Development of Immune Globulin Treatment for Avian Flu

A Phase II Vaccine Dose Finding Pilot Study for Development of an Anti-Influenza A (H5N1) Intravenous Hyper-Immune Globulin

This study will determine how best to use a vaccine for generating high levels of antibodies called immune globulins (IVIG) in people, which, in turn, can be collected and used to develop a possible treatment for avian influenza (bird flu). Immune globulins are proteins made by the body that attack the influenza virus. This study will use an experimental bird flu vaccine to stimulate immune globulin production in healthy people. The vaccine is similar to the regular influenza vaccine and has been studied in more than 450 people. This study will use high doses of the vaccine to generate high antibody levels that can be collected for producing the new treatment.

Healthy adults between 18 and 60 years of age who weigh at least 110 pounds may be eligible for this study. Candidates are screened with a medical history and physical examination.

Participants are given one of three doses of the vaccine, depending on when they enter the study. The first 25 people enrolled receive a dose of 90 micrograms (mcg). If this dose is well tolerated, the next 25 people receive 120 mcg, and if this dose is also well tolerated, the last 25 people receive 180 mcg. Vaccination consists of either two shots (one in the muscle of each arm) or one shot in the buttock on four occasions. Subjects are vaccinated on four occasions, each 4 weeks apart. On the day of each vaccination, subjects provide a blood sample to evaluate blood counts, chemistries, and antibody levels, and to test for HIV, hepatitis B and C, syphilis, and antibody against avian flu. For 7 days after each vaccination, subjects keep a diary card to record any symptoms, such as pain, fever, muscle aches, or others. At the end of the 7 days, they are contacted by study staff to report the symptoms.

In addition to the vaccinations, subjects undergo apheresis to collect IVIG once their blood test shows moderately high antibody levels. For this procedure, blood is collected through a needle in an arm vein and flows through a catheter (plastic tube) into a machine that separates the blood cells from the antibodies and protein. The antibodies and protein are collected and the rest of the blood is returned to the body. Subjects are asked to undergo at least three apheresis procedures.

...

Study Overview

• Status: Terminated
• Conditions: Influenza; Infectious Diseases; Avian Flu
• Intervention / Treatment: Biological: H5N1 vaccine; Procedure: Apheresis

Detailed Description

Avian influenza presents a threat of a future pandemic. Over 200 people have been infected with the influenza A H5N1 virus, and the mortality is near 60 percent. Optimal therapy is not known, and failures of and resistance to currently available anti-virals have been reported.

The primary purpose of this Protocol is to determine the optimal vaccination schedule that creates a pool of hyper immunized individuals with high titer anti-influenza A (H5N1) antibodies. The Protocol will consist of a dose escalation study to determine the optimal vaccination dose and number of vaccinations. There are stopping rules based on the number and severity of adverse events that occur between the doses and between the cohorts. The optimal vaccination schedule that is determined could then be used in a larger population to develop a high titer anti-influenza A (H5N1) intravenous hyper-immune globulin (IVIG).

After all vaccinations have occured, and if an adequate antibody titer is reached in this study population, subjects will begin apheresis. Each subject will be asked to participate in 3 apheresis sessions, but may participate in up to 10 apheresis sessions.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Age ≥ 18 years old, and < 60 years old.

2. Adequate clinical parameters (all of the following):

   • Afebrile (temperature < 38° C)
   • Systolic blood pressure >100 & <180 mmHg
   • Diastolic blood pressure >50 & <100 mmHg
   • Heart rate between 40-100 beats/minute
3. Weight ≥ 110 pounds (50kg)
4. Adequate peripheral venous access for plasmapheresis (as judged by the examiner)

5. Females of child-bearing potential must (one of the following):

   • Be surgically sterile.
   • Be abstinent (or willing to be) 4 weeks prior to date of screening evaluation through the last apheresis session (estimate 6 months).
   • Use oral contraceptives, or other form of hormonal birth control including hormonal vaginal rings or transdermal patches, and have been using these for 3 months prior to date of screening evaluation through the last apheresis session (estimate 6 months).
   • Use an intra-uterine device (IUD) as birth control 4 weeks prior to date of screening evaluation through the last apheresis session (estimate 6 months).
   • Use (by ensuring her male partner(s) uses) barrier contraception (condom) with a spermicide as birth control 4 weeks prior to date of screening evaluation through the last apheresis session (estimate 6 months).

