Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent VLP Vaccine

Healthy Volunteers Clinical Trial

— NOR-107  

Official title:

A Phase II, Randomized, Controlled, Double-Blind, Dosage and Adjuvant Justification, Safety and Immunogenicity Trial of Intramuscular Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine Adjuvanted With or Without Monophosphoryl Lipid A and Aluminum Hydroxide in Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02038907
• Other study ID #: NOR-107
• Secondary ID: 2013-001419-64U1
• Status: Completed
• Phase: Phase 2
• First received: January 15, 2014
• Last updated: August 4, 2017
• Start date: March 28, 2014
• Est. completion date: June 19, 2015

Study information

• Verified date: August 2017
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to select the optimal formulation of the norovirus vaccine from different concentrations of virus-like particles (VLP), Aluminum Hydroxide and MPL adjuvant (3-O-desacyl-4'-monophosphoryl lipid A) for further development.

Description:

The vaccine being tested in this study is called norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine adjuvanted with aluminum hydroxide and with or without monophosphoryl lipid A (MPL). The norovirus vaccine is being tested to assess different formulations of the vaccine that will then be further developed.

This study will look at the number of antibodies to norovirus formed in people who take different formulations of the norovirus vaccine. The study will enroll approximately 420 patients. Participants will be randomly assigned (by chance) to one of fourteen treatment groups—which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need).

All participants will receive a vaccination on Day 1 and Day 28 of the study. Some treatment arms will receive one dose of the norovirus vaccine and some arms will receive two. In order to keep the treatment arms undisclosed to the patient and the doctor, those randomized to the one dose groups will receive a dose of Hepatitis A vaccine on Day 1 followed by the norovirus vaccine 28 days later. Participants will be asked to record any symptoms that may be related to the vaccine or the injection site in a diary card for 7 days after each vaccination.

This multi-centre trial will be conducted in Belgium. The overall time to participate in this study is up to 393 days. Participants will make 6 visits to the clinic, and will be contacted by telephone twice for follow-up assessments.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 420
• Est. completion date: June 19, 2015
• Est. primary completion date: June 19, 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 64 Years

Eligibility

Inclusion Criteria:

1. Male and female participants between 18 and 64 years of age at the time of enrollment.

2. In good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs), and clinical judgment of the investigator.

3. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.

4. Can comply with trial procedures and are available for the duration of the trial.

Exclusion Criteria:

1. Has received any vaccines containing Hepatitis A vaccine within the past 5 years.

2. Has contraindications, warnings, and/or precautions to vaccination with Havrix as specified within the Summary of Product Characteristics.

3. Has a clinically significant active infection (as assessed by the investigator) or oral body temperature 38°C (100.4°F) or higher within 3 days of the intended date of vaccination.

4. Has received antipyretic/analgesic medications within 24 hours prior to the intended vaccine administration.

5. Known hypersensitivity or allergy to investigational vaccine (including excipients of the investigational vaccine).

6. Has behavioral or cognitive impairment or psychiatric disease that, in the opinion of the investigator, may interfere with the participant's ability to participate in the trial.

7. Has a history of any progressive or severe neurologic disorder, seizure disorder, or Guillain-Barré syndrome.

8. Has history of any illness that, in the opinion of the investigator, might interfere with the results of the trial or pose additional risk to the participants due to participation in the trial.

9. Known or inspected impairment/alteration of immune function, including the following:

1. Chronic use of oral steroids (Equivalent to 20 mg/day prednisone for =12 weeks/=2 mg/kg body weight/day for =2 weeks) within 60 days prior to Day 1 (use of inhaled, intranasal, or topical corticosteroids is allowed).

2. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone =12 weeks/=2 mg/kg body weight/day for =2 weeks) within 60 days prior to Day 1.

3. Receipt of immunostimulants within 60 days prior to Day 1.

4. Receipt of parenteral, epidural, or intra-articular immunoglobulin preparation, blood products, and/or plasma derivatives within 3 months prior to Day 1 or planned during the full length of the trial.

5. Receipt of immunosuppressive therapy within 6 months prior to Day 1.

6. Human immunodeficiency virus (HIV) infection or HIV-related disease.

7. Heritable immunodeficiency.

10. Abnormalities of splenic or thymic function.

11. Has a known bleeding diathesis or any condition that may be associated with a prolonged bleeding time.

12. Has any serious chronic or progressive disease according to judgment of the investigator (eg, neoplasm, insulin dependent diabetes, cardiac, renal, or hepatic disease).

13. Has a body mass index (BMI) greater than or equal to 35 kg/m^2 (=weight in kg/[height in meters * height in meters]).

14. Is participating in any clinical trial with another investigational product 30 days prior to first trial visit or intent to participate in another clinical trial at any time during the conduct of this trial.

15. Has received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of investigational vaccine administration.

16. Is first degree relatives of individuals involved in trial conduct.

17. Has history of substance or alcohol abuse within the past 2 years.

18. If female, of childbearing potential, sexually active, and has not used any of the acceptable contraceptive methods for at least 2 months prior to trial entry.

