The Effectiveness of CD388 to Prevent Flu in an Influenza Challenge Model in Healthy Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the preventative antiviral activity of CD388, as compared to saline placebo, when administered as a single dose to healthy adult participants in a human viral challenge model of influenza.

Detailed Description
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This is a single-center, randomized, double-blind, placebo-controlled, proof-of-concept study in healthy adult male and female participants 18 to 55 years of age, inclusive. The primary goal of this Phase 2a study is to assess the prophylactic antiviral activity against influenza, safety, tolerability, and pharmacokinetics (PK) of CD388 via a human viral challenge (HVC) model, and to explore the impact of dose levels on efficacy. Each participant will receive a single administration of CD388 or placebo; multiple dose levels of CD388 may be evaluated.

Official Title
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A Proof-of-concept, Randomized, Double-blind, Placebo-controlled, Phase 2a Study to Assess the Prophylactic Antiviral Activity Against Influenza, Safety, Tolerability, and Pharmacokinetics of CD388 Via a Human Viral Challenge Model

Conditions
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Influenza

Intervention / Treatment
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* Drug: Saline placebo
* Combination Product: CD388


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent signed and dated by the participant and the PI/investigator obtained before any assessment is performed. Adult male or female aged between 18 and 55 years old, inclusive, on the day prior to signing the consent form. A total body weight ≥50 kilograms (kg) and body mass index (BMI) ≥18 kg/meter squared (m^2) and ≤35kg/m^2. In good health with no history, or current evidence, of clinically significant medical conditions, and no clinically significant test abnormalities that will interfere with participant safety, as defined by medical history, physical examination (including vital signs), electrocardiogram (ECG), and routine laboratory tests as determined by the Principal Investigator (PI)/investigator. Participants will have a documented medical history either prior to entering the study or following medical history review with the study physician at screening. The following criteria are applicable to female participants participating in the study. Females of childbearing potential must have a negative pregnancy test prior to enrolment. Females of non-childbearing potential: Postmenopausal females defined as amenorrhea for ≥12 months with no alternative medical cause. A high follicle-stimulating hormone (FSH) level, within appropriate postmenopausal range, may be used to confirm postmenopausal state in the absence of combined hormonal contraception or hormone replacement therapy. If there is <12 months of amenorrhea 2 FSH samples are required at least 4 to 6 weeks apart. Documented status as being surgically sterile (e.g., tubal ligation, hysterectomy, bilateral salpingectomy, and bilateral oophorectomy). The following criteria apply to female and male participants: Female participants of childbearing potential must use 1 form of highly effective contraception. Hormonal methods must be in place from at least 2 weeks prior to the first study visit. The contraception use must continue until 5 effective half-lives (205 days) after the last dose of investigational medicinal product (IMP). Highly effective contraception is as described below: Established use of hormonal methods of contraception described below (for a minimum of 30 days prior to the first study visit). When hormonal methods of contraception are used, male partners are required to use a condom with a spermicide: a) combined (estrogen- and progestogen containing) hormonal contraception associated with inhibition of ovulation: (i) oral (ii) intravaginal (iii) transdermal b) progestogen-only hormonal contraception associated with inhibition of ovulation: (i) oral (ii) injectable (iii) implantable Intrauterine device. Intrauterine hormone-releasing system. Bilateral tubal ligation. Male sterilization (with the appropriate post vasectomy documentation of the absence of sperm in the ejaculate) where the vasectomized male is the sole partner for that woman. True abstinence - sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Male participants must agree to the contraceptive requirements below at entry to quarantine and continuing until 5 effective half-lives (205 days) after the last dose of IMP. Use a condom with a spermicide to prevent pregnancy in a female partner or to prevent exposure of any partner (male or female) to the IMP. Male sterilization with the appropriate post vasectomy documentation of the absence of sperm in the ejaculate (please note that the use of condom with spermicide