Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A

Influenza Clinical Trial

Official title:

A Randomized Double-Blind, Phase 3 Study Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Teatment of Severe Influenza A

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02610478
• Other study ID #: 160022
• Secondary ID: 16-I-0022
• Status: Enrolling by invitation
• Phase: Phase 3
• First received: November 19, 2015
• Last updated: October 18, 2017
• Start date: November 19, 2015
• Est. completion date: November 29, 2019

Study information

• Verified date: September 26, 2017
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

Most people infected with the influenza virus have mild symptoms. But some get very sick and even die. Antibodies in the part of the blood called plasma fight germs like influenza. Researchers want to see if plasma with high levels of antibodies helps more than plasma with low levels when transfused into people with influenza. They have plasma from people with high levels of antibodies from being infected with influenza or getting the influenza vaccine. They also have plasma with low or no antibodies.

Objective:

To see if plasma with high levels of antibodies works better than plasma with low levels to treat influenza.

Eligibility:

People ages 2 weeks and older who are hospitalized for symptoms of influenza

Design:

Participants will be screened with medical history and blood and urine tests. They may have a nasal wash test for influenza. For this, they get a saline rinse in one nostril. A plastic tube inserted in the nostril collects fluid.

The study lasts 28 days.

Participants will get routine influenza care. This includes standard drugs and possible chest x-rays.

On Day 1, participants will have:

Physical exam

Blood tests

Throat swab

2 doses of plasma with high antibodies or low antibodies by IV catheter (tube) in a vein.

On Days 3 and 7, participants will return to the clinic, if no longer hospitalized, for 1-hour visits. The visits include:

Medical exam

Blood tests

Throat swab

On Days 2, 14, and 28, participants will be evaluated either at the clinic or by phone. They will talk about their symptoms.

Description:

Significant morbidity and mortality from influenza infections occur despite treatment with current antivirals. This randomized, double-blinded, multicenter phase 3 trial will assess the efficacy and safety of high-titer versus low-titer anti-influenza immune plasma in addition to standard care antivirals for the treatment of severe influenza A. Hospitalized subjects with severe influenza A will be eligible for study participation. Up to 40 sites in the United States will participate in this protocol. Adults and children may participate. There is no exclusion for pregnancy.

A total of 150 eligible subjects will be randomized in a 2:1 ratio to receive either high-titer anti-influenza plasma or control (low-titer) plasma. All plasma is from male donors to minimize the risk of TRALI.

Subjects will be assessed on Study Day 0 (baseline) and on Study Days 1, 2, 3, 7, 14, and 28. For participants who are not hospitalized on Days 2, 14, and 28, contact with the participant for the purpose of limited study data collection for those days may be performed by telephone. Study visits on Days 1, 3, 7 must occur in person. All subjects will undergo a series of efficacy, safety, and HAI assessments during the study. Blood samples will be collected on Day 0, 1, 3, and 7. OP swabs for influenza PCR will be obtained on Days 0 and 3.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 300
• Est. completion date: November 29, 2019
• Est. primary completion date: November 30, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

• ELIGIBILITY CRITERIA:

INCLUSION CRITERIA FOR ENROLLMENT (SCREENING):

• Hospitalization due to signs and symptoms of influenza (decision for hospitalization will be up to the individual treating clinician).

• Study plasma available on-site or available within 24 hours after randomization.

• Not previously screened nor randomized in this study.

• Willingness to have blood and respiratory samples obtained and stored.

• Willingness to return for all required study visits and participate in study follow up.

INCLUSION CRITERIA FOR RANDOMIZATION:

• Locally determined positive test for influenza A (by PCR, other nucleic acid testing, or by rapid Ag) from a specimen obtained less than or equal to 48 hours prior to randomization.

• Onset of illness less than or equal to 6 days before randomization, defined as when the subject first experienced at least one respiratory symptom or fever.

• Hospitalized due to influenza, with anticipated hospitalization for more than 24 hours after randomization. Criteria for hospitalization will be up to the individual treating clinician.

• NEW or PEW score greater than or equal to 3 within 12 hours prior to randomization.

• ABO-compatible plasma available on-site or available within 24 hours after randomization.

EXCLUSION CRITERIA FOR RANDOMIZATION:

Subjects who meet any of the following criteria will be excluded from study participation:

• Strong clinical evidence in the judgment of the site investigator that the etiology of illness is primarily bacterial super-infection in origin. Co-infection would be allowed, as there may be benefit to resolving influenza illness faster. Super-infection, where influenza illness occurred and is resolving, and new bacterial illness causing deterioration should be excluded. (e.g., if the subject's respiratory infection is thought unlikely to benefit from additional antiviral therapy, this exclusion criteria would be met).

• Prior treatment with any anti-influenza investigational drug, anti-influenza investigational IVIG, or anti-influenza investigational plasma therapy within 30 days prior to screening. Other investigational drug therapies (non-influenza) and administration of plasma and/or IVIG for non-influenza reasons are allowed.

• History of allergic reaction to blood or plasma products (as judged by the site investigator).

• A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the individual at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy). Prior IVIG use alone would not meet exclusion criteria, but the investigator should consider the potential for a hyper-coagulable state.

• Subjects who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol, including being uncontactable following discharge from hospital.

• Medical conditions for which receipt of 450-700 mL of intravenous fluid may be dangerous to the subject (e.g., decompensated congestive heart failure).

• Women that are pregnant or actively breast feeding (NIH site).

Related Conditions & MeSH terms

• Influenza
• Influenza, Human

Intervention

Biological:
• High-Titer Plasma
2 units of human plasma (FFP or FP24, 250-350 mL per unit, or pediatric equivalent) with influenza A/H1N1 and A/H3N2 HAI titers of at least 1:80.
• Low-Titer Plasma
2 units of human plasma (FFP or FP24, 250-350 mL per unit, or pediatric equivalent) with influenza A/H1N1 and A/H3N2 HAI titers of 1:10 or less.

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (3)

de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y, Peiris JS, Tran TH, Farrar J. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005 Dec 22;353(25):2667-72. — View Citation

Hung IFN, To KKW, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CCY, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013 Aug;144(2):464-473. doi: 10.1378/chest.12-2907. — View Citation

Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med. 2006 Oct 17;145(8):599-609. Epub 2006 Aug 29. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Subjects clinical status: non-ICU hospitalization, requiring supplemental oxygen or non-ICU hospitalization, not requiring supplemental oxygen		at Day 7
Primary	Subjects clinical status: death		at Day 7
Primary	Subjects clinical status: not hospitalized, but unable to resume normal activities or not hospitalized with full resumption of normal activities.		at Day 7
Secondary	Clinical Status		Day 1, 2, 3, 14, and 28
Secondary	Duration of initial hospitalization		Date of discharge from the hospital
Secondary	Mortality		Day 28

External Links

•   NIH Clinical Center Detailed Web Page