Questa pagina è stata tradotta automaticamente e l'accuratezza della traduzione non è garantita. Si prega di fare riferimento al Versione inglese per un testo di partenza.

Efficacy of a Synthetic Vaccine Derived From Plasmodium Vivax Circumsporozoite Protein (PvCS) in naïve and Semi-immune Volunteers

25 febbraio 2021 aggiornato da: Malaria Vaccine and Drug Development Center

Safety and Protective Efficacy of a Synthetic Vaccine Derived From the CS Protein of Plasmodium Vivax: a Double-blind, Placebo-controlled, Randomized Clinical Trial in naïve and Pre-immune Colombian Volunteers

This is a randomized, double-blind, controlled, which seeks to compare two groups of volunteers (naive and previously exposed to malaria) vaccinated with three doses of a synthetic derivative of the CS protein of Plasmodium vivax to determine their protective efficacy.

Then volunteers will be subject to an infectious challenge (Controlled Human Malaria Infection) to assess the infectivity of gametocytes in the blood early stage of P. vivax in Anopheles albimanus mosquitoes.

Panoramica dello studio

Stato

Non ancora reclutamento

Condizioni

Intervento / Trattamento

Descrizione dettagliata

This study is a prospective controlled, blinded clinical trial, designed to establish the protective efficacy induced by the vaccine PvCSP between human volunteers with and without history of malaria. Volunteers will be recruited in Cali, Colombia and Quibdó, Colombia.

Study subjects: This study will require the involvement of two types of volunteers, parasite donors and volunteers for immunization

Parasite donors: 5-15 P. vivax-infected patients who will serve as parasites donors for experimental infection of mosquitoes, who will be enrolled in the endemic area.

Volunteers for immunization: Two other groups of volunteers will be immunized with the PvCSP vaccine. A group of 60 people without previous exposure to malaria (naïve) and another 60 people with a history of previous malaria infection (pre-immune).

Methodology Recruitment of infected patients: Parasite donors will be recruited among P. vivax infected patients attending a diagnostic center in the endemic area.

Infection of mosquito's blood from donors will be used to feed three-day-old mosquitoes by artificial membrane feeding technique. At day 7, a sample of mosquitoes will be examined to determine the level of infection by dissection of the mosquito's gut. On day 14, a small number of mosquitoes with a good degree of infectivity will be used to infect challenged volunteers.

Recruitment of pre-immune and naive volunteers: Volunteers for the immunization stage will be recruited both in the city of Cali (Colombia), non-endemic region, and in Quibdó (Colombia), a malaria endemic region, through various activities such as conferences, meetings and other strategies previously approved by the IRB, like posters, radio advertising flyers and social media.

Immunization: Volunteers will be immunized with the vaccine (n=60) or placebo (n=60).

Follow-up of volunteers will be performed under medical vigilance during the first hour following the immunization to detect any adverse reaction. After the first hour period a medical exam will be made. Eight hours after immunization, each volunteer will be contacted via telephone to assess physical condition. Any adverse event (AE) will be registered.

Subsequent follow up will be made on the day next to immunization and 1 or 2 weeks before the next immunization by a new clinical evaluation and AE report. Volunteers will be instructed to contact the research staff at any moment.

Infection of volunteers immunized volunteers will be challenged on day ~150 of the study, 1 month after the third immunization by the bite of 2-4 infected mosquito. A "feeding cage" will be placed on the forearm of a volunteer for 10 minutes, allowing that the feeding window, which will be covered by a mesh surface be placed against the volunteer's skin.

Volunteers will be instructed about the signs and symptoms of malaria and they will have a daily telephone contact during the first 6 days.

Between days 7 and 23 the volunteers will be asked to go to the Clinical Trials Unit daily to establish the presence or absence of disease through thick blood smear and samples will be collected for retrospective real time PCR P. vivax.

From day 23 until day 31, volunteers will receive physical and laboratory evaluation every other day and will have daily telephone contact.

Once the patients present signs and symptoms of the disease curative treatment will be immediately provided, and 15 ml of blood will be drawn, which will be used for immune response assessment.

