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Safety and Immunogenicity of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in an Elderly Population

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02661490
Recruitment Status : Completed
First Posted : January 22, 2016
Results First Posted : May 18, 2020
Last Update Posted : May 18, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to further develop a formulation and dose regimen of the norovirus GI.1/GII.4 bivalent virus-like particle (VLP) vaccine that is immunogenic and safe in an elderly population aged 60 years and above.

Condition or disease Intervention/treatment Phase
Norovirus Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine Drug: 0.9% sodium chloride (saline) Phase 2

Detailed 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 (Formulation A) or adjuvanted with monophosphoryl lipid A (MPL) and aluminum hydroxide (Formulation B). Two norovirus vaccine formulations are being tested to select for further development the formulation that will generate an optimal specific antibody response that may provide protection against norovirus and is safe in a population aged 60 years and above. This study will look at side effects and the level of antibodies to norovirus formed in people who will be injected with different formulations of the norovirus vaccine candidate.

The study will enroll approximately 325 patients. Participants will be randomly assigned (by chance) to one of five treatment groups.

  • Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants ≥ 60 years
  • Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 2-dose, participants ≥ 60 years
  • Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 1-dose, participants ≥ 60 years
  • Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation B) 2-dose, participants ≥ 60 years
  • Norovirus GI.1/GII.4 bivalent VLP vaccine (Formulation A) 1-dose, participants 18 to 49 years All participants in the age of 60 years and older will be administered either NoV vaccine (Formulation A or B) or placebo on Day 1 and NoV vaccine (Formulation A or B) on Day 29 of the study. 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 placebo (this is a saline solution that has no active ingredient) on Day 1 followed by the NoV vaccine on Day 29. Those randomized to 2 doses with receive the NoV vaccine on Day 1 and Day 29. In case of an urgent medical need a participant can be unblinded.

Adults aged 18 to 49 will receive placebo on Day 1 followed by NoV vaccine Formulation A on Day 29.

Participants will be asked to record any reactions/ symptoms that may be related or not to the vaccine in a diary card for 28 days after each vaccination.

This multi-center trial will be conducted in the United States of America. The overall time to participate in this study is up to 393 days. Participants will make multiple visits to the clinic including a final follow-up visit on Day 393.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 320 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase II, Randomized, Double-blind, Safety and Immunogenicity Trial of Norovirus GI.1/GII.4 Bivalent Virus-Like Particle Vaccine in Healthy Elderly Adults
Actual Study Start Date : February 1, 2016
Actual Primary Completion Date : October 28, 2016
Actual Study Completion Date : September 29, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm 1: NoV Vaccine Formulation A _1-Dose
Participants ≥ 60 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, intramuscularly (IM), on Day 1, followed by norovirus (NoV) GI.1 (15 μg)/GII.4 (50 μg) bivalent virus-like particle (VLP) vaccine (Formulation A), IM, on Day 29.
Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with aluminum hydroxide, without MPL for IM injection

Drug: 0.9% sodium chloride (saline)
norovirus bivalent placebo-matching vaccine

Experimental: Arm 2: NoV Vaccine Formulation A _2-Dose
Participants ≥ 60 years of age, 2-dose regimen: Norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine (Formulation A), IM, on Days 1 and 29.
Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with aluminum hydroxide, without MPL for IM injection

Experimental: Arm 3: NoV Vaccine Formulation B_1-Dose
Participants ≥ 60 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, IM on Day 1, followed by norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine with 15 μg monophosphoryl lipid A (MPL) (Formulation B), IM, on Day 29.
Drug: 0.9% sodium chloride (saline)
norovirus bivalent placebo-matching vaccine

Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with MPL and aluminum hydroxide for IM injection

Experimental: Arm 4: NoV Vaccine Formulation B_2-Dose
Participants ≥ 60 years of age, 2-dose regimen: Norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine with 15 μg MPL (Formulation B), IM, on Days 1 and 29.
Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with MPL and aluminum hydroxide for IM injection

Experimental: Arm 5: NoV Vaccine Formulation A_1-Dose
Participants 18 to 49 years of age, 1-dose regimen: Norovirus bivalent placebo-matching vaccine, IM, on Day 1, followed by norovirus GI.1 (15 μg)/GII.4 (50 μg) bivalent VLP vaccine (Formulation A), IM, on Day 29.
Biological: Norovirus GI.1/GII.4 Bivalent VLP Vaccine
Norovirus GI.1/GII.4 bivalent VLP vaccine adjuvanted with aluminum hydroxide, without MPL for IM injection

