| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Allergic asthma |
| allergisk astma |
|
| E.1.1.1 | Medical condition in easily understood language |
| asthma mediated by allergy |
| astma betinget af allergi |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effects of allergen immunotherapy on anti-viral immunity in patients with allergic asthma. Main outcome is to investigate potentiale change in bronchial epithelial cells interferon secretion before and after 6 month of treatment with ACARIZAX or placebo. |
| Hovedformålet med studiet er at undersøge effekten af allergen immunoterapi på immunforsvaret i lungerne hos patienter med allergisk astma. Hovedformålet er at undersøge interferon udskillelse i bronkial epitel celler før og efter 6 måneders terapi med ACARIZAX eller placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate the effect of allergen immunotherapy on anti-bacterial response in patients with allergic asthma.
To investigate the potential change in immunologic phenotype in BAL-fluid.
To investigate the potential change in cell supernatants for epithelial derived Th1/Th2 cytokines aswell as th1/th2 (anti)-inflammatory cytokines.
To investigate the potential change in histologic phenotype in bronchial biopsies
To investigate the potential change in airway inflammation markers in sputum. |
At undersøge virkningen af allergen immunoterapi på det anti-bakteriel respons hos patienter med allergisk astma.
At undersøge den potentielle ændring i immunologisk fænotype i BAL-væske.
At undersøge den potentielle ændring i celle supernatanter for epitel-afledte Th1 / Th2-cytokiner såvel som th1 / th2 (anti) -inflammatoriske cytokiner.
At undersøge den potentielle ændring i histologisk fænotype i bronchiale biopsier
At undersøge den potentielle ændring i luftvejsinflammationsmarkører i sputum. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Written informed consent
Age >18 through < 70, inclusive at the time of V1
A historic verified diagnosis of asthma as defined by ³1 positive of following tests:
Reversibility to ß2-agonist
Positive mannitol challenge test
Positive methacholine test
Positive peak-flow variation test
Positive eucapnic voluntary hyperventilation test
Exercise test
Symptoms of HDM induced rhinitis and/or conjunctivitis
³1 self-reported worsening of asthma symptoms in relations to viral infection within last 12 months
³1 present or historical marker of Th2 asthma:
FeNO > 25 ppb at V0
Blood eosinophils > 0,3 x 109/L
Sputum eosinophils > 3%
A FEV1value of ≥ 70% at V0
ACQ-6 > 1 (partly controlled) at V0
A stable asthma controller regimen with ICS (±LABA) for at least 4 weeks prior to V0
Sensitisation to HDM defined by ≥1 of following:
Positive skin prick test for either: Dermatophagoides pteronyssinus or Dermatophagoides farina
IgEHDM > 0.7 x103IU/L
Subjects must demonstrate acceptable inhaler and spirometry techniques during screening (as evaluated and in the opinion of study site staff) |
Skriftligt informeret samtykke
Alder >18 til <70, inklusive på tidspunktet for V1
En historisk verificeret diagnose af astma som defineret ved ³1 positiv af følgende tests:
Vendbarhed til ß2-agonist
Positiv mannitol-udfordringstest
Positiv methacholine-test
Positive peak-flow variationstest
Positiv eukapnisk frivillig hyperventilationstest
Træningstest
Symptomer på HDM-induceret rhinitis og / eller konjunktivitis
³1 selvrapporteret forværring af astmasymptomer i relation til virusinfektion inden for de sidste 12 måneder
³1 nuværende eller historisk markør for Th2-astma:
FeNO> 25 ppb ved V0
Blod eosinofiler> 0,3 x 109 / l
Sputum eosinophils> 3%
En FEV1-værdi på ≥ 70% ved V0
ACQ-6> 1 (delvist styret) ved V0
Et stabilt astma-controller-regime med ICS (± LABA) i mindst 4 uger før V0
Sensibilisering til HDM defineret af ≥1 af følgende:
Positiv hudprikketest for enten: Dermatophagoides pteronyssinus eller Dermatophagoides farina
IgEHDM> 0,7 x103IU / L
Personer skal demonstrere acceptabel inhalator- og spirometriteknikker under screening (som evalueret og efter vurdering af medarbejderne på studiestedet) |
|
| E.4 | Principal exclusion criteria |
Any of the following would exclude the subject from participation in the study:
1. Oral corticosteroids (any dose for more than 3 days) 8 weeks prior to V1 and during run-in.
2. Acute upper or lower respiratory infections requiring antibiotics or antiviral medications 6 weeks prior to V0 and during run-in.
3. Severe oral conditions such as but not limited to:
Oral ulcers
Oral lichen planus
Oral mycosis
4. Current smokers
5. Any of the following concomitant allergies:
Birch, Cat, Dog, Horse
Ever in treatment with any AIT
7. Previous medical history or evidence of an uncontrolled intercurrent illness that in the opinion of the investigator may compromise the safety of the subject in the study or interfere with evaluation of the investigational product or reduce the subject’s ability to participate in the study. Subjects with well-controlled comorbid disease (eg, hypertension, hyperlipidaemia, gastroesophageal reflux disease) on a stable treatment regimen for 15 days prior to Visit 0 are eligible.
Any concomitant respiratory disease that in the opinion of the investigator and/or medical monitor will interfere with the evaluation of the investigational product or interpretation of subject safety or study results (eg, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, bronchiectasis, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, alpha-1-antitrypsin deficiency, Wegeners granulomatosis, Sarcoidosis).
Any clinically relevant abnormal findings in haematology or clinical chemistry (laboratory results from Visit 1), physical examination, vital signs during the screening, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject’s ability to participate in the study.
Evidence of active liver disease, including jaundice, alanine transaminase, bilirubin, greater than twice the upper limit of normal (laboratory results from Visit 0).
History of cancer:
a. Subjects who have had basal cell carcinoma or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1.
b. Subjects who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1.
A helminth parasitic infection diagnosed within 24 weeks of Visit 1 that has not been treated or has not responded to standard of care therapy.
Known history of active tuberculosis (TB). Subjectsmay be enrolled if they have ALL of the following:
No symptoms of TB: productive, prolonged cough (> 3 weeks); coughing up blood; fever; night sweats; unexplained appetite loss; unintentional weight loss.
No known exposure to a case of active TB after most recent prophylaxis (prophylaxis required only if positive).
No evidence of active TB on chest radiograph within 3 months prior to the first dose of investigational product.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at screening, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol.
A positive human immunodeficiency virus (HIV) test at screening or subject taking antiretroviral medications, as determined by medical history and/or subject’s verbal report.
History of any known primary immunodeficiency disorder excluding asymptomatic selective immunoglobulin A or IgG subclass deficiency.
Use of 5-lipoxygenase inhibitors (eg, zileuton) within 15 days prior to Visit 1.
Use of immunosuppressive medication (eg, methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to Visit 1.
Receipt of any of the following within 30 days prior to Visit 1:
Immunoglobulin or blood products, or
Receipt of any investigational nonbiologic agent within 30 days or 5 half-lives prior Visit 0, whichever is longer.
Receipt or treatment with of any marketed or investigational biologic agent within 6 months or 5 half-lives prior to Visit 1, whichever is longer, specifically:
Anti-IgE
Anti-IL4
Anti-IL-5
Anti-IL5 receptor antagonist
Anti-IL-13
Pregnant, breastfeeding or lactating females
History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
Planned surgical procedures requiring general anaesthesia or in-patient status for > 1 day during the conduct of the study.
Unwillingness or inability to follow the procedures outlined in the protocol.
Concurrent enrolment in another clinical study involving an investigational treatment.
Receipt of the Th2 cytokine inhibitor Suplatast Tosilate within 15 days prior to Visit 1.