If the volunteers do not develop the disease during the follow-up period, on day 31 they will be given antimalarial treatment.

Treatment Volunteers will be treated with antimalarial drugs approved by the Colombian Ministry of Social Health: chloroquine (three (3) doses: 600 mg initially, followed by 450 mg at 24, and 48 hours), associated with primaquine (30mg/day) for 14 days. All the volunteers will be asked to return two weeks after starting treatment for a thick blood smear test to ensure cure of malaria.

Tipo di studio

Interventistico

Iscrizione (Anticipato)

120

Fase

  • Fase 2

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Contatto studio

Luoghi di studio

  • Colombia
    • Valle Del Cauca
      • Cali, Valle Del Cauca, Colombia
        • Malaria Vaccine and Drug Development Center
        • Contatto:

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

Da 18 anni a 45 anni (Adulto)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

Inclusion Criteria:

Naïve group:

  1. Non-pregnant, healthy men and women between 18-45 years old.
  2. Freely and voluntarily sign an IC, accompanied by two witnesses who must also sign.
  3. Absence history of malaria infection.
  4. To have negative serology for the PvCS protein by the ELISA test.
  5. For women, not be pregnant.
  6. Use of an adequate contraceptive method from the beginning until the contraceptive restriction is lifted by a study doctor, at the end of the study.
  7. To accept not to travel to areas considered as endemic for malaria from the infectious challenge period and to the end of its follow-up (1 month).
  8. Be reachable by phone throughout the study period.
  9. To be Duffy positive (Fy +).
  10. Have Hemoglobin (Hb) levels> 11 g / dl.
  11. Be willing to participate during the period in which the study will take place.
  12. Not be participating in another clinical study.
  13. Be affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)

Semi-immune group:

  1. Non-pregnant, healthy men and women between 18-45 years old,
  2. Freely and voluntarily sign an informed consent, accompanied by two witnesses who will also sign.
  3. Have a history of malaria infection (s) and positive serological tests (ELISA) for P. vivax.
  4. For women, not be pregnant or nursing.
  5. For women, use of adequate contraception from inception until the contraceptive restriction is lifted by a study physician.
  6. Be a permanent resident of the municipality of Quibdó during the study.
  7. Be reachable by phone throughout the study period.
  8. Availability to participate during the period in which the study will take place.
  9. Be affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)

Exclusion Criteria:

Naïve group:

  1. Glucose 6 phosphate dehydrogenase deficiency (G-6-P-D).
  2. Present any hemoglobinopathy (eg HbS).
  3. Personal history of allergies to medications or insect bites.
  4. Have received vaccination against malaria.
  5. Clinical or laboratory abnormalities determined by the investigator (s).
  6. IFAT> 1:20 for P. vivax in screening tests.
  7. Have lived in a malaria-endemic region during the 12 months before the study.
  8. Clinical or laboratory evidence of systemic disease, including kidney, liver, cardiovascular, pulmonary, psychiatric, or other diseases that may negatively impact and alter study results.
  9. Evidence of active hepatitis B or Hepatitis C infection
  10. Evidence of active HIV infection.
  11. History of transfusion of any blood product in the 6 (six) months before the study.
  12. Plan to have surgery from the recruitment period to the end of the post-challenge follow-ups.
  13. Presence or history of autoimmune disease (lupus, rheumatoid arthritis, thyroiditis, or other).
  14. Splenectomized volunteers.
  15. Volunteers in treatment with drugs with activity on the immune system (steroids, immunosuppressive agents, or immunomodulators).
  16. History of alcoholism or drug abuse defined as a habit that interferes with the normal social functioning of the individual.
  17. Any condition that may interfere with the ability to provide a free and voluntary IC.
  18. Not being affiliated with the general health social security system of Colombia, in any of its regimes (subsidized or contributory)

Semi-immune group:

  1. IFAT negative (<1:20) for P. vivax in screening tests.
  2. The other criteria used in the case of naïve volunteers, except the antecedent of having lived in the endemic area.

