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Sikkerhedsundersøgelse af inhaleret kulilte til behandling af sepsis-induceret akut respiratorisk distress syndrom (ARDS)

22. maj 2026 opdateret af: Rebecca Baron, Brigham and Women's Hospital

Et fase Ib-forsøg med inhaleret kulilte til behandling af sepsis-induceret akut respiratorisk distress-syndrom (ARDS)

Dette studie er et multicenter, randomiseret, delvist dobbeltblindt og placebokontrolleret fase Ib klinisk forsøg med inhaleret CO (iCO) til behandling af sepsis-induceret akut respiratorisk distress syndrom (ARDS). Formålet med denne undersøgelse er at evaluere sikkerheden og nøjagtigheden af ​​en Coburn-Forster-Kane (CFK) ligningsbaseret personlig iCO doseringsalgoritme for at opnå et mål carboxyhæmoglobin (COHb) niveau på 6-8 % hos patienter med sepsis-induceret ARDS . Vi vil også undersøge de biologiske udlæsninger af lavdosis iCO-terapi hos patienter med sepsis-induceret ARDS.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Detaljeret beskrivelse

ARDS er et syndrom af alvorlig akut lungebetændelse og hypoxæmisk respirationssvigt med en forekomst på 180.000 tilfælde årligt i USA. På trods af de seneste fremskridt inden for intensivbehandling og lungebeskyttende ventilationsstrategier forbliver ARDS-morbiditet og -dødelighed uacceptabelt høj. Ydermere findes der i øjeblikket ingen specifikke effektive farmakologiske terapier. Sepsis, livstruende organdysfunktion forårsaget af et dysreguleret værtsrespons på infektion, repræsenterer en stor risiko for udvikling af ARDS og multi-organ dysfunction syndrome (MODS). I de senere år er antallet af patienter med svær sepsis steget til 750.000 om året i USA, hvilket har en alarmerende prognose for kritisk syge patienter på intensivafdelingen med betydelig risiko for udvikling af ARDS. Manglen på specifikke effektive terapier til ARDS indikerer et behov for nye behandlinger, der retter sig mod nye veje. Kulilte (CO) repræsenterer en ny terapeutisk modalitet i sepsis-induceret ARDS baseret på data opnået i eksperimentelle modeller af sepsis og ARDS i løbet af det seneste årti.

CO har vist sig at være beskyttende i eksperimentelle modeller af akut lungeskade (ALI) og sepsis. Ydermere har flere menneskelige undersøgelser vist, at eksperimentel administration af flere forskellige koncentrationer af CO tolereres godt, og at lavdosis inhaleret CO sikkert kan administreres til forsøgspersoner i et kontrolleret forskningsmiljø. Efterforskerne har tidligere udført et fase I-forsøg med lavdosis iCO i sepsis-induceret ARDS, som viste, at præcis administration af lavdosis iCO (100 og 200 ppm) er mulig, veltolereret og sikker hos patienter med sepsis-induceret ARDS.

Formålet med denne undersøgelse er at vurdere sikkerheden og nøjagtigheden af ​​en CFK-ligningsbaseret iCO-personaliseret doseringsalgoritme af inhaleret kulilte (iCO) for at opnå et mål COHb-niveau på 6-8% hos mekanisk ventilerede patienter med sepsis-induceret ARDS.

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

5

Fase

  • Fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Forenede Stater
    • Massachusetts
      • Boston, Massachusetts, Forenede Stater, 02115
        • Brigham and Women's Hospital
      • Boston, Massachusetts, Forenede Stater, 02114
        • Massachusetts General Hospital
    • Missouri
      • St Louis, Missouri, Forenede Stater, 63110
        • Washington University
    • New York
      • Brooklyn, New York, Forenede Stater, 11215
        • New York-Presbyterian Brooklyn Methodist Hospital
      • New York, New York, Forenede Stater, 10065
        • Weill Cornell Medical College
    • North Carolina
      • Durham, North Carolina, Forenede Stater, 27710
        • Duke University Hospital

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Beskrivelse

Inklusionskriterier:

Alle patienter (18 år og ældre) vil være berettiget til inklusion, hvis de opfylder alle følgende konsensuskriterier for sepsis og ARDS.