19. Female participants of childbearing potential and sexually active, who refuse to use an acceptable contraceptive method from Day 1 through 6 months after the last dose of investigational vaccine.

20. Female participants who plan to donate ova from Day 1 through 6 months after the last dose of investigational vaccine.

21. Female participants with any positive pregnancy test.

22. Female participants who are pregnant or breastfeeding.

Related Conditions & MeSH terms

• Healthy Volunteers
• Norovirus, Prevention

Intervention

Biological:
• Hepatitis A Vaccine
Hepatitis A Vaccine IM injection
• Norovirus Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine IM injection

Locations

Country	Name	City	State
Belgium	Universiteit Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With a Seroresponse (Pan-Ig ELISA)	Seroresponse was defined as 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).	Baseline and Day 56
Primary	Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site After Dose 1	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occurred within 7 days after each vaccination.	Days 1 through 7
Primary	Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site After Dose 2	Solicited local AEs at injection site are defined as: pain, erythema, induration, and swelling that occurred within 7 days after each vaccination.	Days 28 through 34
Primary	Percentage of Participants With Solicited Systemic Adverse Events (AEs) After Dose 1	Solicited systemic AEs are defined as: headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea that occurred within 7 days after each vaccination.	Days 1 through 7
Primary	Percentage of Participants With Solicited Systemic Adverse Events (AEs) After Dose 2	Solicited systemic AEs are defined as: headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea that occurred within 7 days after each vaccination.	Days 28 through 34
Primary	Oral Body Temperature Within 7 Days After Dose 1	Oral body temperature measurement is to be performed using the thermometer provided by the site for 7 days after each vaccination. The highest body temperature observed each day will be recorded on the Diary Card also provided by the site.	Days 1 through 7
Primary	Oral Body Temperature Within 7 Days After Dose 2	Oral body temperature measurement is to be performed using the thermometer provided by the site for 7 days after each vaccination. The highest body temperature observed each day will be recorded on the Diary Card also provided by the site.	Days 28 through 34
Primary	Percentage of Participants With Unsolicited Adverse Events (AEs)	Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study.	Day 1 up to Day 56
Primary	Percentage of Participants With Serious Adverse Events (SAEs)	A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.	Day 1 up to Day 393
Secondary	Percentage of Participants With a Seroresponse on Day 28, Day 208 and Day 393 (Pan-Ig ELISA)	Seroresponse was defined as 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 virus-Like particle (VLP) and GII.4 VLP as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).; D=Day	Baseline and Days 28, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in GI.1 VLP Antibody Titer (Pan-Ig ELISA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-like particle (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in GII.4 VLP Antibody Titer (Pan-Ig ELISA)	The percentage of participants with a 4-fold rise or greater from in serum anti-norovirus antibody titers for GII.4 virus-like particle (VLP) as measured by pan immunoglobulin (Pan-Ig) enzyme-linked immunosorbent assay (ELISA).; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Geometric Mean Titer (GMT) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GI.1 VLP antibody titers as measured by pan-Ig ELISA.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Geometric Mean Titer (GMT) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean titer (GMT) of anti-norovirus GII.4 VLP antibody titers as measured by pan-Ig ELISA.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by pan-Ig ELISA.; D=Day	Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (Pan-Ig ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by pan-Ig ELISA.; D=Day	Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GI.1 VLP and GII.4 VLP Antibody Titers (IgA ELISA)	Percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 VLP and GII.4 VLP as measured by immunoglobulin A (IgA) enzyme-linked immunosorbent assay (ELISA) for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GI.1 VLP Antibody Titers (IgA ELISA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-like particle (VLP) as measured by immunoglobulin A (IgA) enzyme-linked immunosorbent assay (ELISA) for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GII.4 VLP Antibody Titers (IgA ELISA)	The percentage of participants with a 4-fold rise from or greater in serum anti-norovirus antibody titers for GII.4 virus-like particle (VLP) as measured by immunoglobulin A (IgA) enzyme-linked immunosorbent assay (ELISA) for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Geometric Mean Titer (GMT) of GI.1 VLP Antibody Titers (IgA ELISA)	Geometric mean titer (GMT) of anti-norovirus GI.1 VLP antibody titers as measured by IgA ELISA for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Geometric Mean Titer (GMT) of GII.4 VLP Antibody Titers (IgA ELISA)	Geometric mean titer (GMT) of anti-norovirus GII.4 VLP antibody titers as measured by IgA ELISA for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (IgA ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by IgA ELISA for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (IgA ELISA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by IgA ELISA for all arms on day 28 and day 56 and for selected arms on day 208 and day 393.; D=Day	Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum Antibody Titers for GI.1 VLP and GII.4 VLP(HBGA)	Percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for both GI.1 VLP and GII.4 VLP as measured by histoblood group antigen (HBGA) binding assay.