| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the immunologic noninferiority of MEDI3250 to MEDI-558 in children 2 to 17 years of age by comparing the post dose strain-specific geometric mean titers (GMTs) of serum hemagglutination inhibition (HAI) antibody. |
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| E.2.2 | Secondary objectives of the trial |
1) To estimate the proportion of subjects 2 to 17 years of age who experience post dose strain-specific HAI antibody seroresponse;
2) To estimate the proportion of subjects 2 to 17 years of age who achieve a post dose strain-specific HAI antibody titer ≥ 32;
3) To assess the safety and tolerability of 2 doses of MEDI3250 in subjects 2 to 8 years of age and of a single dose of MEDI3250 in subjects 9 to 17 years of age. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female.
2) Age 2 through 17 years at the time of randomization.
3) Written informed consent and any locally required authorization (eg, HIPAA in the USA, EU Data Privacy Directive in the EU, and written informed assent if applicable) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations.
4) Females of childbearing potential, unless surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), has sterile male partner, is premenarchal, or practices abstinence, must have used an effective method of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap with spermicide, or use of a condom with spermicide by the sexual partner) for 30 days prior to the first dose of investigational product, and must agree to continue using such precautions for 60 days after the final dose of investigational product.
5) A subject who is considered by the investigator to be at risk of pregnancy must also have a negative urine pregnancy test at screening and, if screening and Day 0 do not occur on the same day, on the day of vaccination prior to randomization. Investigator judgment is required to assess each subject's need for pregnancy testing.
6) Healthy by medical history and physical examination OR presence of stable underlying chronic medical condition for which hospitalization has not been required in the previous year.
7) Able to complete follow-up period of 180 days post last dose of vaccine as required by the protocol.
8) Subject/legal representative is available by telephone.
9) Child's legal representative is able to understand and comply with the requirements of the protocol, as judged by the investigator. |
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| E.4 | Principal exclusion criteria |
1) Acute illness or evidence of significant active infection at randomization.
2) Fever ≥ 100.4 F ((38.0 C) at randomization.
3) History of asthma, or in children < 5 years of age, history of recurrent wheezing.
4) Any drug therapy from 15 days prior to randomization or expected drug therapy through 28 days post last dose with the exception of the following classes/types of medications, which are allowed:
a. contraceptives (change in contraceptive type or method is acceptable as long as guidelines are followed for prevention of pregnancy during change).
b. topical corticosteriods, calcineurin inhibitors, or antifungals for uncomplicated dermatitis.
c. chronic medications (including those taken on an as-needed basis) that have been well tolerated and were not initiated and/or did not have a dosage change within 90 days prior to randomization.
5) Current or expected receipt of immunosuppressive medications within a 28-day window around any dose, including an immunosuppressive dose of corticosteriods, which is defined as ≥ 20 mg/day of prednisone or its equivalent, given daily or on alternative days for ≥ 15 days (intranasal, intra-articular, and topical corticosteroids are permitted);
Note: topical cortiscosteriods for uncomplicated dermatitis may be used throughout the study according to the judgement of the investigator; topical calcineurin inhibitors may be used in accordance with their package insert at entry and during study participation.
6) Receipt of immunoglobulin or blood products within 90 days before randomization into the study or expected receipt during study participation.
7) Receipt of any investigational drug therapy within 28 days prior to Dose 1 or planned receipt of any investigational drug therapy through 90 days after final dosing of investigational product (use of licensed agents for indications not listed in the package insert is permitted).
8) Receipt of any nonstudy vaccine within 28 days prior to randomization or planned receipt of nonstudy vaccine through 28 days after final dosing.
9) Receipt of any nonstudy seasonal influenza vaccine within 90 days of Dose 1 or planned receipt of nonstudy seasonal influenza vaccine prior to 35 days post last dose of investigational product.
10) Any known immunosuppressive condition or immune deficiency disease including known or suspected infection with human immunodeficiency virus (HIV).
11) History of allergic disease or reactions likely to be exacerbated by any component of the investigational product including allergy to eggs, egg proteins, gentamicin, or gelatin or serious, life threatening, or severe reactions to previous influenza vaccinations.
12) Use of aspirin or salicylate-containing medications within 28 days prior to randomization or expected receipt through 28 days after final vaccination.
13) History of Guillain-Barré syndrome.
14) Use of antiviral agents with activity against influenza virus (including amantadine, rimantadine, oseltamivir, and zanamivir) within 28 days prior to first dose of investigational product or anticipated use of such agents within 28 days after last scheduled vaccination.
15) Known or suspected mitochondrial encephalomyopathy.
16) Pregnant or lactating female.
17) History of alcohol or drug abuse that, in the opinion of the investigator, would affect the subject's safety or compliance with study.
18) Any condition that, in the opinion of the investigator, might compromise the safety of the subject in the study or would interfere with evaluation of the safety or immunogenicity of the investigational products.
19) Subject, legal representative or immediate family member of subject who is an employee of the clinical study site or who is otherwise involved with the conduct of the study.
20) A history of epilepsy, seizure, or an evolving neurological condition except that a single febrile seizure that occurred 3 or more years prior to enrollment would not disqualify a subject.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The post dose strain-specific serum HAI antibody GMT, regardless of baseline serostatus. Immunologic noninferiority of MEDI3250 to MEDI-558 will be demonstrated if the post dose strain-specific serum HAI antibody GMTs in the MEDI3250 arm are noninferior to those in the MEDI-558 arms for all 4 strains.
The post dose serum HAI antibody GMTs for the A/H1N1 and A/H3N2 strains in MEDI3250 will be compared to those in the combined MEDI-558-Y and MEDI-558-V arms, and the post dose serum HAI antibody GMTs for the B strains of Yamagata and Victoria lineage in MEDI3250 will be compared to those in the MEDI-558-Y arm and MEDI-558-V arm, respectively. The noninferior immune response will be assessed by evaluating the upper bound of the 2-sided 95% confidence intervals (CIs) for the strain-specific HAI antibody GMT ratios (MEDI-558 divided by MEDI3250) to the noninferiority margin of 1.5. If the upper bound of CI is ≤ 1.5 for all 4 strains, the immunologic noninferiority of MEDI3250 compared to MEDI-558 will be declared. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Day 28 post immunogenicity dose |
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| E.5.2 | Secondary end point(s) |
1. The proportion of subjects who experience post dose strain-specific HAI antibody seroresponse by baseline serostatus (seronegative, serosusceptible, and regardless of serostatus). Timepoint: Day 28 post immunogenicity dose.
2. The proportion of subjects who achieve a post dose strain-specific HAI antibody titer ≥ 32 by baseline serostatus (seronegative, serosusceptible, and regardless of serostatus). Timepoint: Day 28 post immunogenicity dose.
3. Solicited symptoms experienced from administration of investigational product through 14 days post vaccination by dose number (as appropriate).
4. Adverse events experienced from administration of investigational product through 28 days post vaccination by dose number (as appropriate).
5. Treatment-emergent serious adverse event (SAE) experienced from administration of investigational product through 28 days post vaccination by dose number (as appropriate).
6. Treatment-emergent SAEs experienced from administration of investigational product through 180 days post last dose.
7. Description of new onset chronic diseases (NOCDs) from administration of investigational product through 180 days post last dose.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See each secondary endpoint for timeframe. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunological non inferiority |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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