will still be required to prevent partner exposure). This applies only to males participating in the study. In addition, for female partners of childbearing potential, that partner must use another form of contraception such as one of the highly effective methods mentioned above for female participants. True abstinence - sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. In addition to the contraceptive requirements above, male participants must agree not to donate sperm following discharge from quarantine until 5 effective half-lives (205 days) after the last dose of IMP. Sero-suitable for the challenge virus. A participant must be sero-suitable to take part in the study, i.e., he/she must have no or low pre-existing serum levels of antibodies specific to the challenge agent. Serology testing will be carried out by a hemagglutination inhibitory assay to determine serum antibody titers. As an example, a participant is considered sero-suitable if their serology (hemagglutination inhibition [HAI]) titer result is ≤10. Exclusion Criteria: History of, or currently active, symptoms or signs suggestive of upper respiratory tract (URT) or lower respiratory tract (LRT) infection within 4 weeks prior to the first study visit. Any history or evidence of any clinically significant or currently active cardiovascular, respiratory, dermatological, gastrointestinal, endocrinological, hematological, hepatic, immunological (including immunosuppression), metabolic, urological, renal, neurological, or psychiatric disease and/or other major disease that, in the opinion of the PI/investigator may interfere with a participant completing the study and necessary investigations. The following conditions apply: Participants with a history of resolved depression and/or anxiety 1 or more years ago can be included if the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Questionnaire (GAD-7) is less than or equal to 4 on admission. Participants with a history of stress-related illness, which is not ongoing or requiring current therapy, with good evidence of preceding stressors may be included at the PI's discretion. As required, participants will be assessed prior to enrolment with a PHQ-9 and GAD-7 questionnaire. Rhinitis (including hay fever) which is clinically active or history of moderate to severe rhinitis, or history of seasonal allergic rhinitis likely to be active at the time of inclusion into the study and/or requiring regular nasal corticosteroids on an at least weekly basis, within 30 days of admission to quarantine will be excluded. Participants with a history of currently inactive rhinitis (within the last 30 days) or mild rhinitis may be included at the PI's discretion. Atopic dermatitis/eczema which is clinically severe and/or requiring moderate to large amounts of daily dermal corticosteroids will be excluded. Participants with mild to moderate atopic dermatitis/eczema, taking small amounts of regular dermal corticosteroids may be included at the PI's discretion. Any concurrent serious illness, including history of malignancy, that may interfere with a participant completing the study. Basal cell carcinoma within 5 years of initial diagnosis or with evidence of recurrence is also an exclusion. Participants reporting physician-diagnosed migraine can be included provided there are no associated neurological symptoms such as hemiplegia or visual loss. Cluster headache/migraine or prophylactic treatment for migraine is an exclusion. Participants with physician diagnosed mild irritable bowel syndrome not requiring regular treatment can be included at the discretion of the PI. Participants with a history of asthma where their last symptoms/treatment were in adolescence and over 6 years ago may be included at the discretion of the PI. Any participants with symptoms or treatment in adulthood would be excluded. Any participants who have smoked ≥10 pack years at any time (10 pack years is equivalent to 1 pack of 20 cigarettes a day for 10 years). Females who: Are breastfeeding, or Have been pregnant within 6 months prior to the study, or Have a positive pregnancy test at any point during screening or prior to dosing with IMP. Lifetime history of anaphylaxis and/or a history of severe allergic reaction or significant intolerance to any food or drug in the last 12 months, as assessed by the PI. Venous access deemed inadequate for the phlebotomy and cannulation demands of the study. . . 