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
|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|
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 Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||3 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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|
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
Diagnostic Test: Abdominal and liver ultrasound.
Diagnostic Test: Brain MRI
In case of abnormal neurological examination
- Tolerance Assessment [ Time Frame: From day 0 to day 75 ]No adverse event from day 0 to day 75.
- Respiratory rate (cycles /min) [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]number of cycles per minute
- Oxygen need (L/min) [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]Flow in L/min
- Respiratory signs of struggle [ Time Frame: At day 0, day 15, day 30, day 45, day 60, day 75 ]Presence or absence of signs
- Lung lesions [ Time Frame: At Day 60 ]Lesions appearance on thoracic CT scan, scored form 0 to 4
- Lipo-proteinaceous material [ Time Frame: At each bronchial-alveolar washes during the 2,5 months ]Fluid examination
- Weight [ Time Frame: At Day 15, Day 30, Day 45, Day 60, Day 75 ]To evaluate Nutritional status
- mid upper arm circumference / head circumference rapport [ Time Frame: At Day 15, Day 30, Day 45, Day 60, Day 75 ]To evaluate Nutritional status
- Hepatomegaly [ Time Frame: 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 [ Time Frame: At Day 0, Day 15, Day 30, Day 60, Day 75 ]liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin
- Hepatomegaly [ Time Frame: At Day 0 and Day 60 ]liver damage evaluate by echography
- C reactive protein [ Time Frame: At Day 0, Day 30, Day 60 ]Biological parameters to evaluate Systemic inflammation
- sedimentation rate [ Time Frame: At Day 0, Day 30, Day 60 ]Biological parameters to evaluate Systemic inflammation
- Immunoglobulin G level [ Time Frame: At Day 0, Day 30, Day 60 ]Biological parameters to evaluate Systemic inflammation
- Haemoglobin level [ Time Frame: At Day 0, Day 30, Day 60 ]Biological parameters to evaluate inflammatory anaemia
- Plasma concentration of methionine [ Time Frame: From Day 0 to Day 75 ]Variation of the concentration for each patient
- Plasma concentration of homocysteine [ Time Frame: From Day 0 to Day 75 ]Variation of the concentration for each patient
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
|Hôpital Necker-Enfants Malades|
|Paris, Ile De France, France, 75015|
|Principal Investigator:||Alice HADCHOUEL, PhD||Hospital Necker Enfants Malades|