Double-Blind, Randomised, Placebo-Controlled Exploratory Study to Estimate the Prophylactic Efficacy of Palivizumab in Healthy Adult Participants Inoculated with Respiratory Syncytial Virus (RSV).
As no data exists for Palivizumab in the RSV human challenge model, this exploratory study is therefore planned to establish the margins of effect and variance of prophylactically administered Palivizumab within the RSV-A Memphis 37b challenge model in healthy adult volunteers. The study will be performed in adults aged 18-55 years, in two parts. • Part 1: All participants will be administered Palivizumab (8mg/Kg, intravenously). Pharmacokinetic (PK), safety will be measured. If there are no safety concerns in Part 1, and PK analysis of Palivizumab treated participants confirm the modelling of 8mg/Kg to be appropriate, Part 2 will commence with the planned 8mg/Kg treatment dose. However, if PK analysis of Part 1 suggests that 8mg/kg may be insufficient dose to provide suitable efficacious coverage in Part 2, then Part 2 will proceed with a dose of 15mg/Kg. • Part 2: Participants will be either administered Palivizumab (8mg/Kg or 15mg/Kg, as determined in Part ) or a placebo and they will subsequently be challenged with an RSV-A strain (Memphis 37b). The margin of effect and variance between groups will be measured, as well as safety and reactogenicity.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
TRIPLE
Enrollment
56
Liquid solution in sterile water for injection (final concentration of 20mg/mL), intravenous infusion, single dose of 8mg/kg or 15mg/kg, administered at a rate of 1mL/min
Sodium Chloride 0.9% Solution (Normal Saline), intravenous infusion, single dose of 0mg/Kg, administered at a rate of 1mL/min
Single Intranasal Virus Dose (challenge dose is approximately 4.5log10 PFU)
hVIVO Services Limited
London, United Kingdom
Mean Serum Concentrations (Cmax) for Open-label Palivizumab (Part 1) on Day 12.
The PK assessment up to and including Day 12 exposure was used as a decision information for the dose to be given to participants in Part 2. Pharmacokinetic exposure data from at least 5 out of 6 participants were required for dose decision making with a projected exposure of ≥40 μg/mL on Day 12 according to the protocol. This was achieved after administration of a single IV dose of Palivizumab at 8 mg/kg. Therefore, a dose of 8 mg/kg was chosen for Part 2.
Time frame: In Part 1: before the start of infusion; at end of infusion,15 minutes and 0.5, 1, 4, 8, and 12 hours after infusion; and at 1, 2, 3, 7, and 12 days after infusion.
Area Under the Viral Load-time Curve (VL-AUC) as Determined by Polymerase Chain Reaction (qRT-PCR) on Nasal Samples, for Double-blind Palivizumab or Placebo (Part 2).
RSV viral load of RSV-A Memphis 37b as determined by qRT-PCR on nasal samples collected twice daily: Assessment of the Area under the viral load-time curve (VL-AUC)
Time frame: From two days post viral challenge (Day 2) to the end of quarantine (Day 12) in Part 2 on nasal samples collected twice daily.
qRT-PCR Peak Viral Load for Double-blind Palivizumab or Placebo (Part 2).
Peak viral load of RSV-A Memphis 37b as determined by qRT-PCR on nasal samples collected twice daily.
Time frame: From two days post viral challenge (Day 2) to the end of quarantine (Day 12) in Part 2
Area Under the Viral Load-time Curve (VL-AUC) as Determined by Cell Culture on Nasal Samples, for Double-blind Palivizumab (Part 2).
RSV Viral Load of RSV-A Memphis 37b as Determined by Cell Culture on Nasal Samples collected twice daily: Area under the viral load-time curve (VL-AUC) of RSV-A Memphis 37b
Time frame: From two days post viral challenge (Day 2) to the end of quarantine (Day 12) in Part 2 on nasal samples collected twice daily.
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Cell Culture Peak Viral Load for Double-blind Palivizumab or Placebo (Part 2).
Peak Viral Load of RSV-A Memphis 37b as Determined by Cell Culture on Nasal Sample
Time frame: From Day 2 to Day 12 in Part 2
Number of Participants With Laboratory-confirmed Infection of RSV-A Memphis 37b in Nasal Samples (Variant 1) for Double-blind Palivizumab or Placebo (Part 2).