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 (historical nasal polyps can be included, but large nasal polyps causing current and significant symptoms and/or requiring regular treatments in the last month will be excluded). Any clinically significant history of epistaxis (large nosebleeds) within the last 3 months of the first study visit and/or history of being hospitalized due to epistaxis on any previous occasion. Any nasal or sinus surgery within 3 months of the first study visit. . . Evidence of vaccinations within the 4 weeks prior to the planned date of dosing with IMP. Intention to receive any vaccination(s) before the last day of follow-up (with the exception of vaccinations recommended for Coronavirus Disease 2019 [COVID-19] as defined by Medicines and Healthcare products Regulatory Agency (MHRA)/government vaccination guidelines). No travel restrictions apply after the Day 28 [±3 days] follow-up visit; however, we expect participants to be available to attend the clinic at the Day 60, Day 120, and Day 180 follow-up visits. Receipt of influenza vaccine in the last 6 months prior to the planned date of viral challenge. Receipt of blood or blood products, or loss (including blood donations) of 550 milliliters (mL) or more of blood during the 3 months prior to the planned dosing with IMP or planned during the 3 months after the final visit. . . Receipt of any investigational drug within 3 months prior to the planned date of dosing with IMP. Receipt of 3 or more investigational drugs within the previous 12 months prior to the planned date of dosing with IMP. Prior inoculation with a virus from the same virus-family as the challenge virus. Prior participation in another human viral challenge (HVC) study with a respiratory virus in the preceding 3 months, taken from the date of viral challenge in the previous study to the date of expected viral challenge in this study. Use or anticipated use during the conduct of the study of concomitant medications (prescription and/or non-prescription), including vitamins or herbal and dietary supplements within the specified windows, unless in the opinion of the study physician/PI, the medication will not interfere with the study procedures or compromise participant safety. Specifically, the following are excluded: Herbal supplements within 7 days prior to the planned date of dosing with IMP. Chronically used medications, vitamins, or dietary supplements within 21 days prior to the planned date of dosing with IMP. Over-the-counter medications (e.g., paracetamol or ibuprofen) where the dose taken over the preceding 7 days prior to the planned date dosing with IMP has exceeded the maximum permissible 24-hour dose (e.g., ≥4 grams paracetamol over the preceding week). Systemic antiviral administration within 4 weeks of the planned date of dosing with IMP. . . Confirmed positive test for drugs of misuse and cotinine on first study visit. One repeat test is allowed at PI discretion. Recent history or presence of alcohol addiction, or excessive use of alcohol (weekly intake in excess of 28 units alcohol; 1 unit being a half glass of beer, a small glass of wine, or a measure of spirits), or excessive consumption of xanthine-containing substances (e.g., daily intake in excess of 5 cups of caffeinated drinks, e.g., coffee, tea, cola). A forced expiratory volume in 1 second (FEV1) <80 percent. Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) test (HIV positive - via 3 confirmatory tests - Vidas, Genenius, and Determine; HBV confirmed via hepatitis B surface antigen [HbsAG], hepatitis B surface antibody [anti-HBs], and hepatitis B core antibody [anti-HBc] [immunoglobulin G/immunoglobulin M]; and HCV confirmed via hepatitis C viral load). Presence of fever, defined as participant presenting with a temperature reading of ≥37.9 degrees Celsius (°C) on Day -7/-6 and/or pre-dose on Day -5. Those employed or immediate relatives of those employed at hVIVO Services Limited (hVIVO) or the sponsor. Any other finding that, in the opinion of the PI/investigator, deems the participant unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo (Arm 1)<br>In Cohort 1, up to 30 participants will be randomized to receive a single dose of placebo, administered by subcutaneous (SQ) injection, prior to being inoculated with the influenza challenge virus. Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, additional participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in an extension of this Arm 1, to receive a single dose of placebo by SQ injection prior to viral challenge. | Drug: Saline placebo<br>* Sterile normal saline for injection<br>|
| Experimental: CD388 High Dose (Arm 2)<br>In Cohort 1, up to 30 participants will be randomized to receive a single dose of 150 milligrams (mg) CD388, administered by SQ injection, prior to being inoculated with the influenza challenge virus. Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, additional participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in an extension of this Arm 2, to receive a single dose of 150 mg CD388 by SQ injection prior to viral challenge. | Combination Product: CD388<br>* CD388 liquid for injection<br>|