Receipt of any live or attenuated vaccines within 15 days prior to Visit 1.
|
Et af følgende vil udelukke emnet fra deltagelse i undersøgelsen:
1. Orale kortikosteroider (enhver dosis i mere end 3 dage) 8 uger før V1 og under indkørsel.
2. Akutte øvre eller nedre luftvejsinfektioner, der kræver antibiotika eller antiviral medicin 6 uger før V0 og under indkørsel.
3. Alvorlige orale tilstande såsom, men ikke begrænset til:
Orale sår
Oral lichen planus
Oral mykose
4. Nuværende rygere
5. Enhver af følgende samtidige allergier: Birk, kat, hund, hest
Nogensinde i behandling med enhver AIT
7. Tidligere medicinsk historie eller bevis for en ukontrolleret samtidige sygdom, der efter undersøgelsens mening kan gå på kompromis med individets sikkerhed i undersøgelsen eller forstyrre evalueringen af undersøgelsesproduktet eller reducere individets evne til at deltage i undersøgelsen. Personer med godt kontrolleret comorbid sygdom (f.eks. Hypertension, hyperlipidæmi, gastroøsofageal reflukssygdom) på et stabilt behandlingsregime i 15 dage før besøg 0 er berettigede.
Enhver samtidig respiratorisk sygdom, der efter undersøgelsens mening og / eller medicinsk monitor vil forstyrre evalueringen af undersøgelsesproduktet eller fortolkning af individets sikkerhed eller undersøgelsesresultater (f.eks. Kronisk obstruktiv lungesygdom, cystisk fibrose, lungefibrose, bronchiectasis, allergisk bronchopulmonal aspergillosis, Churg-Strauss syndrom, alfa-1-antitrypsinmangel, Wegeners granulomatosis, Sarcoidosis).
Eventuelle klinisk relevante unormale fund i hæmatologi eller klinisk kemi (laboratorieresultater fra besøg 1), fysisk undersøgelse, vitale tegn under screeningen, som efter forskerens mening kan sætte emnet i fare på grund af hans / hendes deltagelse i undersøgelsen , eller kan have indflydelse på resultaterne af undersøgelsen eller individets evne til at deltage i undersøgelsen.
Bevis for aktiv leversygdom, herunder gulsot, alanintransaminase, bilirubin, større end det dobbelte af den øvre normalgrænse (laboratorieresultater fra Visit 0).
Kræftens historie:
en. Personer, der har haft basalcellekarcinom eller livmoderhalscancer i livmoderhalsen, er berettigede til at deltage i undersøgelsen, forudsat at helbredelsesbehandling blev afsluttet mindst 12 måneder før besøg 1.
b. Motiver, der har haft andre maligne lidelser, er berettigede, forudsat at kurativ terapi blev afsluttet mindst 5 år før besøg 1.
En helminth parasitisk infektion diagnosticeret inden for 24 uger efter besøg 1, som ikke er blevet behandlet eller ikke har responderet på plejeterapi standard.
Kendt historie med aktiv tuberkulose (TB). Emner kan tilmeldes, hvis de har ALLE af følgende:
Ingen symptomer på tuberkulose: produktiv, langvarig hoste (> 3 uger); hoste op blod; feber; nattesved; uforklarlig tab af appetit; utilsigtet vægttab.
Ingen kendt eksponering for et tilfælde af aktiv tuberkulose efter den seneste profylakse (profylakse kræves kun, hvis den er positiv).
Intet bevis for aktiv TB på røntgenbillede inden for brystet inden for 3 måneder før den første dosis af undersøgelsesprodukt.
Positiv hepatitis B-overfladeantigen eller hepatitis C-virusantistofserologi ved screening eller en positiv medicinsk historie for hepatitis B eller C. Personer med en historie med hepatitis B-vaccination uden historie med hepatitis B har tilladelse til at tilmelde sig.
En positiv human immundefektvirus (HIV) -test ved screening eller individ, der tager antiretrovirale medikamenter, som bestemt af medicinsk historie og / eller individets verbale rapport.