Patienter med sepsis er defineret som dem med livstruende organdysfunktion forårsaget af et dysreguleret værtsrespons på infektion:

  1. Mistænkt eller påvist infektion: Infektionssteder omfatter thorax, urinveje, mave, hud, bihuler, centrale venekatetre og centralnervesystemet
  2. Forøgelse i sekventiel organsvigtvurdering (SOFA) score ≥ 2 i forhold til baseline

ARDS er defineret, når alle fire af følgende kriterier er opfyldt:

  1. Et PaO2/FiO2-forhold ≤ 300 med mindst 5 cm H2O positivt end-ekspiratorisk luftvejstryk (PEEP)
  2. Bilateral opacitet på frontalt røntgenbillede af thorax (ikke fuldt ud forklaret af effusioner, lobar/lungekollaps eller knuder) inden for 1 uge efter en kendt klinisk fornærmelse eller nye eller forværrede luftvejssymptomer
  3. Et behov for overtryksventilation med en endotracheal- eller trachealtube
  4. Åndedrætssvigt ikke fuldt ud forklaret af hjertesvigt eller væskeoverbelastning; behov for objektiv vurdering (f.eks. ekkokardiografi) for at udelukke hydrostatisk ødem, hvis der ikke er nogen risikofaktor til stede

Ekskluderingskriterier:

En person, der opfylder et af følgende kriterier, vil blive udelukket fra deltagelse i denne undersøgelse:

  1. Alder under 18 år
  2. Mere end 168 timer siden ARDS debut
  3. Gravid eller ammende
  4. Fange
  5. Patient, surrogat eller læge, der ikke er forpligtet til fuld støtte (undtagelse: en patient vil ikke blive udelukket, hvis han/hun ville modtage al støttende behandling med undtagelse af forsøg på genoplivning fra hjertestop)
  6. Intet samtykke/manglende evne til at opnå samtykke eller passende juridisk repræsentant ikke tilgængelig
  7. Lægen nægtede at tillade optagelse i retssagen
  8. Døende patient forventes ikke at overleve 24 timer
  9. Ingen arteriel linje eller central linje/ingen hensigt om at placere en arteriel eller central linje
  10. Ingen hensigt/uvilje til at følge lungebeskyttende ventilationsstrategi
  11. Alvorlig hypoxæmi defineret som SpO2 < 95 eller PaO2 < 90 på FiO2 ≥ 0,9
  12. Hæmoglobin < 7,0 g/dL
  13. Forsøgspersoner, der er Jehovas Vidner eller på anden måde ikke er i stand til eller uvillige til at modtage blodtransfusioner under indlæggelse
  14. Akut myokardieinfarkt (MI) eller akut koronarsyndrom (ACS) inden for de sidste 90 dage
  15. Koronararterie-bypass-operation (CABG) inden for 30 dage
  16. Angina pectoris eller brug af nitrater med daglige aktiviteter
  17. Svær hjerte-lungesygdom klassificeret som New York Heart Association (NYHA) klasse IV
  18. Slagtilfælde (iskæmisk eller hæmoragisk) inden for den foregående 1 måned, hjertestop, der kræver CPR inden for de foregående 72 timer, eller manglende evne til at vurdere mental status efter hjertestop
  19. Forbrændinger > 40 % af kroppens samlede overfladeareal
  20. Alvorlig inhalationsskade i luftvejene
  21. Brug af højfrekvent oscillerende ventilation
  22. Brug af ekstrakorporal membraniltning (ECMO)
  23. Brug af inhaleret pulmonal vasodilatorterapi (f. nitrogenoxid [NO] eller prostaglandiner)
  24. Diffus alveolær blødning fra vaskulitis
  25. Samtidig deltagelse i anden lægemiddelundersøgelse

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: Randomiseret
  • Interventionel model: Parallel tildeling
  • Maskning: Dobbelt

