Intranasal Challenge of Healthy Adults With Respiratory Syncytial Virus (RSV)

Study Overview
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Brief Summary
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The primary objective is to evaluate the suitability of the challenge model in measuring the efficacy of MEDI-557 compared to placebo in healthy adult participants for the reduction in the incidence of RSV through 12 days post-RSV challenge with the RSV Memphis-37 strain.

Detailed Description
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This is designed to be a double-blind, placebo-controlled, randomized study. Approximately 30 participants will be randomized, dosed and followed. Participants will be randomly assigned to receive a single intravenous (IV) dose of MEDI-557 or placebo. Participants will be inoculated with RSV-A. Participants will be followed for efficacy for 12 days post-RSV challenge. Safety follow-up will be approximately 12 months from randomization.

Official Title
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A Phase 1 Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of MEDI-557 in Healthy Adults Intranasally Challenged With Respiratory Syncytial Virus (RSV)

Conditions
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RSV Infection

Intervention / Treatment
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* Drug: Placebo
* Drug: MEDI-557


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy as determined by medical history and physical examination. Age 19 through 38 years at the time of screening. Written informed consent and any locally required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations. Weight less than or equal to (<=) 10 kilogram (kg) with body mass index (BMI) less than (<) 32 kilogram per meter square (kg/m^2). Normotensive (systolic blood pressure [BP] <150 millimeters of mercury (mmHg) and diastolic BP < 90 mmHg). Females of childbearing age using contraception. Males who are sexually active with a female partner of childbearing potential, using contraception. Sero-suitable (that is, low serum RSV neutralizing antibody titre) for RSV infection. Exclusion Criteria: Current medical conditions as follows: Clinical evidence of chronic pulmonary disease or any use of a bronchodilator or other asthma medication. Current smoker unwilling/unable to desist for the quarantine phase of the study. History or clinical evidence of recurrent lower respiratory tract infection. Evidence of infection with hepatitis A, B, or C virus or human immunodeficiency virus (HIV) by serology. Medical history as follows: History of immunodeficiency. History of chronic sinusitis. History of frequent epistaxis. History of or current diagnosis of diabetes. Prior/concomitant therapy including Receipt of any systemic chemotherapeutic agent at any time; Receipt of systemic glucocorticoids within 1 month, or any other immunosuppressive drug within 6 months prior to challenge. Receipt of any investigational drug within 6 months prior to dose or concurrent enrolment in another clinical study. Prior participation in a clinical trial of any experimental RSV viral challenge delivered directly to the respiratory tract at any time, or any other respiratory virus challenge within 1 year prior to dose. Nursing mother. Alcohol or drug addiction/abuse within the past 2 years. A positive urine Class A drug or alcohol screen unless there is a medical reason. History of seasonal hay fever or seasonal allergies. Employees of the clinical study site or sponsor, any other individuals involved with the conduct of the study, or immediate family members of such individuals. Health care workers anticipated to have patient contact within 2 weeks after viral challenge. Participants who, for an additional 2 weeks after discharge from the isolation facility, are likely to have contact with a household member or close contact with someone who is: (a) less than 3 years of age; (b) any person with any known immunodeficiency; (c) any person receiving immunosuppressant medications; (d) any person undergoing or soon to undergo cancer chemotherapy within 28 days of challenge; (e) any person who has diagnosed emphysema or COPD, is elderly residing in a nursing home, or with severe lung disease or medical condition; or (f) any person who has received a transplant (bone marrow or solid organ). As a result of the medical interview, physical examination, or screening investigations, the investigator(s) considers the participant unfit for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received single intravenous (IV) dose of placebo matched to MEDI-557 on Day 1 and were inoculated with respiratory syncytial virus (RSV-A) (Memphis-37 strain) as intranasal drops on Day 3. | Drug: Placebo<br>* Participants received single intravenous (IV) dose of placebo matched to MEDI-557 on Day 1 and were inoculated with respiratory syncytial virus (RSV-A) (Memphis-37 strain) as intranasal drops on Day 3.<br>|
| Experimental: MEDI-557<br>Participants received single IV dose of 30 milligram per kilogram (mg/kg) MEDI-557 on Day 1 and were inoculated with RSV-A (Memphis-37 strain) as intranasal drops on Day 3. | Drug: MEDI-557<br>* Participants received single IV dose of 30 milligram per kilogram (mg/kg) MEDI-557 on Day 1 and were inoculated with RSV-A (Memphis-37 strain) as intranasal drops on Day 3.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Developing Respiratory Syncytial Virus (RSV) Infection Post-RSV Challenge Measured by Plaque Assay Culture | RSV infection is defined as positive plaque assay culture sample for greater than or equal to (>=) 1 day through 12 days post-RSV challenge. A sample was determined positive if log10 plaque-forming units per milliliter [pfu/mL] greater than or equal lower limit of quantitation (LLOQ; 1.69 log10 pfu/mL) and 2 of the 3 replicates must have greater than (>) 0 pfu/mL. | From Day 4 to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Developing Respiratory Syncytial Virus (RSV) Infection Post-RSV Challenge Measured by Quantitative Real-Time Reverse Transcriptase Polymerase Chain Reaction (RT-PCR), Direct Fluorescent Antibody (DFA), And by Any Method | RSV infection defined as positive quantitative real-time RT-PCR (RSV-A only) sample for >= 2 consecutive days through 12 days post-RSV challenge. A sample was determined positive if log10 copies/ml >= limit of quantitation (LLOQ; 2.80 log10 copies/mL). RSV infection defined as positive DFA sample for >= 2 consecutive days through 12 days post-RSV challenge. RSV infection by any method included positive plaque assay culture sample for >=1 day through 12 days post-RSV challenge, or positive quantitative real-time RT-PCR (RSV-A only) sample for >= 2 consecutive days through 12 days post-RSV challenge, or positive DFA sample for >=2 consecutive days through 12 days post-RSV challenge. | From Day 4 to Day 15 | 