Historie om enhver kendt primær immundeficienslidelse undtagen asymptomatisk selektiv immunoglobulin A eller IgG underklasse mangel.
Anvendelse af 5-lipoxygenaseinhibitorer (f.eks. Zileuton) inden for 15 dage før besøg 1.
Brug af immunsuppressiv medicin (f.eks. Methotrexat, troleandomycin, oral guld, cyclosporin, azathioprin, intramuskulær langtidsvirkende depot kortikosteroid eller enhver eksperimentel antiinflammatorisk terapi) inden for 3 måneder før besøg 1.
Modtagelse af noget af følgende inden for 30 dage før besøg 1:
Immunoglobulin eller blodprodukter eller
Modtagelse af ethvert undersøgende ikke-biologisk middel inden for 30 dage eller 5 halveringstider forud for besøg 0, alt efter hvad der er længere.
Modtagelse eller behandling af et markedsført eller undersøgende biologisk middel inden for 6 måneder eller 5 halveringstider før besøg 1, alt efter hvad der er længere, specifikt:
Anti-IgE
Anti-IL-4
Anti-IL-5
Anti-IL5-receptorantagonist
Anti-IL-13
Gravide, ammende eller lakterende kvinder
Kronisk alkohol/stofmisbrug
Uvillighed eller manglende evne til at følge procedurerne beskrevet i protokollen.
Samtidig tilmelding til en anden klinisk undersøgelse, der involverer en undersøgelsesbehandling.
Modtagelse af Th2-cytokininhibitoren Suplatast Tosilate inden for 15 dage før besøg 1.
Modtagelse af levende eller svækkede vacciner inden for 15 dage før besøg 1. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Change in interferon-B gene / and or protein expression
Cahnge in interferon-gamma gene/and or protein expression
Change in viral load and/or TCID50 assay |
Ændring i interferon-B gen / og eller proteinekspression
Ændring i interferon-gamma gen / og eller proteinekspression
Ændring i viral belastning og / eller TCID50 assay |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Bronchoscopy at V2 and V7. |
| Bronkoskopi ved V2 og V7 |
|
| E.5.2 | Secondary end point(s) |
Change in:
- IFN-ß mRNA expression
- IFN-λ mRNA expression
Anti-bacterial measures:
- IL-12
- ß-defensin
- IFN- γ
- Th1/Th2 balance
- NK-cells
- CD8+ T-cells.
- Treg-cells, Breg-cells
- Inflammatory cytokines such as but not restricted to: IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß and TSLP
- Anti-inflammatory cytokines such as but not restricted to: IL-10, TGF-ß
- IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß and TSLP
- IL-10, TGF-ß
- IFN-ß/TSLP ratio.
Number / percentage of eosinophils and neutrophils in airway submucosa, sputum and blood.
Cell count of following types:
- Mast cells
- Eosinophils
- Neutrophils
- pDC’s
|
Ændring i:
- IFN-ß mRNA-ekspression
- IFN-λ mRNA-ekspression
Antibakterielle forholdsregler:
- IL-12
- ß-defensin
- IFN- γ
- Th1 / Th2 balance
- NK-celler
- CD8 + T-celler.
- Treg-celler, Breg-celler
- Inflammatoriske cytokiner såsom, men ikke begrænset til: IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß og TSLP
- Antiinflammatoriske cytokiner såsom, men ikke begrænset til: IL-10, TGF-ß
- IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß og TSLP
- IL-10, TGF-ß
- IFN-ß / TSLP-forhold.
Antal / procentdel af eosinophiler og neutrofiler i luftvejs submucosa, sputum og blod.
Celleantallet af følgende typer:
- Mastceller
- Eosinofile
- neutrofiler
- PDC s |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Bronchoscopy at V2 and V7
Sputum at: V1 and V6. |
Bronkoskopi ved V2 og V7
Sputum ved V1 og V6. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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