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Placebo komparator: Medicinsk luft
Inhaleret medicinsk luft i op til 90 minutter dagligt i 3 dage.
Andet: Indåndet medicinsk luft
Inhaleret medicinsk luft i op til 90 minutter dagligt i 3 dage.
Eksperimentel: Inhaleret kulilte
Inhaleret kulilte ved CFK-ligningsbestemt personlig dosis (200-500 ppm for at opnå et COHb-niveau på 6-8%) i op til 90 minutter dagligt i 3 dage.
Medicin: Inhaleret kulilte ved CFK-ligningsbestemt personlig dosis (200-500 ppm for at opnå et COHb-niveau på 6-8%)
Inhaleret kulilte ved CFK-ligningsbestemt personlig dosis (200-500 ppm for at opnå et COHb-niveau på 6-8%) i op til 90 minutter dagligt i 3 dage.
Andre navne:
  • iCO

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Primary Safety Outcome: Number of Pre-specified Administration-related Adverse Events (AEs).
Tidsramme: 7 days

Safety of inhaled CO, defined by the incidence of pre-specified administration-related AEs (as defined below) and spontaneously reported AEs through study day 7.

  1. Acute myocardial infarction within 48 hours of study drug administration
  2. Acute cerebrovascular accident (CVA) within 48 hours of study drug administration
  3. New onset atrial or ventricular arrhythmia requiring DC cardioversion within 48 hours of study drug administration
  4. Increased oxygenation requirements defined as: an increase in FiO2 of ≥ 0.2 AND increase in PEEP ≥ 5 cm H2O within 6 hours of study drug administration
  5. Increase in COHb ≥ 10%
  6. Increase in lactate by ≥ 2 mmol/L within 6 hours of study drug administration
7 days
Percentage Change Measured Relative to Target COHb Level
Tidsramme: Post exposure 90 min day 1
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. We present average data from the two available subjects in the CO group and report as "Mean" with standard deviation.
Post exposure 90 min day 1
Variance of Measured Relative to Target COHb Level
Tidsramme: Post exposure 90 min day 2
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Post exposure 90 min day 2
Variance of Measured Relative to Target COHb Level
Tidsramme: Post exposure 90 min day 3
This was assessed by comparing the measured 90-minute COHb level and the target COHb level of 6-8% post exposure. The limited number of measurements prevent the variance and measures of dispersion calculations; therefore we present the data from one available subject in the CO group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Post exposure 90 min day 3

