Influenza Viral Infections
Conditions
Keywords
Influenza, Human Challenge, Prophylaxis
Brief summary
Study to assess the efficacy and safety of a multiple dose regimen and a single dose regimen of intranasal Neumifil, administered prior to challenge with Influenza virus in healthy adult participants
Detailed description
This is a single-centre, randomized, double-blind, placebo-controlled study in healthy adult participants to assess the pre-exposure prophylactic antiviral activity of Neumifil via a human viral challenge model. Participants will enter the quarantine unit on Day -4. Participants will be randomized to receive either active (single dose), active (multiple dose) or placebo in a 3:3:4 ratio followed by influenza viral challenge on Day 0. Participants will leave the unit on Day 8, provided that no virus is detected by a qualitative virus antigen test and the participant has no clinically significant symptoms. A final follow-up will be performed on Day 28.
Interventions
DRUGNeumifil
Liquid for intranasal spray administration
DRUGPlacebo
Liquid for intranasal spray administration
Sponsors
Pneumagen Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Randomized, Double-blind, Placebo-controlled study
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Written informed consent signed and dated by the participant and the investigator obtained before any assessment is performed. 2. Adult male or female aged between 18 and 55 years old, inclusive, on the day prior to signing the consent form. 3. A total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2. 4. In good health with no history, or current evidence, of clinically significant medical conditions, and no clinically significant test abnormalities that that will interfere with participant safety, as defined by medical history, physical examination, (including vital signs), ECG, and routine laboratory tests as determined by the investigator. 5. Participants will have a documented medical history either prior to entering the study or following medical history review with the study physician at screening. 6. Agree to use highly effective contraception 7. Serosuitable for the challenge virus
Exclusion criteria
1. History of, or currently active, symptoms or signs suggestive of upper or lower respiratory tract (URT, LRT) infection within 4 weeks prior to the first study visit. 2. Any history or evidence of any clinically significant or currently active cardiovascular, respiratory, dermatological, gastrointestinal, endocrinological, haematological, hepatic, immunological (including immunosuppression), metabolic, urological, renal, neurological, or psychiatric disease and/or other major disease that, in the opinion of the investigator, may interfere with a participant completing the study and necessary investigations. Includes a history of depression or anxiety. 3. Any participants who have smoked ≥ 10 pack years at any time. 4. Females who are pregnant or breastfeeding 5. Any history of anaphylaxis or history of severe allergic reactions to any foods, drugs, insect bites or stings or any known allergy to tetracycline antibiotics. 6. Venous access deemed inadequate for the phlebotomy and cannulation demands of the study. 7. a) Any significant abnormality altering the anatomy of the nose in a substantial way or nasopharynx that may interfere with the aims of the study and, in particular, any of the nasal assessments or viral challenge b) Any evidence of nasal inflammation or nasal polyps within the last month c) Any clinically significant history of epistaxis (large nosebleeds) within the last 3 months of the first study visit and/or history of being hospitalised due to epistaxis on any previous occasion. d) Any nasal or sinus surgery within 3 months of the first study visit. Prior or Concomitant Medications and Assessments 8. a) Evidence of vaccinations within the 4 weeks prior to the planned date of first dosing with IMP. b) Intention to receive any vaccination(s) before the last day of follow-up (with the exception of vaccinations recommended for COVID19 as defined by Medicines and Healthcare Regulatory Agency (MHRA)/government vaccination guidelines). No travel restrictions apply after the Day 28 (±3 days) follow-up visit. c) Receipt of influenza vaccine (or another IMP relating to treatment of influenza) in the last 6 months prior to the planned date of viral challenge OR a diagnosis of influenza or influenza-like illness confirmed by a physician within the last 2 months prior to screening. 9. Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more of blood during the 3 months prior to the planned date of first dosing with IMP or planned during the 3 months after the final follow-up visit. 10. a) Receipt of any investigational drug within 3 months (or 5 half-lives of the IMP used in the other study, whichever is greater), prior to the planned date of first dosing with IMP. b) Receipt of 3 or more investigational drugs within the previous 12 months prior to the planned date of first dosing with IMP. c) Prior inoculation with a virus from the same virus-family as the challenge virus. d) Prior participation in another human viral challenge study with a respiratory virus in the preceding 3 months. 11. Use or anticipated use during the conduct of the study of concomitant medications 12. Confirmed positive test for drugs of misuse and cotinine on first study visit 13 Recent history or presence of alcohol addiction, or excessive use of alcohol 14\. A FEV1 \<80%, a FVC \<80% predicted, or an FEV1/FVC ratio \<0.7. 15. Positive HIV, hepatitis B virus, or hepatitis C virus test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Symptomatic Influenza Infection | Day 1 to Day 8 | Number of subjects with quantifiable viral shedding on 2 consecutive days AND with any symptom score of grade 2 or greater at a single time point. Viral shedding was measured by RT-qPCR. Eleven symptoms were assessed by 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). |