Drug: 0.9% sodium chloride (saline)
norovirus bivalent placebo-matching vaccine




Primary Outcome Measures :
  1. Percentage of Participants With a 4-Fold Rise or Greater in Serum Anti-norovirus Antibody Titers for Both GI.1 and GII.4 Virus Like Particles (VLP) as Measured by Histoblood Group Antigen (HBGA) Blocking Assay on Day 57 [ Time Frame: Day 57 ]
  2. Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site for 7-day Period (Including Day of Vaccination) After First Vaccination on Day 1 [ Time Frame: Within 7 days of first vaccination on Day 1 ]
    Solicited local AEs at the injection site that occurred within 7 days after each vaccination were collected using a diary and included pain, erythema swelling and induration.

  3. Percentage of Participants With Solicited Local Adverse Events (AEs) at Injection Site for 7-day Period (Including Day of Vaccination) After Second Vaccination on Day 29 [ Time Frame: Within 7 days of second vaccination on Day 29 ]
    Solicited local AEs at the injection site that occurred within 7 days after each vaccination were collected using a diary and included pain, erythema, swelling and induration.

  4. Percentage of Participants With Solicited Systemic Adverse Events (AEs) for 7-day Period (Including Day of Vaccination) After First Vaccination on Day 1 [ Time Frame: Within 7 days of first vaccination on Day 1 ]
    Solicited systemic AEs that occurred within 7 days after each vaccination were collected using a diary and included headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea.

  5. Percentage of Participants With Solicited Systemic Adverse Events (AEs) for 7-day Period (Including Day of Vaccination) After Second Vaccination on Day 29 [ Time Frame: Within 7 days of second vaccination on Day 29 ]
    Solicited systemic AEs that occurred within 7 days after each vaccination were collected using a diary and included headache, fatigue, myalgia, arthralgia, vomiting, and diarrhea.

  6. Percentage of Participants With Elevated Body Temperature ≥38°C (Defined as Fever) for 7-day Period (Including Day of Vaccination) After First Vaccination on Day 1 [ Time Frame: Within 7 days of first vaccination on Day 1 ]
    The body temperature measurement was performed using the thermometer for 7 days after each vaccination. The highest body temperature observed each day was recorded on the diary card. An elevated temperature is ≥ 38 °C or 100.4°F (considered as fever).

  7. Percentage of Participants With Elevated Body Temperature ≥38°C (Defined as Fever) for 7-day Period (Including Day of Vaccination) After Second Vaccination on Day 29 [ Time Frame: Within 7 days of second vaccination on Day 29 ]
    The body temperature measurement was performed using the thermometer for 7 days after each vaccination. The highest body temperature observed each day was recorded on the diary card. An elevated temperature is ≥ 38 °C or 100.4°F (considered as fever).

  8. Percentage of Participants With At Least One Unsolicited Adverse Event (AE) Within 28-days After First Vaccination on Day 1 [ Time Frame: Within 28 days of first vaccination on Day 1 ]
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

  9. Percentage of Participants With At Least One Unsolicited Adverse Event (AE) Within 28-days After Second Vaccination on Day 29 [ Time Frame: Within 28 days of second vaccination on Day 29 ]
    An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.

  10. Percentage of Participants With At Least One Serious Adverse Event (SAE) [ Time Frame: From first vaccination up to Day 393 ]
    An SAE is any untoward medical occurrence 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.


Secondary Outcome Measures :
  1. 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 HBGA Blocking Assay [ Time Frame: Days 8, 29, 36, 211 and 393 ]
  2. Percentage of Participants With a 4-Fold Rise or Greater in Serum Anti-norovirus GI.1 VLP Antibody Titers (HBGA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
  3. Percentage of Participants With a 4-Fold Rise or Greater in Serum Anti-norovirus GII.4 VLP Antibody Titers (HBGA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
  4. Geometric Mean Titer (GMT) GI.1 VLP Antibody Titers (HBGA) [ Time Frame: Baseline (Day 1), Days 8, 29, 36, 57, 211 and 393 ]
    GMT GI.1 VLP antibody titers measured by HBGA blocking assay are reported.