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Lung Injury Score (LIS) on Days 1-5 Days
Tidsramme: 5 days
The Lung Injury Score (LIS) is a composite 4-point scoring system including the PaO2/FiO2, PEEP, quasi-static respiratory compliance, and the extent of infiltrates on the chest X-ray. Each of the four components is categorized from 0 to 4, where a higher number is worse. The total Lung Injury Score is obtained by dividing the aggregate sum by the number of components used. Previous randomized clinical trials in ARDS have shown that a decreased LIS correlates with improvement in lung physiology as well as important clinical outcomes including mortality and ventilator-free days (VFDs). The number presented is the average difference from beginning to end of treatment. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation.
5 days
Percent Change in PaO2/FiO2 Ratio Between Baseline and Day 5
Tidsramme: Baseline to day 5
PaO2/FiO2 was to be measured on days 1-5 in ventilated subjects. We are providing percent change in PaO2/FiO2 ratio from baseline to day 5. We present the average of data from the 2 available subjects in each group and report as "Mean" with standard deviation.
Baseline to day 5
Oxygenation Index (OI) on Days 1-5 Days
Tidsramme: 5 days
The oxygenation index will be measured on days 1-5 in ventilated subjects. Oxygenation index is calculated as (FiO2 X mean airway pressure)/PaO2. We provide change in Oi from baseline. Oi is only measured when subjects are ventilated, therefore not all timepoints are available. Limited number of measurements prevents variance and measures of dispersion analyses; therefore we present the data from the subjects available in each group and report as "Mean" without standard deviation, where measures of dispersion cannot be calculated.
5 days
Dead Space Fraction (Vd/Vt) on Days 1-3
Tidsramme: Day 3
The dead space fraction will be measured days 1-3 in ventilated subjects. We present change in dead space fraction between initial and final measurements that were available (measurements only taken while the subjects were intubated). We present the data from the subjects available in each group and report as "Mean" with standard deviation.
Day 3
Sequential Organ Failure Assessment (SOFA) Score on Days 1-5.
Tidsramme: 1-5 days
Organ failure will be assessed using the SOFA score. SOFA scores will be assessed daily on days 1-5, as the SOFA score has been shown to be a reliable prognostic indicator of outcomes in critically ill patients. To calculate the Sequential Organ Failure Assessment (SOFA) score, each of the six components (Respiratory, Coagulation, Liver, Cardiovascular, Central Nervous System, Renal) is categorized from 0-4, where a higher number is worse. The SOFA score (0-24) will be calculated by summing all six components. We present changes in SOFA score over the time of hospitalization, over the time of ICU admission (up to days 3 and 5 for the enrolled subjects). We present the data from the subjects available in each group and report as "Mean" with standard deviation.
1-5 days
Ventilator-free Days at Day 28
Tidsramme: 28 days
Ventilator-free days to day 28 are defined as the number of days from the time of initiating unassisted breathing to day 28 after randomization, assuming survival for at least two consecutive calendar days after initiating unassisted breathing and continued unassisted breathing to day 28. If a subject returns to assisted breathing and subsequently achieves unassisted breathing to day 28, VFDs will be counted from the end of the last period of assisted breathing to day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. We present data of ventilator free days for enrolled subjects. Note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
28 days
ICU-free Days at Day 28
Tidsramme: 28 days
ICU-free days will be assessed on day 28. ICU-free days is defined as the number of days between randomization and day 28 in which the patient is in the ICU (for any part of a day). We present average number of ICU free days. Please note that one subject in the medical air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
28 days
Hospital-free Days at Day 60
Tidsramme: 60 days
Hospital-free days will be assessed on day 60. Hospital-free days are days alive post hospital discharge through day 60. Patients who die on or prior to day 60 are assigned zero hospital-free days. We present hospital free days at day 60. Please note that one subject in the air group died at day 9. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
60 days
Hospital Mortality to Day 28 and 60
Tidsramme: 60 days
Mortality will be assessed on day 28 and day 60.
60 days
Montreal Cognitive Assessment- MoCA-Blind
Tidsramme: 3 months

Montreal Cognitive Assessment - Blind Version (MoCA-Blind) The MoCA-Blind is a remote adaptation of the Montreal Cognitive Assessment (MoCA) used as a screening assessment for detecting cognitive impairment. It is administered via telephone interview.

The MoCA-Blind assesses the following cognitive domains (points):

  • Attention (0-6)
  • Language: (0-3 (Repetition (0-2) and fluency (0-1))
  • Abstraction (0-2)
  • Memory: Delayed recall (0-5)
  • Orientation (0-6)

The minimum score is 0 and maximum score is 22 points. Calculated as the sum of all domains. Interpretation: Higher scores indicate better cognitive functioning. Lower scores indicate worse cognitive functioning (greater cognitive impairment). A score of 18 or above is within the normal range. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated.
3 months
Montreal Cognitive Assessment- MoCA-Blind
Tidsramme: 6 months

Montreal Cognitive Assessment - Blind Version (MoCA-Blind) The MoCA-Blind is a remote adaptation of the Montreal Cognitive Assessment (MoCA) used as a screening assessment for detecting cognitive impairment. It is administered via telephone interview.

The MoCA-Blind assesses the following cognitive domains (points):

  • Attention (0-6)
  • Language: (0-3 (Repetition (0-2) and fluency (0-1))
  • Abstraction (0-2)
  • Memory: Delayed recall (0-5)
  • Orientation (0-6)

The minimum score is 0 and maximum score is 22 points. Calculated as the sum of all domains. Interpretation: Higher scores indicate better cognitive functioning. Lower scores indicate worse cognitive functioning (greater cognitive impairment). A score of 18 or above is within the normal range. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation, since dispersion cannot be calculated.
6 months
Hayling Sentence Completion Test
Tidsramme: 3 months

The Hayling Sentence Completion Test assesses executive functioning (response initiation and inhibition), administered via telephone. With 30 sentence-completion items split into 2 sections (15 each).

