Two Doses of GHB04L1 for Pandemic Influenza Prophylaxis in Healthy Adults

Study Overview
=================
Brief Summary
-----------------
This study evaluates safety, tolerability and immunogenicity of two doses of GHB04L1, a liquid formulation of the replication- deficient influenza A/Vietnam/1203/04(H5N1)-like ∆NS1 virus in healthy adults. Subjects are randomised at a ratio of 2:1 for GHB04L1 (6.8 log10 or 7.5 log10 TCID50/dose/volunteer) or placebo.

Detailed Description
-----------------
GHB04L1 is intended to provide a novel treatment approach for influenza virus H5N1 infection. Based on preclinical data from ferrets that demonstrated protection against challenge with wild-type virus following treatment with various dose levels of GHB04L1, vaccination with GHB04L1 might protect humans from influenza A (H5N1) virus infection. Due to the lack of the NS1 protein, the ΔNS1 virus replicates efficiently in interferon-deficient cells but has lost its ability to grow in normal hosts and organisms. Immunisation with ΔNS1 mutant virus can cause only an abortive replication cycle in the nasal mucosa of vaccinated individuals. This allows development of replication-deficient intranasal vaccines with genetic stability of the attenuated phenotype and without virus shedding.

Official Title
-----------------
Randomised, Double-blind, Placebo-controlled, Phase I Dose- Escalation Study of Two Doses GHB04L1 in Healthy Adults

Conditions
-----------------
Influenza, Avian

Intervention / Treatment
-----------------
* Biological: GHB04L1
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female healthy volunteers, 18-50 years of age Seronegative for H5N1 (with antibody titres <1:10 detected in HAI assay) Seronegative for H1N1 (with antibody titres ≤1:20 detected in HAI assay) Written informed consent to participate in this study Exclusion Criteria: Acute febrile illness (>37.0°C) Positive influenza immunoassay at baseline Signs of acute or chronic upper or lower respiratory tract illnesses (sneezing, cough, tonsillitis, otitis, etc.) History of severe atopy Influenza vaccination 2006/2007 and/or later Known increased tendency of nose bleeding Volunteers with clinically relevant abnormal paranasal anatomy Volunteers with clinically relevant abnormal laboratory values Females with positive urine pregnancy test prior to vaccination Simultaneous treatment with immunosuppressive drugs incl. corticosteroids (≥ 2 weeks) within 4 weeks prior to study medication application Clinically relevant history of renal, hepatic, GI, cardiovascular, haematological, skin, endocrine, neurological or immunological diseases History of leukaemia or cancer HIV or hepatitis B or C seropositivity Volunteers who had undergone rhino or sinus surgery or surgery of another traumatic injury of the nose within 30 days prior to application of study medication Volunteers who had received antiviral drugs, treatment with immunoglobulins or blood transfusions or an investigational drug within four weeks prior to study medication application Volunteers who had received anti-inflammatory drugs 2 days prior to study medication application Volunteers who were not likely to cope with the requirements of the study or with a significant physical or mental condition that may interfere with the completion of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GHB04L1<br>GHB04L1 is administered as intranasal aerosol at a dose of 6.8 log10 or 7.5 log10 TCID50/dose/subject on day 1 and on day 29. | Biological: GHB04L1<br>* Solution<br>|
| Placebo Comparator: Placebo<br>Placebo (buffer) is administered as intranasal aerosol on day 1 and on day 29. | Other: Placebo<br>* Buffer solution<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of adverse events | Occurrence of local and systemic adverse events overall and within 7 days after each study medication administration | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral shedding | Presence of GHB04L1 in mucosal samples from the nose | 3 days | 
| Local immune response | Local influenza A virus-specific immune response (IgA) in mucosal samples from the nose | 8 weeks | 
| Local cytokines response | Local cytokines response in mucosal samples from the nose | 3 days | 
| Systemic influenza A virus-specific antibody response | Systemic influenza A virus-specific antibody response determined by haemagglutination-inhibition assay (HAI) and micro-neutralisation assay (MNA) in serum samples | 8 weeks | 
| Systemic influenza A virus-specific T-cell response | Systemic influenza A virus-specific T-cell response determined by T-cell proliferation assay in blood samples | 8 weeks | 
| Systemic natural killer cell cytotoxicity | Systemic natural killer cell cytotoxicity in blood samples | 5 weeks | 
| Systemic T-cell Granzyme B assay | Systemic T-cell Granzyme B assay in blood samples | 8 weeks |