  5. GMT of Anti-norovirus GII.4 VLP Antibody Titers (HBGA) [ Time Frame: Baseline (Day 1), Days 8, 29, 36, 57, 211 and 393 ]
    GMT of anti-norovirus GII.4 VLP antibody titers measured by HBGA blocking assay are reported.

  6. Geometric Mean Fold Rise (GMFR) of Anti-norovirus GI.1 VLP Antibody Titers (HBGA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    GMFR of anti-norovirus GI.1 VLP antibody titers measured by HBGA blocking assay are reported. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.

  7. GMFR of Anti-norovirus GII.4 VLP Antibody Titers (HBGA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    GMFR of anti-norovirus GII.4 VLP antibody titers measured by HBGA blocking assay are reported. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.

  8. 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 Total Immunoglobulin-Enzyme-linked Immunosorbent Assay (Pan-Ig ELISA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    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 measured by Pan-Ig ELISA are reported.

  9. Percentage of Participants With a 4-Fold Rise or Greater in Serum Anti-norovirus GI.1 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    Percentage of participants with a 4-Fold rise or greater in serum anti-norovirus GI.1 VLP antibody titers measured by Pan-Ig ELISA are reported.

  10. Percentage of Participants With a 4-Fold Rise or Greater in Serum Anti-norovirus GII.4 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    Percentage of participants with a 4-fold rise or greater in serum anti-norovirus GII.4 VLP antibody titers measured by Pan-Ig ELISA are reported.

  11. GMT of Anti-norovirus GI.1 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Baseline (Day 1), Days 8, 29, 36, 57, 211 and 393 ]
    GMT of anti-norovirus GI.1 VLP antibody titers measured by Pan-Ig ELISA are reported.

  12. GMT of Anti-norovirus GII.4 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Baseline (Day 1), Days 8, 29, 36, 57, 211 and 393 ]
    GMT of anti-norovirus GII.4 VLP antibody titers measured by Pan-Ig ELISA are reported.

  13. GMFR of Anti-norovirus GI.1 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    GMFR of anti-norovirus GI.1 VLP antibody titers measured by Pan-Ig ELISA are reported. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.

  14. GMFR of Anti-norovirus GII.4 VLP Antibody Titers (Pan-Ig ELISA) [ Time Frame: Days 8, 29, 36, 57, 211 and 393 ]
    GMFR of anti-norovirus GII.4 VLP antibody titers measured by Pan-Ig ELISA are reported. The fold rise was calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level.

  15. Percentage of Participants With At Least One Adverse Event of Special Interest (AESI) [ Time Frame: From first vaccination up to Day 393 ]
    AESIs are AEs that are not solicited local or systemic AEs, they are predefined AEs that required close monitoring and prompt reporting to the sponsor. AESI included protocol specified Cardiac Disorders, Gastrointestinal Disorders, Immune System Disorders, Infections and Infestations, Musculoskeletal and Connective Tissue Diseases, Neuroinflammatory Disorders, Renal and Urinary Disorders, Skin Disorders, Thyroid Disorders, Vascular Disorders and Other Disorders.

  16. Percentage of Participants With At Least One Adverse Event (AE) Leading to Participant's Withdrawal From the Study [ Time Frame: From first vaccination up to Day 393 ]
    Withdrawal due to an AE will occur if the participant experiences an AE that requires early termination of treatment, because continued participation imposes an unacceptable risk to the participant's health or the participant is unwilling to continue because of the AE.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Is aged 18 to 49 years, or 60 years and older at the time of enrollment;
  2. Participants who are in good health, or in stable health status with no exclusionary medical or neuropsychiatric conditions 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. Participant signs and dates a written, Informed Consent Form (ICF) 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. Participants who can comply with trial procedures and are available for the duration of follow-up.

Exclusion Criteria:

  1. Has a known hypersensitivity or allergy to any of the Norovirus (NoV) GI.1/GII.4 Bivalent virus-like particle (VLP) Vaccine components;
  2. Has a clinically significant active infection (as assessed by the Investigator) or body temperature ≥38°C/100.4°F within 3 days of the intended date of vaccination;
  3. Participants with the presence of significant acute or chronic, uncontrolled medical or neuropsychiatric illness. Uncontrolled was defined as:

    Requiring institution of new medical or surgical treatment within 3 months prior to immunization, or Requiring a change in medication dosage in the 3 months prior to immunization due to uncontrolled symptoms or drug toxicity (elective dosage adjustments in stable participants were acceptable), or Hospitalization or an event fulfilling the definition of a serious adverse event within 3 months prior immunization.