Percentage of Participants Infected Post-viral Challenge (Infectivity Status and Rate): occurrence of at least 2 positive "quantifiable" qRT-PCR measurements in nasal samples. Laboratory-confirmed infection (variant 1): At least 2 positive quantifiable detections by viral load qRT-PCR assay specific for the challenge virus, reported within 4 consecutive scheduled assessments and from 2 independent samples from Day 2 until discharge and/or 1 positive detection by viral load qRT-PCR assay, specific for the challenge virus, in which an aliquot of the same sample has also tested positive in a viral culture assay appropriate for detecting the challenge virus from Day 2 until discharge.
Time frame: From Day 2 to Day 12 in Part 2
Number of Participants With Laboratory-confirmed Infection of RSV-A Memphis 37b in Nasal Samples (Variant 2), for Double-blind Palivizumab or Placebo (Part 2).
Percentage of Participants Infected Post-viral Challenge (Infectivity Status and Rate): Occurrence of at least 2 positive "detectable" qRT-PCR measurements in nasal samples. Laboratory-confirmed infection (variant 2): At least 2 positive detectable assessments by viral load qRT-PCR assay specific for the challenge virus, reported within 4 consecutive scheduled assessments and from 2 independent samples from Day 2 until discharge and/or 1 positive detection by viral load qRT-PCR assay, specific for the challenge virus, in which an aliquot of the same sample has also tested positive in a viral culture assay appropriate for detecting the challenge virus from Day 2 until discharge.
Time frame: From Day 2 to Day 12 in Part 2
Viral Shedding of RSV-A Memphis 37b in Nasal Samples in Terms of Duration, for Double-blind Palivizumab or Placebo (Part 2).
Estimation of the duration of viral shedding by the number of days with quantifiable qRT-PCR measurements in nasal samples starting 2 days post viral challenge (Day 2) up to the end of quarantine.
Time frame: From Day 2 to Day 12 in Part 2
Viral Shedding of RSV-A Memphis 37b in Nasal Samples in Terms of Time to Peak Viral Load, for Double-blind Palivizumab or Placebo (Part 2).
Estimation of the duration of viral shedding by the time to peak viral load of RSV by quantifiable qRT-PCR.
Time frame: From Day 2 to Day 12 in Part 2
Viral Shedding of RSV-A Memphis 37b in Nasal Samples in Terms of Peak Viral Load, for Double-blind Palivizumab or Placebo (Part 2).
Peak viral load of RSV-A Memphis 37b as defined by the maximum viral load determined by quantifiable qRT PCR measurements in nasal samples starting 2 days post viral challenge (Day 2) up to the end of quarantine.
Time frame: From Day 2 to Day 12 in Part 2
Total Symptom Score (TSS)-Time Curve (AUC) Collected Daily in the Participant Symptom Diary Card
Mean TSS values (collected daily in the symptom diary card) over time. Symptoms were collected using the hVIVO (services provider) symptom diary card. Several symptoms (such as runny nose, sore throat, earache, etc) in the 13-item questionnaire were graded on a scale of 0-3 (grade 0: No symptoms; grade 1: just noticeable; grade 2: clearly bothersome from time to time but does not interfere with me doing my normal daily activities; grade 3: Quite bothersome most or all of the time, and it stops me participating in activities). Shortness of breath and wheeze have an additional grade 4: Symptoms at rest. The total symptom score (TSS) was determined as the sum of the symptom scores ranging from 0.0 (min) to 41(max) \[or a maximum of 41x11.33=464.67 depending on what the reviewer is asking\] using a 13-items self-reported diary card. 11.33 is the number of days symptom diary cards were included (Day +1 morning dairy card to Day 12 morning diary card). Higher scores mean worse outcome.
Time frame: From two days post viral challenge (Day 2) to the end of quarantine (Day 12) in Part 2 on nasal samples collected twice daily.