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Prevenzione
  • Assegnazione: Randomizzato
  • Modello interventistico: Assegnazione parallela
  • Mascheramento: Quadruplicare

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: Arm N Vaccine
30 malaria-naïve subjects from non-endemic areas of Cali, Colombia.
Biologico: Vaccine PvCS N+C+R 150 mcg
Vaccine PvCS N+C+R 150 mcg (Montanide ISA-51), freeze dried powder.
Comparatore placebo: Arm N Placebo
30 malaria-naïve subjects from non-endemic areas of Cali, Colombia.
Altro: Placebo SSN Montanide ISA-51 1 mL
SSN Montanide ISA-51 1 mL
Sperimentale: Arm S Vaccine
30 semi-immune subjects from malaria endemic areas of Chocó, Colombia.
Biologico: Vaccine PvCS N+C+R 150 mcg
Vaccine PvCS N+C+R 150 mcg (Montanide ISA-51), freeze dried powder.
Comparatore placebo: Arm S Placebo
30 semi-immune subjects from malaria endemic areas of Chocó, Colombia.
Altro: Placebo SSN Montanide ISA-51 1 mL
SSN Montanide ISA-51 1 mL

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Frequency of first case of P. vivax malaria after CHMI and meeting the primary case definition.
Lasso di tempo: Assessed over average of 16-18 days post CHMI (range 7 to 60 days)
The first case of malaria meeting the primary case definition will be defined as the first or only episodes with the presence of Plasmodium vivax parasitemia ≥ 0.1% by thick blood smear and malaria qPCR.
Assessed over average of 16-18 days post CHMI (range 7 to 60 days)

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Concentration of specific anti-PvCS IgG antibodies IgG (isotypes) against the different functional fragments of the Pv-CS protein.
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.

Concentration of specific anti-PvCS IgG antibodies IgG (isotypes) against the different functional fragments of the Pv-CS protein (Amino, Central Repeat and Carboxilo terminal). Expressed both as antibody titers and Reactive Indices (RI) measured by in enzyme-linked immunosorbent assay (ELISA) and Immunofluorescence Test (IFAT). Antibody titers by IFAT are determine as the reciprocal of the end-points dilution showing a positive fluorescence.

Concentrations will be presented as geometric mean concentrations (GMCs).
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Specific cytokine induction
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Specific cytokine induction will be measured by IFN- γ, TNF-α, IL-2; IL- 4, IL-6, IL-10
Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Flow cytometry
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
In vitro proliferation of CD3+ T-cells (CD4+ and CD8+) and intracellular production of cytokines IFN-gamma, TNF-a, IL-12 by flow cytometry. Result will be expressed as percentages.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - ELIspot
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Production of IFN-gamma and IL-10 in total PBMC stimulated with the different antigens and / or synthetic peptides by ELIspot assay. Results expressed as the mean number of IFN-γ spot-forming cells (sfc) per 106 Peripheral Blood Mononuclear Cells.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
T-cell response measurement - Bioplex
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Multiplex cytokines profile (Th1/Th2/Treg) in sera by bioplex. Cytokine concentrations were calculated from the standard curve using seven-parameter curve fitting software and the results were expressed in pg/mL. The limit of detection for the assay was 10 pg/mL for all cytokines. Results will be expressed as percentages.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of T lymphocytes
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Phenotyping and profiles of memory T lymphocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Characterization of B lymphocytes.
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240
Phenotyping and profiles of B lymphocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Days 0, 30, 60, 90, 120, 180, 210 and 240
Characterization of monocytes
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Phenotyping and profiles of monocytes will be done in PBMCs using specific panels of markers by flow cytometry. The frequency of cells as a biomarker post CHMI infection will be performed. Cells will be stained by using different antibody cocktails targeting specific cell populations. Cells acquisition will be done on a 4-laser BD flow cytometer and gating analysis with FlowJo software version 10.4.2. Results will be expressed as percentages.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Antibody functionality in vitro through inhibition of sporozoite invasion (ISI) to Hep-G2 cells.
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Antibody functionality will be tested in vitro through essays of inhibition of sporozoite invasion (ISI) to Hep-G2 cells.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Vaccine-induced protection for P. vivax
Lasso di tempo: Thirty days after mosquito bite challenge (Controlled Human Malaria Infection)
Vaccine-induced protection for P. vivax will be assessed by pre-patent period onset after infected mosquito bites exposure
Thirty days after mosquito bite challenge (Controlled Human Malaria Infection)
Multiomics testing (i.e., transcriptomics, genomics)
Lasso di tempo: Days 0, 30, 90, 195 and 225.