Exclusion Criteria:

1. Has a medical history of

   • Thrombocytopenia or other blood dyscrasias
   • congestive heart failure
   • pulmonary hypertension
   • bleeding diathesis or therapeutic anticoagulation
   • HIV/AIDS
   • Hepatitis B
   • Hepatitis C
   • Known history of hepatitis after the 11th birthday.
   • Trypanosomiasis (Chagas' disease and sleeping sickness)
   • Leishmaniasis (Kala-azar)
   • Filariasis
   • Q fever
   • Yaws
   • Allergy to eggs, thimerosal, or other components of the vaccine
   • Severe reactions following immunization with contemporary influenza virus vaccines
   • Autoimmune disease or a history of Guillain-Barré

2. History of cancer that meets any one of the following criteria:

   • Non-melanoma skin cancers within the last 1 year
   • Melanoma or any other cancer (excluding non-melanoma skin cancers) at any time

3. Medication history that includes any of the following:

   • Current use of oral or parenteral steroids, high-dose inhaled steroids (>800 mcg/day of beclomethasone dipropionate or equivalent) or other immunosuppressive or cytotoxic drugs
   • Finasteride (Proscar, Propecia) within the last 1 month.
   • Isotretinoin (Accutane) within the last 1 month.
   • Acitretin (Soriatane) within the last 3 years.
   • Etretinate (Tegison) at any time.
   • Dutasteride (Avodart) within the last 6 months.
   • Growth hormone made from human pituitary glands at any time.
   • Beef insulin from the United Kingdom at any time.

4. Has ever had any of the following:

   • Sexual contact with someone known to have HIV.
   • Had a relative with Creutzfeldt-Jakob Disease, or been told that this disease is inherited within the family.
   • Received blood transfusion in the United Kingdom.
   • History of receiving money, drugs or other payment for sex.
   • History of receiving clotting factor concentrates.
   • History of a dura mater graft.
   • History of babesiosis.
   • For male donors, history of sexual contact with another male.
   • Used needles to take drugs, steroids, or other medications not prescribed by a physician.
   • Was born, lived in, had blood donation in or ever had sexual contact with anyone who lived in Cameroon, Central African Republic, Chad, Congo, Equatorial Guinea, Gabon, Niger, or Nigeria after 1977.
   • History of living 3 or more months total (need not be consecutive) in the UK from 1980-1996.
   • History of living 5 or more years total (need not be consecutive) in Europe since 1980.
   • History of living 6 or more months total (need not be consecutive) on a U.S. military base in Europe from 1980-1996 (specifically from 1980 through 1990 in Belgium, the Netherlands, or Germany, and from 1980 through 1996 in Spain, Portugal, Turkey, Italy or Greece).
5. Within the last 3 weeks received the seasonal (conventional trivalent) flu vaccine

6. Within the last 8 weeks:

   • Was vaccinated with the small pox vaccine, or was in close contact with someone who was vaccinated (i.e., close family member).

7. Within the last 3 months has:

   • Current or previous participation in any other apheresis procedures/protocols (not related to this protocol).

8. Within the last 4 months has had:

   • A blood donation of a double unit of red cells.

9. Within the last 12 months has:

   • Received any blood or blood component.
   • Donated blood at a paid donation center (donations at a hospital blood bank do not apply).
   • History of unsafe (multiple-use equipment) tattoo, acupuncture, or piercing practices.
   • Received an organ transplant.
   • Received a bone or skin graft.
   • Lived with someone who has any type of hepatitis.
   • Traveled to areas with malaria.
   • Been incarcerated for more than 72 hours.
   • Oral or inhalation use of illegal drugs (i.e. those not prescribed by a physician).
   • Had or has been treated (with or without confirmatory diagnosis) for syphilis or gonorrhea

10. Within the last 12 months has had sexual contact with (any of the following):

    • An individual having viral hepatitis.
    • A prostitute or anyone else who takes money or drugs or other payment for sex.
    • Anyone who has ever used needles to take drugs, steroids, or anything else not prescribed by their doctor.
    • Anyone who has hemophilia or has used clotting factor concentrates.
    • For females, a male who has ever had sexual contact with another male.