| Severity of Symptoms | Day 1 to Day 8 | Change in Peak Total Symptom Score (TSS) as measured by graded symptom scoring system collected 3 times daily; symptom questionnaire was 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).Lower score means better outcome. The range was 0 to 33. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Weight of Nasal Discharge | Day 1 (am) to Day 8 (am) | Measurement of total weight of mucus produced by participants. The total weight of used tissues was measured to assess the weight of mucus produced. The greater the weight of the tissues the more mucus produced and the worse the outcome. |
| Nasal Discharge | Day 1 (am) to Day 8 (am) | The number of tissues used by participants were counted. The greater the number of tissues used the worse the outcome. |
| Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS) | Day 1 to Day 8 | Participants completed a self-assessment symptom score 3 times daily, 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).Lower score means better outcome. Range 0 to 33 |
| Adverse Events, Unsolicited | From intake of first dose of IMP on Day -3 to Day 28 | Number of participants reporting treatment emergent adverse events, unsolicited |
| Adverse Events, Solicited | From intake of first dose of IMP (Day -3) up to 12 hours post the last IMP dose (Day -1) | Number of participants reporting a solicited adverse event during the treatment period of IMP |
| Viral Shedding Over Time | Day 1 (pm) to Day 8 (am) | Measurement of influenza viral load (VL) area under the curve (VL-AUC) of quantifiable measurements by RT-qPCR in nasal samples. The AUC is expressed as the log to the base 10 copies in a mL of nasal fluid multiplied by the time in days \[(log10 copies/mL)\*day\]. The higher the viral load AUC, by PCR, the worse the outcome. |
Countries
United Kingdom
Participant flow
Recruitment details
Following screening (Day -93 to Day -5), this study was conducted with an inpatient phase (Day -4 to Day 8) and an outpatient follow-up on Day 28 (plus or minus 3 days). During the inpatient quarantine phase, participants received Neumifil or placebo according to the randomisation on Day -3, Day -2 and Day -1, and then received Influenza Challenge Virus on Day 0. The study was conducted at one site in the UK between 12 August 2022 and 03 May 2023.
Participants by arm
| Arm | Count |
|---|---|
| Neumifil Multiple Dose Prophylactic Treatment Neumifil intranasal spray administered as 3 single daily doses prior to viral challenge
Neumifil: Liquid for intranasal spray administration | 32 |
| Neumifil Single Dose Prophylactic Treatment Neumifil intranasal spray administered as a single dose on Day -3 and blinded by placebo administered as two single daily doses. All administrations completed prior to viral challenge
Neumifil: Liquid for intranasal spray administration
Placebo: Liquid for intranasal spray administration | 31 |
| Placebo Intranasal spray administered as 3 single daily doses prior to viral challenge
Placebo: Liquid for intranasal spray administration | 41 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| From Challenge Virus to End of Study | Withdrawal by Subject | 0 | 2 | 0 |
| Randomised and Received Challenge Virus | Did not complete quarantine | 1 | 0 | 0 |
| Randomised and Received Challenge Virus | Lost to Follow-up | 0 | 0 | 1 |
| Randomised and Received Challenge Virus | Physician Decision | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Neumifil Multiple Dose Prophylactic Treatment | Neumifil Single Dose Prophylactic Treatment | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 31.22 years STANDARD_DEVIATION 6.79 | 30.32 years STANDARD_DEVIATION 7.06 | 31.05 years STANDARD_DEVIATION 8.82 | 30.88 years STANDARD_DEVIATION 7.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants | 29 Participants | 39 Participants | 99 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 3 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) White | 21 Participants | 22 Participants | 33 Participants | 76 Participants |
| Region of Enrollment United Kingdom | 32 participants | 31 participants | 41 participants | 104 participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 14 Participants | 32 Participants |
| Sex: Female, Male Male | 23 Participants | 22 Participants | 27 Participants | 72 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 31 | 0 / 41 |
| other Total, other adverse events | 30 / 32 | 25 / 31 | 34 / 41 |
| serious Total, serious adverse events | 0 / 32 | 0 / 31 | 0 / 41 |
Outcome results
Primary
Incidence of Symptomatic Influenza Infection
Number of subjects with quantifiable viral shedding on 2 consecutive days AND with any symptom score of grade 2 or greater at a single time point. Viral shedding was measured by RT-qPCR. Eleven symptoms were assessed by 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).
Time frame: Day 1 to Day 8
Population: Per Protocol population (participants who received all doses, challenge virus and completed quarantine up to Day 8)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Incidence of Symptomatic Influenza Infection | 6 Participants |
| Neumifil Single Dose Prophylactic Treatment | Incidence of Symptomatic Influenza Infection | 6 Participants |
| Placebo | Incidence of Symptomatic Influenza Infection | 16 Participants |
| Pooled Neumifil Groups | Incidence of Symptomatic Influenza Infection | 12 Participants |
Comparison: A priori primary analysis groupp-value: 0.0331Chi-squared
Primary
Severity of Symptoms
Change in Peak Total Symptom Score (TSS) as measured by graded symptom scoring system collected 3 times daily; symptom questionnaire was 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).Lower score means better outcome. The range was 0 to 33.