| Experimental: CD388 Low Dose 1 (Arm 3)<br>In Cohort 1, up to 30 participants will be randomized to receive a single dose of 50 mg CD388, administered by SQ injection, prior to being inoculated with the influenza challenge virus. Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, additional participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in an extension of this Arm 3, to receive a single dose of 50mg CD388 by SQ injection prior to viral challenge. | Combination Product: CD388<br>* CD388 liquid for injection<br>|
| Experimental: CD388 Low Dose 2 (Optional Arm 4)<br>Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in this Optional Arm 4, to receive a single dose of CD388 lower than 150 mg (TBD based on PK results obtained in the first-in-human study CD388.IM.SQ.1.01, as well as the interim analysis), administered by SQ injection, prior to being inoculated with the influenza challenge virus. | Combination Product: CD388<br>* CD388 liquid for injection<br>|
| Experimental: CD388 Low Dose 3 (Optional Arm 5)<br>Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in this Optional Arm 5, to receive a single dose of CD388 lower than 150 mg (TBD based on PK results obtained in the first-in-human study CD388.IM.SQ.1.01, as well as the interim analysis), administered by SQ injection, prior to being inoculated with the influenza challenge virus. | Combination Product: CD388<br>* CD388 liquid for injection<br>|
| Experimental: CD388 Low Dose 4 (Optional Arm 6)<br>Based on an interim analysis to be performed on data collected from the evaluation of Cohort 1 participants who have completed the inpatient phase at the time the interim analysis is performed, participants (of a number to be informed by the interim analysis) may be randomized into Cohort 2 in this Optional Arm 6, to receive a single dose of CD388 lower than 150 mg (TBD based on PK results obtained in the first-in-human study CD388.IM.SQ.1.01, as well as the interim analysis), administered by SQ injection, prior to being inoculated with the influenza challenge virus. | Combination Product: CD388<br>* CD388 liquid for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Viral Load-Time Curve (VL-AUC) after Influenza Viral Challenge | Evaluation of the prophylactic effect of CD388, when compared to placebo, on VL-AUC of influenza challenge virus as determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on nasal samples starting 1 day post viral challenge. | Day 1 (evening [pm]); Days 2, 3, 4, 5, 6, and 7 (morning [am] and pm); Day 8 (am) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Viral Load by qRT-PCR after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the peak (i.e., maximum) viral load of influenza as determined by quantifiable qRT-PCR measurements in nasal samples starting 1 day post viral challenge. | Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) | 
| Time to Confirmed Negative Test by qRT-PCR after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the time (hours) to confirmed negative test for influenza as determined by quantifiable qRT-PCR measurements in nasal samples starting 1 day post viral challenge. | From Day 1 (pm) until the first confirmed undetectable assessment after peak measurement, assessed up to Day 8 (am) | 
| VL-AUC by Viral Culture after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on VL-AUC of influenza challenge virus as determined by viral culture on nasal samples starting 1 day post viral challenge. | Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) | 
| Peak Viral Load by Viral Culture after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the peak (i.e., maximum) viral load of influenza as determined by quantitative viral culture measurements in nasal samples starting 1 day post viral challenge. | Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) | 
| Time to Confirmed Negative Test by Viral Culture after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the time (hours) to confirmed negative test for influenza as determined by quantifiable viral culture measurements in nasal samples starting 1 day post viral challenge. | From Day 1 (pm) until the first confirmed undetectable assessment after peak measurement, assessed up to Day 8 (am) | 
| Area Under the Total Clinical Symptoms Score-Time Curve (TSS-AUC) after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on TSS-AUC as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily starting 1 day post viral challenge. | Three (3) times per day, at the same time each day (±1 hour), on Days 1, 2, 3, 4, 5, 6, and 7; and on Day 8 (am only) | 
| Peak Total Clinical Symptoms Score (TSS) after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the peak (i.e., maximum) TSS score as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily starting 1 day post viral challenge. | Three (3) times per day, at the same time each day (±1 hour), on Days 1, 2, 3, 4, 5, 6, and 7; and on Day 8 (am only) | 