Peak Symptom Scores
Peak symptom scores for symptoms collected daily in the participant symptom diary card. Symptoms (such as runny nose, sore throat, earache, etc) were collected using the 13-item hVIVO symptom questionnaire and were graded on a scale of 0-3 (grade 0: No symptoms; grade 1: just noticeable; grade 2: clearly bothersome from time to time but does not interfere with me doing my normal daily activities; grade 3: Quite bothersome most or all of the time, and it stops me participating in activities). Shortness of breath and wheeze have an additional grade 4: Symptoms at rest. The total symptom score (TSS) was determined as the sum of the symptom scores ranging from 0.0 (min) to 41(max) \[or a maximum of 41x11.33=464.67 depending on what the reviewer is asking\] using a 13-items self-reported diary card. 11.33 is the number of days symptom diary cards were included (Day +1 morning dairy card to Day 12 morning diary card). Higher scores mean worse outcome.
Time frame: From Day 2 to Day 12 in Part 2
Total Weight of Nasal Discharge Produced
Nasal Discharge Collection from Paper Tissues by means of the total weight of nasal discharge produced.
Time frame: From Day 1 to Day 12 in Part 2
Total Number of Tissues Used by Participants
Nasal Discharge Collection from Paper Tissues by means of the total number of tissues used.
Time frame: From Day 1 to Day 12 in Part 2
Number of Participants With Laboratory-confirmed Virus-like Illness (Variant 1) Using Viral Shedding Variant 1, for Double-blind Palivizumab or Placebo (Part 2).
Illness Post-viral challenge measured by means of the proportion of participants with any symptom ≥grade 1 for the evaluable population.
Time frame: From Day 2 to Day 12 in Part 2
The Occurrence of Laboratory-confirmed Virus-like Illness (Variant 1) Using Viral Shedding Variant 2, for Double-blind Palivizumab or Placebo (Part 2).
Illness Post-viral challenge measured by means of the proportion of participants with any symptom ≥grade 1 for the evaluable population.
Time frame: From Day 2 to Day 12 in Part 2
The Occurrence of Laboratory-confirmed Virus-like Illness (Variant 2) Using Viral Shedding Variant 1, for Double-blind Palivizumab or Placebo (Part 2).
Illness Post-viral challenge measured by means of the proportion of participants with any symptom ≥grade 1 for the evaluable population.
Time frame: From Day 2 to Day 12 in Part 2
The Occurrence of Laboratory-confirmed Virus-like Illness (Variant 2) Using Viral Shedding Variant 2, for Double-blind Palivizumab or Placebo (Part 2).
Illness Post-viral challenge measured by means of the proportion of participants with any symptom ≥grade 1 for the evaluable population.
Time frame: From Day 2 to Day 12 in Part 2
Cmax
Evaluation of Palivizumab PK levels throughout the study, by means of Cmax after intravenous administration of Palivizumab.
Time frame: Before the start of infusion; at end of infusion, 15 minutes and 0.5, 1, 4, 8, and 12 hours after infusion; and at 1, 2, 3, 7 and 12 days after infusion (Part 1) or at 1, 2, 3, 7, 13, 21, and 29 days after infusion (Part 2)
Tmax
Palivizumab PK levels throughout the study, by means of Tmax after intravenous administration of Palivizumab.
Time frame: Before the start of infusion; at end of infusion, 15 minutes and 0.5, 1, 4, 8, and 12 hours after infusion; and at 1, 2, 3, 7, and 12 days after infusion (Part 1) or at 1, 2, 3, 7, 13, 21, and 29 days after infusion (Part 2)
Safety Adults: Number of Participants With Adverse Events (AEs)
Incidence of AEs, treatment-emergent AEs (TEAEs), serious AEs (SAEs) and; drug-related or challenge-virus related TEAEs and SAEs
Time frame: From Day 1 to Day 18 in Part 1 and from Day 1 to Day 28 in Part 2
Immunogenicity: Number of Participants Positive for Anti-palivizumab Antibody (ADA)
Determination of the incidence of anti-palivizumab ADA (number and percent of participants tested positive for anti-palivizumab ADA). ADA positive participant: baseline negative and any sample after treatment positive, or baseline positive and titre increased 4- to 9-fold after treatment) before the dose of palivizumab and at scheduled post-dose assessments.
Time frame: Part 2: prior to infusion with Palivizumab and 7, 13, and 29 days post Palivizumab infusion.