Time frame: Day 1 to Day 8
Population: Per Protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Severity of Symptoms | 3.00 Scores on a scale |
| Neumifil Single Dose Prophylactic Treatment | Severity of Symptoms | 1.00 Scores on a scale |
| Placebo | Severity of Symptoms | 3.00 Scores on a scale |
| Pooled Neumifil Groups | Severity of Symptoms | 2.00 Scores on a scale |
p-value: 0.1427Wilcoxon (Mann-Whitney)
Secondary
Adverse Events, Solicited
Number of participants reporting a solicited adverse event during the treatment period of IMP
Time frame: From intake of first dose of IMP (Day -3) up to 12 hours post the last IMP dose (Day -1)
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Adverse Events, Solicited | 29 Participants |
| Neumifil Single Dose Prophylactic Treatment | Adverse Events, Solicited | 22 Participants |
| Placebo | Adverse Events, Solicited | 29 Participants |
Secondary
Adverse Events, Unsolicited
Number of participants reporting treatment emergent adverse events, unsolicited
Time frame: From intake of first dose of IMP on Day -3 to Day 28
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Adverse Events, Unsolicited | 9 Participants |
| Neumifil Single Dose Prophylactic Treatment | Adverse Events, Unsolicited | 8 Participants |
| Placebo | Adverse Events, Unsolicited | 17 Participants |
Secondary
Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS)
Participants completed a self-assessment symptom score 3 times daily, 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).Lower score means better outcome. Range 0 to 33
Time frame: Day 1 to Day 8
Population: Per Protocol population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS) | 4.05 (Units on a scale)*day |
| Neumifil Single Dose Prophylactic Treatment | Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS) | 0.11 (Units on a scale)*day |
| Placebo | Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS) | 3.73 (Units on a scale)*day |
| Pooled Neumifil Groups | Area Under the Curve (AUC) Over Time of Total Symptom Score (TSS) | 2.44 (Units on a scale)*day |
p-value: 0.1307Wilcoxon (Mann-Whitney)
Secondary
Nasal Discharge
The number of tissues used by participants were counted. The greater the number of tissues used the worse the outcome.
Time frame: Day 1 (am) to Day 8 (am)
Population: Per Protocol population (Data not available for all participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Nasal Discharge | 14.00 sum of number of tissues |
| Neumifil Single Dose Prophylactic Treatment | Nasal Discharge | 2.00 sum of number of tissues |
| Placebo | Nasal Discharge | 7.00 sum of number of tissues |
| Pooled Neumifil Groups | Nasal Discharge | 5.5 sum of number of tissues |
Secondary
Viral Shedding Over Time
Measurement of influenza viral load (VL) in nasal samples over time (VL-AUC) measured by viral culture. Nasal secretions were cultured and the Tissue Culture Infectious Dose (TCID50) calculated. The AUC of log to the base 10 of the TCID50 in each mL of nasal secretions, multiplied by the time in days \[(log10 TCID50/mL)\*day\] was calculated. The higher the viral load AUC by culture, the worse the outcome.
Time frame: Day 1 (pm) to Day 8 (am)
Population: Per Protocol population (one participant in the placebo group had a missing value)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Viral Shedding Over Time | 3.29 (log10 TCID50/mL)*day |
| Neumifil Single Dose Prophylactic Treatment | Viral Shedding Over Time | 3.30 (log10 TCID50/mL)*day |
| Placebo | Viral Shedding Over Time | 4.79 (log10 TCID50/mL)*day |
| Pooled Neumifil Groups | Viral Shedding Over Time | 3.30 (log10 TCID50/mL)*day |
p-value: 0.011Wilcoxon (Mann-Whitney)
Secondary
Viral Shedding Over Time
Measurement of influenza viral load (VL) area under the curve (VL-AUC) of quantifiable measurements by RT-qPCR in nasal samples. The AUC is expressed as the log to the base 10 copies in a mL of nasal fluid multiplied by the time in days \[(log10 copies/mL)\*day\]. The higher the viral load AUC, by PCR, the worse the outcome.
Time frame: Day 1 (pm) to Day 8 (am)
Population: Per Protocol Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Viral Shedding Over Time | 9.96 (log10 copies/mL)*day |
| Neumifil Single Dose Prophylactic Treatment | Viral Shedding Over Time | 8.60 (log10 copies/mL)*day |
| Placebo | Viral Shedding Over Time | 17.24 (log10 copies/mL)*day |
| Pooled Neumifil Groups | Viral Shedding Over Time | 9.39 (log10 copies/mL)*day |
p-value: 0.0382Wilcoxon (Mann-Whitney)
Secondary
Weight of Nasal Discharge
Measurement of total weight of mucus produced by participants. The total weight of used tissues was measured to assess the weight of mucus produced. The greater the weight of the tissues the more mucus produced and the worse the outcome.
Time frame: Day 1 (am) to Day 8 (am)
Population: Per Protocol population (Data not available for all participants)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neumifil Multiple Dose Prophylactic Treatment | Weight of Nasal Discharge | 5.24 grams |
| Neumifil Single Dose Prophylactic Treatment | Weight of Nasal Discharge | 0.26 grams |
| Placebo | Weight of Nasal Discharge | 2.74 grams |
| Pooled Neumifil Groups | Weight of Nasal Discharge | 0.97 grams |