| Peak Daily Symptom Score after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the peak (i.e., maximum) daily symptom score (i.e., individual maximum daily sum of symptom score) as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily starting 1 day post viral challenge. | From Day 1 up to Day 8 | 
| Time to Symptom Resolution after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the time to symptom resolution as measured by graded daily symptom scoring system (participant completed symptom diary card) collected 3 times daily starting 1 day post viral challenge. | Starting Day 1, from the time of peak daily symptom score until the time of returning to baseline score, up to Day 8 | 
| Incidence of RT-PCR-Confirmed Influenza Infection after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the incidence of RT-PCR-confirmed influenza infection, defined as 2 quantifiable (≥ lower limit of quantification [LLOQ]) qRT-PCR measurements (reported on 2 or more independent nasal samples over 2 days), starting 1 day post viral challenge. | Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) | 
| Incidence of Occurrence of at Least One Positive Quantitative (≥LLOQ) Cell Culture after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on the occurrence of at least 1 positive quantitative (≥LLOQ) cell culture measurement in nasal samples starting 1 day post viral challenge. | Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) | 
| Incidence of RT-PCR-Confirmed Symptomatic Influenza Infection after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on RT-PCR-confirmed symptomatic influenza infection starting 1 day post viral challenge, defined as: RT-PCR-confirmed influenza infection (2 quantifiable [≥LLOQ] qRT-PCR measurements [reported on 2 or more independent nasal samples over 2 days]), AND TSS score ≥2 at any single time point (i.e., any individual symptom diary card for which the sum of symptom scores is ≥2; e.g., at a minimum, ≥1 symptom of grade ≥2, or ≥2 symptoms of grade ≥1), as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily. | • For qRT-PCR measurements: Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) • For TSS measurements: Three (3) times per day, at the same time each day (±1 hour), on Days 1, 2, 3, 4, 5, 6, and 7; and on Day 8 (am only) | 
| Incidence of RT-PCR-Confirmed Moderately Severe Symptomatic Influenza Infection after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on RT-PCR-confirmed moderately severe symptomatic influenza infection starting 1 day post viral challenge, defined as: RT-PCR-confirmed influenza infection (2 quantifiable [≥LLOQ] qRT-PCR measurements [reported on 2 or more independent nasal samples over 2 days]), AND One or more symptoms of grade ≥2 at a single time point (i.e., on any individual symptom card), as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily. | • For qRT-PCR measurements: Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) • For TSS measurements: Three (3) times per day, at the same time each day (±1 hour), on Days 1, 2, 3, 4, 5, 6, and 7; and on Day 8 (am only) | 
| Incidence of Culture Lab-Confirmed Symptomatic Influenza Infection after Influenza Viral Challenge | Evaluation of the effect of CD388, when compared to placebo, on culture lab-confirmed symptomatic influenza infection starting 1 day post viral challenge, defined as: Lab-confirmed culturable influenza infection (1 quantifiable [≥LLOQ] cell culture measurement in nasal samples), AND TSS score ≥2 at any single time point (i.e., any individual symptom diary card for which the sum of symptom scores is ≥2; e.g., at a minimum, ≥1 symptom of grade ≥2, or ≥2 symptoms of grade ≥1), as measured by graded symptom scoring system (participant completed symptom diary card) collected 3 times daily. | • For viral culture measurements: Day 1 (pm); Days 2, 3, 4, 5, 6, and 7 (am and pm); Day 8 (am) • For TSS measurements: Three (3) times per day, at the same time each day (±1 hour), on Days 1, 2, 3, 4, 5, 6, and 7; and on Day 8 (am only) | 
| Incidence of Occurrence of Solicited Adverse Events (AEs) from Subcutaneous (SQ) Dosing up to Viral Challenge | Evaluation of the occurrence of solicited AEs in participants dosed with CD388, when compared with placebo, from the time of SQ dosing up to the time of inoculation with the influenza challenge virus. | From Day -5 (dosing) up to Day 0 (viral challenge) | 
| Incidence of Occurrence of Unsolicited AEs from SQ Dosing up to Day 28 Follow-up Visit | Evaluation of the occurrence of unsolicited AEs in participants dosed with CD388, when compared with placebo, from the time of SQ dosing up to the time of the Day 28 follow-up visit. | From Day -5 (dosing) up to Day 28 (±3 days) | 
| Incidence of Occurrence of Unsolicited AEs from SQ Dosing up to the Final Follow-up Visit | Evaluation of the occurrence of unsolicited AEs in participants dosed with CD388, when compared with placebo, from the time of SQ dosing up to the time of the Day 180 final follow-up visit. | From Day -5 (dosing) up to Day 180 (±14 days) |