11. Participation in medical research that includes:

    • Protocols that are currently ongoing or will start during the duration of this study that require more than 100cc of blood to be given in any 6-week period of time.
    • Administration of any unlicensed drug within the last 3 months or during the duration of this study.
    • Administration of any unlicensed vaccine within the last 12 months or during the duration of this study.
12. Currently pregnant (if known).
13. Any condition that, in the opinion of the investigator, would render vaccination unsafe, would interfere with the antibody response or the evaluation of these responses, or would place the subject at increased risk of injury from apheresis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cohort 1; H5N1 vaccine - 90 mcg IM every 4 week x 4 doses Apheresis - if HAI titer above 1:160	Biological: H5N1 vaccine; Monovalent subvirion H5N1 vaccine (rgA/Vietnam/1203/2004) 90 mcg/mL Manufactured by Sanofi Pasteur Inc, Swiftwater, PA.; Procedure: Apheresis; Once subjects achieved a high antibody titer (>1:160), they could begin apheresis to collect plasma.
Active Comparator: Cohort 2; H5N1 vaccine - 120 mcg IM every 4 week x 4 doses Apheresis - if HAI titer above 1:160	Biological: H5N1 vaccine; Monovalent subvirion H5N1 vaccine (rgA/Vietnam/1203/2004) 90 mcg/mL Manufactured by Sanofi Pasteur Inc, Swiftwater, PA.; Procedure: Apheresis; Once subjects achieved a high antibody titer (>1:160), they could begin apheresis to collect plasma.
Active Comparator: Cohort 3; H5N1 vaccine - 180 mcg IM every 4 week x 4 doses Apheresis - if HAI titer above 1:160	Biological: H5N1 vaccine; Monovalent subvirion H5N1 vaccine (rgA/Vietnam/1203/2004) 90 mcg/mL Manufactured by Sanofi Pasteur Inc, Swiftwater, PA.; Procedure: Apheresis; Once subjects achieved a high antibody titer (>1:160), they could begin apheresis to collect plasma.
Active Comparator: Cohort 4; H5N1 vaccine - 180 mcg IM every 4 weeks x 2 doses, injection site randomized to either deltoid or gluteus Apheresis - if HAI titer above 1:160	Biological: H5N1 vaccine; Monovalent subvirion H5N1 vaccine (rgA/Vietnam/1203/2004) 90 mcg/mL Manufactured by Sanofi Pasteur Inc, Swiftwater, PA.; Procedure: Apheresis; Once subjects achieved a high antibody titer (>1:160), they could begin apheresis to collect plasma.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of H5N1 Vaccine as Measured by Adverse Events	The number of subjects experiencing adverse events after receiving H5N1 vaccine	Day 28, 56, 84

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: H. Clifford Lane, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. doi: 10.3201/eid0101.950102.
• 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. doi: 10.1056/NEJMoa054512.
• Chotpitayasunondh T, Ungchusak K, Hanshaoworakul W, Chunsuthiwat S, Sawanpanyalert P, Kijphati R, Lochindarat S, Srisan P, Suwan P, Osotthanakorn Y, Anantasetagoon T, Kanjanawasri S, Tanupattarachai S, Weerakul J, Chaiwirattana R, Maneerattanaporn M, Poolsavathitikool R, Chokephaibulkit K, Apisarnthanarak A, Dowell SF. Human disease from influenza A (H5N1), Thailand, 2004. Emerg Infect Dis. 2005 Feb;11(2):201-9. doi: 10.3201/eid1102.041061.
• Lu H, Khurana S, Verma N, Manischewitz J, King L, Beigel JH, Golding H. A rapid Flp-In system for expression of secreted H5N1 influenza hemagglutinin vaccine immunogen in mammalian cells. PLoS One. 2011 Feb 28;6(2):e17297. doi: 10.1371/journal.pone.0017297.
• Beigel JH, Voell J, Huang CY, Burbelo PD, Lane HC. Safety and immunogenicity of multiple and higher doses of an inactivated influenza A/H5N1 vaccine. J Infect Dis. 2009 Aug 15;200(4):501-9. doi: 10.1086/599992.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: August 1, 2006
• Primary Completion (Actual): March 1, 2010
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: September 29, 2006
• First Submitted That Met QC Criteria: September 29, 2006
• First Posted (Estimate): October 2, 2006

Study Record Updates

• Last Update Posted (Actual): July 31, 2018
• Last Update Submitted That Met QC Criteria: July 2, 2018
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: HV; Healthy Volunteer; Healthy Volunteers; Apheresis; Avian Flu; Infectious Diseases; IVIG
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Disease Attributes; Orthomyxoviridae Infections; Infections; Communicable Diseases; Influenza, Human; Influenza in Birds
• Other Study ID Numbers: 06-I-0235; 060235 (Other Identifier: NIH Protocol Services)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No