  4. Has any unstable medical or neuropsychiatric condition, which in the Investigator's opinion poses a risk of unusual magnitude for the participant's age group of hospitalization, death, or an event meeting the definition of a serious adverse event within 2 months of immunization. The intent of this criterion is to recognize and allow for the frequent existence of significant health concerns in this population; but exclude those participants who are experiencing an acute decline in health status;
  5. Has any medical or neuropsychiatric condition, which in the Investigator's opinion, rendered the participant incompetent to provide informed consent or unable to provide valid safety observations and reports;
  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. Participants with any history of progressive or severe neurologic disorder, history of seizure, or history of neuro-inflammatory disease (e.g. Guillain-Barre syndrome);
  8. Participants with history or 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. Has known or suspected autoimmune disease;
  10. Has known or suspected impairment/alteration of immune function, including:

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

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

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

    Human Immunodeficiency Virus (HIV) infection or HIV-related disease. Genetic immunodeficiency.

  11. Has abnormalities of splenic or thymic function;
  12. Has any significant disorder of coagulation or treatment with anticoagulant therapy that would increase the risk of intramuscular (IM) injection. Persons receiving prophylactic antiplatelet medication such as low dose of acetylsalicylic acid are eligible;
  13. Has any serious chronic or progressive disease according to judgment of the Investigator: cancer (malignancy other than resolved/excised skin lesion), insulin dependent Type I diabetes (Type II diabetes is accepted), cardiac, renal or hepatic disease;
  14. Has body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg/[height in meters^2]);
  15. 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;
  16. Participants who 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;
  17. Participants involved in trial conduct or their first degree relatives;
  18. Has history of substance or alcohol abuse within the past 2 years;
  19. Females who are pregnant or breastfeeding;
  20. If female of childbearing potential, sexually active with a male partner who has not been sterilized, and has not used any of the "acceptable contraceptive methods" for at least 2 months prior to trial entry:

    Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: menopausal for at least 2 years, status after bilateral tubal ligation for at least 1 year, status after bilateral oophorectomy, or status after hysterectomy.

    Acceptable birth control methods are defined as one or more of the following: i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring); ii. Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse; iii. Intrauterine device (IUD); iv. Monogamous relationship with vasectomized partner. Partner must have been vasectomized for at least six months prior to the participants' trial entry.

  21. If female of childbearing potential and sexually active, refusal to use an "acceptable contraceptive method" from Day 1 and throughout the duration of the trial. In addition, they must be advised not to donate ova during this period;
  22. Females with any positive or indeterminate pregnancy test.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02661490


Locations
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United States, Alabama
Simon Williamson Clinic
Birmingham, Alabama, United States, 35211
United States, Arizona
Fountain Hills Family Practice, P.C.
Fountain Hills, Arizona, United States, 85268
United States, Colorado
Southwest Family Medicine
Littleton, Colorado, United States, 80127
United States, Florida
Miami Research Associates
Miami, Florida, United States, 33143
United States, Kansas
Johnson County Clin-Trials
Lenexa, Kansas, United States, 66219
United States, Missouri
St. Louis University, School of Medicine
Saint Louis, Missouri, United States, 63104
United States, New York
Regional Clinical Research Inc.
Endwell, New York, United States, 13760
University of Rochester
Rochester, New York, United States, 14642
United States, Ohio
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, United States, 45229-3039
United States, Washington
Group Health Research Institute
Seattle, Washington, United States, 98101
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Clinical Science Takeda
  Study Documents (Full-Text)

Documents provided by Takeda:
Statistical Analysis Plan  [PDF] February 2, 2017
Study Protocol  [PDF] November 16, 2015

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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02661490    
Other Study ID Numbers: NOR-204
U1111-1162-4913 ( Registry Identifier: WHO )
First Posted: January 22, 2016    Key Record Dates
Results First Posted: May 18, 2020
Last Update Posted: May 18, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Keywords provided by Takeda:
Norovirus
Additional relevant MeSH terms:
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Vaccines
Immunologic Factors
Physiological Effects of Drugs