H-IVIG Treatment for Severe H1N1 2009

Study Overview
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Brief Summary
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Treatment with hyperimmune intravenous immunoglobulin (H-IVIG), derived from convalescent plasma from patients recovered from H1N1 2009 influenza A infection, for patients with severe H1N1 2009 infection will decrease mortality, reduce viral load, and shorten the length of stay in ICU and hospital.

Detailed Description
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Since the emergence of the novel swine origin influenza A virus (H1N1 2009) in Mexico in March 2009, the virus has led to a pandemic in over 170 countries, resulting in over 180 thousands microbiologically confirmed cases and over 18000 mortality. This strain represents a quadruple re-assortment of two swine strains, one human strain, and one avian strain of influenza. Although the H1N1 2009 is causing a mild disease and has a relatively low mortality rate currently in Hong Kong, severe cases have been reported. Patients infected with severe H1N1 2009 have overwhelmed the intensive care services in these countries and the mortality has rose up to 6% in Argentina and Brazil, and 0.4% in Australia. This is very much higher than the 0.06% mortality rate of the seasonal flu. Furthermore, there were reports of H1N1 2009 oseltamivir resistance and zanamivir is difficult to be delivered to the consolidated lungs in the severe cases when such drug is most needed. In Hong Kong, vaccination for the H1N1 2009 was prioritised to the older people aged 65 or above with chronic illness, younger people with chronic illness and health care workers. The healthy adults aged 18 to 65, who are most at risk of developing severe H1N1 2009 was not covered by the vaccination program. Experience from 1918 H1N1 pandemic and single case report on the treatment for severe H5N1 infection (Zhou et al. 2007) showed that hyperimmune convalescent plasma is useful (Luke et al. 2006). Mice experiments also showed that antibody therapy is highly effective in the case of H5N1 infection (Heltzer ML et al. 2009, Writing Committee of the Second World Heath Organization, 2008). Therefore, convalescent plasma from patients recovered from H1N1 2009 infection can be harvested to prepare for hyperimmune intravenous immunoglobulin (H-IVIG) and the prepared H-IVIG can be assessed in a randomised controlled trial for treatment of patients with severe H1N1 2009 infection.

Official Title
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Hyperimmune Intravenous Immunoglobulin Treatment for Severe H1N1 2009 Infection

Conditions
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Novel 2009 Influenza A (H1N1) Infection

Intervention / Treatment
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* Drug: Hyperimmune intravenous immunoglobulin
* Drug: Intravenous immunoglobulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: (fulfill all criteria): male or female patients 18 years or older written informed consent by patient or next of kin (if patients too ill) diagnosis of H1N1 2009 infection satisfying both clinical and laboratory criteria: Laboratory criteria: at least one RT-PCR positive for H1N1 2009 from one of the clinical specimens (NPA, ETA, blood, urine or stool). Clinical criteria: patients admitted to ICU with severe community acquired pneumonia as defined by a CURB-65 score of 3 or more deterioration during treatment with optimal antiviral (oral or inhaler agents only) and typical and atypical antimicrobial coverage required ICU and ventilatory support and within 7 days onset of symptoms. Exclusion Criteria: age below 18 years known hypersensitivity to immune globulin or any components of the formulation known IgA deficiency acquire the H1N1 2009 infection from health care facility moribund patients or refusal of informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intravenous immunoglobulin<br>Single intravenous infusion of 0.4g/kg of simple IVIG which contain no H1N1 2009 antibody (manufactured before 2009). | Drug: Intravenous immunoglobulin<br>* Single intravenous infusion of 0.4g/kg of simple IVIG<br>* Other names: IVIG;|
| Experimental: Hyperimmune intravenous immunoglobulin<br>Single intravenous infusion of 0.4g/kg of H1N1 2009 H-IVIG fractionated from convalescent plasma (H1N1 2009 antibody titer was 1:320 by hemagglutination inhibition and neutralizing antibody assays) | Drug: Hyperimmune intravenous immunoglobulin<br>* Single intravenous infusion of 0.4g/kg of H1N1 2009 H-IVIG<br>* Other names: H-IVIG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | From date of randomization until the date of death from any cause during hospitalization, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | To assess the safety of H-IVIG and IVIG treatment | From date of randomization until the date of first documented adverse events due to treatment, assessed up to 1 week | 
| ICU length of stay |  | Participants will be followed for the duration of ICU stay, an expected average of 4 weeks | 
| Hospital length of stay |  | Participants will be followed for the duration of hospital stay, an expected average of 12 weeks | 
| Nasopharyngeal viral load | To assess the change in nasopharyngeal viral load one day before randomization and 5 days after treatment | One day before randomization and up to 5 days after treatment | 
| Cytokine/ chemokine | To assess the change in cytokine/ chemokine response one day before randomization and 5 days after treatment | One day before randomization and up to 5 days after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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H1N1 2009, hyperimmune IVIG, mortality, length of stay, viral load, cytokine