5 months ]
    Fluid examination

  6. Weight [ Time Frame: At Day 15, Day 30, Day 45, Day 60, Day 75 ]
    To evaluate Nutritional status

  7. mid upper arm circumference / head circumference rapport [ Time Frame: At Day 15, Day 30, Day 45, Day 60, Day 75 ]
    To evaluate Nutritional status

  8. Hepatomegaly [ Time Frame: At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75 ]
    liver damage evaluate by physician during clinical examination

  9. cholestasis and hepatic cytolysis [ Time Frame: At Day 0, Day 15, Day 30, Day 60, Day 75 ]
    liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin

  10. Hepatomegaly [ Time Frame: At Day 0 and Day 60 ]
    liver damage evaluate by echography

  11. C reactive protein [ Time Frame: At Day 0, Day 30, Day 60 ]
    Biological parameters to evaluate Systemic inflammation

  12. sedimentation rate [ Time Frame: At Day 0, Day 30, Day 60 ]
    Biological parameters to evaluate Systemic inflammation

  13. Immunoglobulin G level [ Time Frame: At Day 0, Day 30, Day 60 ]
    Biological parameters to evaluate Systemic inflammation

  14. Haemoglobin level [ Time Frame: At Day 0, Day 30, Day 60 ]
    Biological parameters to evaluate inflammatory anaemia

  15. Plasma concentration of methionine [ Time Frame: From Day 0 to Day 75 ]
    Variation of the concentration for each patient

  16. Plasma concentration of homocysteine [ Time Frame: From Day 0 to Day 75 ]
    Variation of the concentration for each patient



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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03887169


Locations
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France
Hôpital Necker-Enfants Malades
Paris, Ile De France, France, 75015
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: Alice HADCHOUEL, PhD Hospital Necker Enfants Malades
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03887169    
Other Study ID Numbers: DC20180338
2018-004140-28 ( EudraCT Number )
First Posted: March 22, 2019    Key Record Dates
Last Update Posted: November 9, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Pulmonary alveolar proteinosis
MARS gene
methionine
Additional relevant MeSH terms:
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Pulmonary Alveolar Proteinosis
Lung Diseases
Respiratory Tract Diseases
Vitamin B 12
Hydroxocobalamin
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Vitamin B Complex
Hematinics