Tthe present study also seeks to evaluate host-related variables, especially those affected by the immune status prior to vaccination (naïve vs pre-immune participants).

To accomplish this, transcriptomics and genomics tests will be undertaken on days 0, 30, 195 and, 225.
Days 0, 30, 90, 195 and 225.
Safety - Number of Subjects With Any and Grade 3 Solicited Local Symptoms
Lasso di tempo: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Assessed solicited local symptoms will be pain and swelling. Any = occurrence of the symptom regardless of intensity grade. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 20 millimeters (mm) of injection site.
During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
Lasso di tempo: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses

Assessed solicited general symptoms will be drowsiness, fever [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], irritability and loss of appetite.

Any = occurrence of the symptom regardless of intensity grade. Grade 3 symptom = symptom that prevented normal activity.

Grade 3 fever = fever higher than (>) 39.0 °C. Related = symptom assessed by the investigator as related to the vaccination.
During the 7-day (Days 0-6) post-vaccination period following each dose and across doses
Safety - Number of Subjects With Any Unsolicited Adverse Events (AEs)
Lasso di tempo: Within the 30-day (Days 0-29) post-vaccination follow-up period

An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms.

Any will be defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.
Within the 30-day (Days 0-29) post-vaccination follow-up period
Safety - Number of Subjects With Serious Adverse Events (SAEs)
Lasso di tempo: Throughout the study period (Day 0 - Month 14)
Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.
Throughout the study period (Day 0 - Month 14)
Safety - Number of Subjects With Hemoglobin Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With White Blood Cell (WBC) Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Platelet Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alanine Aminotransferase (ALT) Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Creatinine Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Bilirubin Values Outside Normal Ranges With Toxicity Grades
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Alkaline phosphatase Values Outside Normal Ranges With Toxicity
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Blood urea nitrogen (BUN) Values Outside Normal Ranges With Toxicity
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Aspartate aminotransferase (AST) Values Outside Normal Ranges With Toxicity
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Prothrombin time (PT)) Values Outside Normal Ranges With Toxicity
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of Subjects With Partial thromboplastin time (PTT) Values Outside Normal Ranges With Toxicity
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Toxicity levels will be measured according to the Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Number of participants with confirmed pregnancy
Lasso di tempo: Days 0, 30, 60, 90, 120, 180, 210 and 240.
Number of participants with confirmed pregnancy during the study duration.
Days 0, 30, 60, 90, 120, 180, 210 and 240.
Safety - Glucose-6-phosphate dehydrogenase deficiency
Lasso di tempo: Day 0.
Glucose-6-phosphate dehydrogenase deficiency test will be done during baseline evaluation.
Day 0.

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Malaria Vaccine and Drug Development Center

Investigatori

  • Investigatore principale: Socrates Herrera, MD, Director

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Anticipato)

1 giugno 2021

Completamento primario (Anticipato)

1 giugno 2022

Completamento dello studio (Anticipato)

1 dicembre 2022

Date di iscrizione allo studio

Primo inviato

25 gennaio 2021

Primo inviato che soddisfa i criteri di controllo qualità

1 febbraio 2021

Primo Inserito (Effettivo)

5 febbraio 2021

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

1 marzo 2021

Ultimo aggiornamento inviato che soddisfa i criteri QC

25 febbraio 2021

Ultimo verificato

1 febbraio 2021

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • MVDC-2021-001

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

No

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

Prove cliniche su Malaria, Vivax

Prove cliniche su Vaccine PvCS N+C+R 150 mcg

Cerca prove simili

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

CROs by country

CROs in Jordan

Condizioni

Malattie rare

Interventi farmacologici

Supplementi dietetici

Sponsor / Collaboratori

Sedi

Sottoscrivi