Sections:

  • 1: Response initiation (time to provide a contextually appropriate word).
  • 2: Response inhibition (time and error score for providing an unrelated word).

Scores (response time and errors) from both sections are combined and converted to an age-adjusted standardized total score.

Total combined standardized score ranges from 1-10:

  1. Impaired
  2. Abnormal
  3. Poor
  4. Low Average
  5. Moderate Average
  6. Average
  7. High Average
  8. Good
  9. Superior
  10. Very Superior

Higher scores= Better executive functioning Lower scores= Greater impairment. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation where dispersion cannot be calculated.
3 months
Hayling Sentence Completion Test
Tidsramme: 6 months

The Hayling Sentence Completion Test assesses executive functioning (response initiation and inhibition), administered via telephone. With 30 sentence-completion items split into 2 sections (15 each).

Sections:

  • 1: Response initiation (time to provide a contextually appropriate word).
  • 2: Response inhibition (time and error score for providing an unrelated word).

Scores (response time and errors) from both sections are combined and converted to an age-adjusted standardized total score.

Total combined standardized score ranges from 1-10:

  1. Impaired
  2. Abnormal
  3. Poor
  4. Low Average
  5. Moderate Average
  6. Average
  7. High Average
  8. Good
  9. Superior
  10. Very Superior

Higher scores= Better executive functioning Lower scores= Greater impairment. A limited number of measurements prevents variance and dispersion analyses; therefore, we report available group data as "means" without standard deviation, since dispersion cannot be calculated.
6 months

Andre resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Change in Biomarkers of Mitochondrial Dysfunction
Tidsramme: Baseline and 3 days
Mitochondrial DNA (mtDNA) plasma levels will be measured on days 1-3 by quantitative PCR of human NADH dehydrogenase 1. Limited number of measurements prevents variance analyses; therefore we present the data from the subjects available in each group and report as "Mean" without standard deviation, since measures of dispersion cannot be calculated.
Baseline and 3 days
Change in Biomarkers of Inflammasome Activation
Tidsramme: 5 days
Plasma IL-18 levels will be measured on days 1-3 and day 5 by ELISA. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
5 days
Change in Biomarkers of Necroptosis
Tidsramme: 5 days
Plasma RIPK3 levels will be measured on days 1-3 and day 5 by ELISA. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
5 days
Plasma Lipid Mediators (LM) and Specialized Pro-resolving Mediators (SPMs)
Tidsramme: 5 days
Lipid mediators (LM) and specialized pro-resolving mediators (SPMs) will be measured in plasma on days 1-3 and day 5 using liquid chromatography-tandem mass spectrometry (LC-MS-MS) based methods. We present the data from the subjects available in each group and report as "Mean" with standard deviation.
5 days

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Brigham and Women's Hospital

Samarbejdspartnere

Massachusetts General Hospital
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Duke University
Weill Medical College of Cornell University

Efterforskere

  • Ledende efterforsker: Rebecca M Baron, MD, Brigham and Women's Hospital

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

6. december 2023

Primær færdiggørelse (Faktiske)

25. oktober 2024

Studieafslutning (Faktiske)

25. oktober 2024

Datoer for studieregistrering

Først indsendt

26. april 2021

Først indsendt, der opfyldte QC-kriterier

28. april 2021

Først opslået (Faktiske)

3. maj 2021

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

26. maj 2026

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

22. maj 2026

Sidst verificeret

1. maj 2026

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 2021P000745
  • 1R61HL153011-01 (U.S. NIH-bevilling/kontrakt)

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

JA

IPD-planbeskrivelse

Vi vil indsende afidentificerede datasæt og tilhørende dokumentation fra det kliniske forsøg til NHLBI-datalageret Biological Specimen and Data Repository Information Coordinating Center (BioLINCC).

IPD-delingstidsramme

Ifølge NHLBI retningslinjer

IPD-delingsadgangskriterier

Ifølge NHLBI retningslinjer

IPD-deling Understøttende informationstype

  • STUDY_PROTOCOL
  • ICF

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

produkt fremstillet i og eksporteret fra U.S.A.

Ingen

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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