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GI.1 VLP Antibody Titers (HBGA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GI.1 virus-like particle (VLP) as measured by HBGA binding assay.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Percentage of Participants With a 4-Fold Rise or Greater in Serum GII.4 VLP Antibody Titers (HBGA)	The percentage of participants with a 4-fold rise or greater in serum anti-norovirus antibody titers for GII.4 virus-like particle (VLP) as measured by HBGA binding assay.; D=Day	Baseline and Days 28, 56, 208 and 393
Secondary	Blocking Titers 50 (BT50) of Anti-Norovirus GI.1 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GI.1 VLP antibody titers as measured by HBGA binding assay.; D=Day	Baseline (Day 1) and Days 28, 56, 208 and 393
Secondary	Blocking Titers 50 (BT50) of GII.4 VLP Antibody Titers (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GII.4 VLP antibody titers as measured by HBGA binding assay.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GI.1 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GI.1 VLP antibody titers as measured by HBGA binding assay.; D=Day	Days 28, 56, 208 and 393
Secondary	Geometric Mean Fold Rise (GMFR) of GII.4 VLP Antibody Titers (HBGA)	Geometric mean fold rise (GMFR) of anti-norovirus GII.4 VLP antibody titers as measured by the HBGA binding assay.; D=Day	Days 28, 56, 208 and 393
Secondary	GMFR of Antibody Titers of a Strain Not Represented in the Investigational Vaccine: GII.4 Cincinnati (HBGA)	GMFR of anti-norovirus GII.4 Cincinnati antibody titers as measured by HBGA binding assay.; D=Day	Days 28, 56, 208 and 393
Secondary	GMFR of Antibody Titers of a Strain Not Represented in the Investigational Vaccine: GII.4 Sydney (HBGA)	GMFR of anti-norovirus GII.4 Sydney antibody titers as measured by HBGA binding assay.; D=Day	Days 28, 56, 208 and 393
Secondary	GMFR of Antibody Titers of Strains Not Represented in the Investigational Vaccine: Cross-Protection Assays	GMFR of anti-norovirus Cross-Protection Assays: GII.2 EC50, GI.3 EC50 and GII.4.2012 EC50 antibody titers as measured by HBGA binding assay. Data was collected for selected arms only.; D=Day	Day 56
Secondary	Blocking Titers 50 (BT50) of a Strain Not Represented in the Investigational Vaccine: GII.4 Cincinnati (HBGA)	Blocking titers 50 (BT50) of anti-norovirus GII.4 Cincinnati antibody titers as measured by HBGA binding assay.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Blocking Titers 50 (BT50) of a Strain Not Represented in the Investigational Vaccine: GII.4 Sydney (HBGA)	Blocking Titers 50 (BT50) of anti-norovirus GII.4 Sydney antibody titers as measured by HBGA binding assay.; D=Day	Day 1 (Baseline) and Days 28, 56, 208 and 393
Secondary	Blocking Titers 50 (BT50) of a Strain Not Represented in the Investigational Vaccine: Cross-Protection Assay: GII.2 EC50 (HBGA)	Blocking titers 50 (BT50) of anti-norovirus Cross-Protection Assay: GII.2 EC50 antibody titers as measured by HBGA binding assay. Data was collected for selected arms only.; D=Day	Day 1 (Baseline) and Day 56
Secondary	Blocking Titers 50 (BT50) of a Strain Not Represented in the Investigational Vaccine: Cross-Protection Assay: GI.3 EC50 (HBGA)	Blocking titers 50 (BT50) of anti-norovirus Cross-Protection Assay: GI.3 EC50 antibody titers as measured by HBGA binding assay. Data was collected for selected arms only.; D=Day	Day 1 (Baseline) and Day 56
Secondary	Blocking Titers 50 (BT50) of a Strain Not Represented in the Investigational Vaccine: Cross-Protection Assay: GII.4.2012 EC50 (HBGA)	Blocking titers 50 (BT50) of anti-norovirus Cross-Protection Assay: GII.4.2012 EC50 antibody titers as measured by HBGA binding assay. Data was collected for selected arms only.; D=Day	Day 1 (Baseline) and Day 56
Secondary	Percentage of Participants With Significant New Medical Conditions	Significant new medical conditions will be evaluated by the investigator for the co-existence of any of the following conditions: Adverse events of special interest (AESIs) are predefined events for potential immune mediated disorders. All AESIs are medically evaluated to assess if they might indicate an immune-mediated disorder.; Immune mediated events (IMEs) are AEs that represent a new diagnosis of a chronic medical condition that was not present or suspected prior to enrollment.	Day 1 up to Day 56
Secondary	Percentage of Participants With Any Adverse Event (AE) Leading to Withdrawal From the Study	Withdrawal due to an AE will occur if the participant experiences an AE that requires early termination because continued participation imposes an unacceptable risk to the participant's health or the participants is unwilling to continue because of the AE.	Day 1 up to Day 56