| Mean Viral Load AUC0-t by Plaque Assay Culture | RSV infection by plaque assay culture defined as positive sample for >= 1 day through 12 days post-RSV challenge. | From Day 5 through Day 31 | 
| Mean Viral Load AUC0-t by Realtime Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) | RSV infection by plaque assay culture defined as positive sample for >= 2 consecutive days through 12 days post-RSV challenge. | From Day 5 through Day 31 | 
| Mean Nasal RSV Peak as Measured by Plaque Assay Culture | RSV infection by plaque assay culture defined as positive sample for >= 1 day through 12 days post-RSV challenge. log10 pfu/mL = log10 plaque-forming unit per milliliter. | From Day 5 through Day 31 | 
| Mean Nasal RSV Peak as Measured by Quantitative Realtime Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) | RSV infection by plaque assay culture defined as positive sample for >= 2 consecutive days through 12 days post-RSV challenge. | From Day 5 through Day 31 | 
| Duration of Respiratory Syncytial Virus (RSV) Viral Shedding | Duration of viral shedding defined as the number of days from the first sample positive by any assay (that is, plaque assay culture, quantitative real-time (RT-PCR), or direct fluorescent Antibody (DFA) to the last sample positive by any assay. | From Day 5 through Day 31 | 
| Mean Serum MEDI-557 Concentration Through Day 360 | MEDI-557 serum concentrations were summarized by each sampling point [LLOQ for MEDI-557 concentration assay was 1.56 microgram per millilitre (μg/mL) for serum]. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Maximum Serum Concentration (Cmax) of MEDI-557 | The Cmax is the maximum observed serum concentration of MEDI-557. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Time to Reach Maximum Serum Concentration (Tmax) of MEDI-557 | The Tmax is defined as actual sampling time to reach maximum observed MEDI-557 concentration. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Serum Half Life (t1/2) of MEDI-557 | Serum decay half-life is the time measured for the serum concentration to decrease by one half. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Area Under the Serum Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of MEDI-557 | The AUC(0-t) is the area under the serum concentration-time curve from time zero to any time 't'. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of MEDI-557 | The AUC (0-infinity) is the area under the serum concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Volume of Distribution at Steady-State (Vss) of MEDI-557 | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the serum concentration-time curve from time zero to infinite time. | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Mean Clearance of MEDI-557 | Clearance (CL) is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by the serum Area Under the Serum Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]). | Pre-dose (Day 1); 1,4 and 8 hours post-dose on Day 1 and post-dose on Days 2, 3, 5, 7, 9, 11, 15, 31, 61, 91, 120, 150, 180, 240, 300 and 360 | 
| Mean Nasal Wash Concentration of MEDI-557 at Respective Time-Points | MEDI-557 nasal wash concentrations were summarized by each sampling point [LLOQ for MEDI-557 concentration assay was 20.00 nanogram per millilitre (ng/mL) for nasal wash]. | Pre-dose (Day 1) and post-dose on Days 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 31 | 
| Maximum Nasal Wash Concentration (Cmax) of MEDI-557 | The Cmax is the maximum observed nasal wash concentration of MEDI-557. | Pre-dose (Day 1) and post-dose on Days 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 31 | 
| Time to Reach Maximum Nasal Wash Concentration (Tmax) of MEDI-557 | The Tmax is defined as actual sampling time to reach maximum observed MEDI-557 concentration. | Pre-dose (Day 1) and post-dose on Days 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 31 | 
| Area Under the Nasal Wash Concentration-Time Curve From Time Zero to Time 't' (AUC[0-t]) of MEDI-557 | The AUC(0-t) is the area under the nasal wash concentration-time curve from time zero to any time 't'. | Pre-dose (Day 1) and post-dose on Days 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 31 | 
| Percentage of Participants With Positive Anti-MEDI-557 Antibodies | Anti-drug antibodies in the participants blood sample were detected using a validated immunoassay. Antidrug antibodies to MEDI-557 were defined as a detectable antibody titer with a dilution value of 1:30 or greater. | Day 1 (pre-dose); Day 31, 91, 150, 180, 240, 300 and 360 post-dose | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and Day 360 that were absent before treatment or that worsened relative to pretreatment state. | From Day 1 (immediately following administration of study drug) to Day 360 | 
| Number of Participants With Vital Signs Abnormalities Reported as Adverse Events (AEs) | Vital signs included temperature, respiration rate, heart rate, blood pressure. Abnormal vital sign parameters included Cardiac Disorders (Bradycardia), Respiratory, Thoracic and Mediastinal Disorders (Tachypnoea, Hyperventilation, Hypopnoea). Participants with abnormalities in these vital Signs investigations recorded as AEs were reported. | From Day 1 through Day 31 | 
| Number of Participants With Abnormalities in Laboratory Investigations Reported as Adverse Events (AEs) | Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs were reported. | From Day 1 through Day 91 | 
| Number of Participants With Clinically Meaningful Changes From Baseline in Spirometry Values | Spirometry is a standardized assessment to evaluate lung function. Baseline values for spirometry is defined as the last measure prior to viral challenge. Spirometry assessments included percent predicted forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), and forced expiratory flow (FEF) 25%-75% values. | Days 1, 2, 3 (Baseline), 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 31 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Respiratory Syncytial Virus (RSV), Healthy adults, MEDI-557, Intranasal challenge, Human model