Pulmonary Alveolar ProteinosisPhase 1/2MetPAPNCT03887169
Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
A Phase 1/2 study testing Methionine, Vitamin B12, B9, B6, C supplementation and Methionine/homocysteine Dosage in people with Pulmonary Alveolar Proteinosis and Mutation Ala393Thr of the MARS Gene, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
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. Read more about this study
- Who is it for?
- Ages Up to 18 years
- Conditions the study is for
- Pulmonary Alveolar Proteinosis, Mutation Ala393Thr of the MARS Gene, mutationSer567Leu of the MARS Gene
- What is being tested?
- Methionine, Vitamin B12, B9, B6, C supplementation and Methionine/homocysteine Dosage
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteFrance
- Study dates
- 16 Sep 2019to 1 Jun 2020
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
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.
Read the 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.
- Conditions
- Pulmonary Alveolar Proteinosis, Mutation Ala393Thr of the MARS Gene, mutationSer567Leu of the MARS Gene
- Being tested
- Methionine, Vitamin B12, B9, B6, C supplementation, Methionine/homocysteine Dosage, Thoracic CT scan, Abdominal and liver ultrasound.
- Keywords
- Pulmonary alveolar proteinosis, MARS gene, methionine
- Medical subject headings
- Pulmonary Alveolar Proteinosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethionineDrug
Administration of methionine from D1 to D60
Vitamin B12, B9, B6, C supplementationDrug
In case of hyperhomocysteinemia
Methionine/homocysteine DosageDiagnostic test
Plasma concentration control of methionine and homocysteine from D0 to D75
Thoracic CT scanDiagnostic test
At D60
Abdominal and liver ultrasound.Diagnostic test
At D60
Brain MRIDiagnostic test
In case of abnormal neurological examination
| Study group | Role | What they receive |
|---|---|---|
| Methionine | Experimental | Not described Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Tolerance Assessment
No adverse event from day 0 to day 75.
Measured: From day 0 to day 75
Secondary outcomes (16)
Respiratory rate (cycles /min)
number of cycles per minute
Measured: At day 0, day 15, day 30, day 45, day 60, day 75
Oxygen need (L/min)
Flow in L/min
Measured: At day 0, day 15, day 30, day 45, day 60, day 75
Respiratory signs of struggle
Presence or absence of signs
Measured: At day 0, day 15, day 30, day 45, day 60, day 75
Lung lesions
Lesions appearance on thoracic CT scan, scored form 0 to 4
Measured: At Day 60
Lipo-proteinaceous material
Fluid examination
Measured: At each bronchial-alveolar washes during the 2,5 months
Weight
To evaluate Nutritional status
Measured: At Day 15, Day 30, Day 45, Day 60, Day 75
mid upper arm circumference / head circumference rapport
To evaluate Nutritional status
Measured: At Day 15, Day 30, Day 45, Day 60, Day 75
Hepatomegaly
liver damage evaluate by physician during clinical examination
Measured: At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75
cholestasis and hepatic cytolysis
liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin
Measured: At Day 0, Day 15, Day 30, Day 60, Day 75
Hepatomegaly
liver damage evaluate by echography
Measured: At Day 0 and Day 60
C reactive protein
Biological parameters to evaluate Systemic inflammation
Measured: At Day 0, Day 30, Day 60
sedimentation rate
Biological parameters to evaluate Systemic inflammation
Measured: At Day 0, Day 30, Day 60
Immunoglobulin G level
Biological parameters to evaluate Systemic inflammation
Measured: At Day 0, Day 30, Day 60
Haemoglobin level
Biological parameters to evaluate inflammatory anaemia
Measured: At Day 0, Day 30, Day 60
Plasma concentration of methionine
Variation of the concentration for each patient
Measured: From Day 0 to Day 75
Plasma concentration of homocysteine
Variation of the concentration for each patient
Measured: From Day 0 to Day 75
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Mar 2019
- Study start16 Sep 2019
- Primary completion1 Jun 2020
- Study completion1 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Alveolar ProteinosisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Responsible party
- Sponsor
- Investigators
- Alice HADCHOUEL, PhD, Principal investigator, Hospital Necker Enfants Malades
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03887169
- Sponsor's protocol ID
- DC20180338
- Other IDs
- 2018-004140-28, 2018
- Acronym
- MetPAP
- Status last verified
- Oct 2025
- First submitted
- 12 Mar 2019
- Last updated
- 20 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 34503986
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
- ClinicalTrials.gov ID
- NCT03887169
- Acronym / sponsor ID
- MetPAP / DC20180338
- Conditions
- Pulmonary Alveolar Proteinosis, Mutation Ala393Thr of the MARS Gene, mutationSer567Leu of the MARS Gene
- Keywords
- Pulmonary alveolar proteinosis, MARS gene, methionine
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Study start
- 16 Sep 2019 (actual)
- Primary completion
- 1 Jun 2020 (actual)
- Study completion
- 1 Jun 2020 (actual)
- First posted
- 22 Mar 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 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 |
Who may qualify
- Ages
- Up to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MethionineAdministration of methionine from D1 to D60 | Drug | Methionine |
| Vitamin B12, B9, B6, C supplementationIn case of hyperhomocysteinemia | Drug | Methionine |
| Methionine/homocysteine DosagePlasma concentration control of methionine and homocysteine from D0 to D75 | Diagnostic test | Methionine |
| Thoracic CT scanAt D60 | Diagnostic test | Methionine |
| Abdominal and liver ultrasound.At D60 | Diagnostic test | Methionine |
| Brain MRIIn case of abnormal neurological examination | Diagnostic test | Methionine |
Primary outcome
Tolerance Assessment
Time frame: From day 0 to day 75
No adverse event from day 0 to day 75.
16 secondary outcomes
Respiratory rate (cycles /min)
Time frame: At day 0, day 15, day 30, day 45, day 60, day 75
Oxygen need (L/min)
Time frame: At day 0, day 15, day 30, day 45, day 60, day 75
Respiratory signs of struggle
Time frame: At day 0, day 15, day 30, day 45, day 60, day 75
Lung lesions
Time frame: At Day 60
Lipo-proteinaceous material
Time frame: At each bronchial-alveolar washes during the 2,5 months
Weight
Time frame: At Day 15, Day 30, Day 45, Day 60, Day 75
mid upper arm circumference / head circumference rapport
Time frame: At Day 15, Day 30, Day 45, Day 60, Day 75
Hepatomegaly
Time frame: At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75
cholestasis and hepatic cytolysis
Time frame: At Day 0, Day 15, Day 30, Day 60, Day 75
Hepatomegaly
Time frame: At Day 0 and Day 60
C reactive protein
Time frame: At Day 0, Day 30, Day 60
sedimentation rate
Time frame: At Day 0, Day 30, Day 60
Immunoglobulin G level
Time frame: At Day 0, Day 30, Day 60
Haemoglobin level
Time frame: At Day 0, Day 30, Day 60
Plasma concentration of methionine
Time frame: From Day 0 to Day 75
Plasma concentration of homocysteine
Time frame: From Day 0 to Day 75
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2025.
- Results publication: PubMed 34503986Hadchouel 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alice HADCHOUEL, PhD principal investigator
Hospital Necker Enfants Malades
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Methionine, Vitamin B12, B9, B6, C supplementation and Methionine/homocysteine Dosage in people with Pulmonary Alveolar Proteinosis and Mutation Ala393Thr of the MARS Gene, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tolerance Assessment (time frame: From day 0 to day 75). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03887169, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2025.