Phase 2a Study of the Efficacy and Safety of TRX-100 in a Human Influenza A Challenge Model

This is a Phase 2a study in healthy adult participants between 18 and 55 years of age. Study design is a single-center, randomized, double-blind, placebo-controlled study to evaluate the prophylactic efficacy and safety of TRX-100 followed by inoculation with influenza A challenge agent in healthy adults.

Inclusion criteria

• Written informed consent signed and dated by the participant and the PI/investigator obtained before any assessment is performed.
• Aged between 18 and 55 years old on the day prior to signing the consent form, inclusive.
• A total body weight ≥50 kg and body mass index (BMI) ≥18 kg/m2 and ≤35kg/m2.
• 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), ECG, and routine laboratory tests as determined by the 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 enrollment.
• Females of non-childbearing potential:

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• Postmenopausal females defined as amenorrhea for 12 months or greater 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 less than 12 months of amenorrhea 2 FSH samples are required at least 4 to 6 weeks apart.
• Documented status as being permanently sterile (e.g., hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).
• Female participants of childbearing potential must use one form of highly effective contraception (birth control). Hormonal methods must be in place from at least 2 weeks prior to the first study visit (IMP administration visit). The contraception use must continue until 28 days after the date of challenge agent administration.

Male participants must agree to use one of the contraceptive requirements below from the first study visit and continuing until 28 days after the date of challenge agent administration.

• Serosuitable for the challenge agent. The serology result obtained from the influenza antibody assay suggests that the participant is sensitive to influenza infection (i.e., they are likely to be infected following inoculation with the challenge agent).

Exclusion criteria

• History of, or currently active, symptoms or signs suggestive of upper or lower respiratory tract (URT or 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, hematologic, 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 may be included at the discretion of the PI/investigator. Participants with a history of stress-related illness, which is not ongoing or requiring current therapy, with good evidence of preceding stressors may also be included at the PI/investigator's discretion. As required, participants will be assessed prior to enrollment with a Patient Health Questionnaire (PHQ)-9 and/or Generalized Anxiety Disorder (GAD)-7 questionnaire which must score ≤4 on admission.
• Rhinitis (including hay fever) which is clinically active or a 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/investigator'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/investigator'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 PI/investigator's discretion.
• Any participants who have smoked ≥10 pack years at any time (10 pack years is equivalent to one pack of 20 cigarettes a day for 10 years) including (as applicable) any calculable or self-reported significant vaping history.
• 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 lifetime history of severe allergic reaction. Significant intolerance to any food or drug in the last 12 months, as assessed by the PI/investigator.
• Venous access deemed inadequate for the phlebotomy and cannulation demands of the study.
• 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 challenge agent administration (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).

b) 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.

c) Any nasal or sinus surgery within 3 months of the first study visit.

• a) Evidence of vaccinations within the 4 weeks prior to the planned date of dosing with IMP.

b) Intention to receive any vaccination(s) before the last day of follow-up. c) Receipt of influenza vaccine in the last 180 days prior to the planned date of viral challenge.

d) Received antiviral medication for influenza in the last 180 days prior to the planned date of viral challenge.

e) Having had confirmed influenza illness in the last 180 days prior to the planned dosing of IMP.

• 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 dosing with IMP or planned during the 3 months after the final follow-up visit.
• a) Receipt of any investigational drug within 3 months or 5 half-lives (whichever is greater) prior to the planned date of dosing with IMP.

b) Receipt of ≥3 investigational drugs within the previous 12 months prior to the planned date of dosing with IMP.

c) Prior inoculation with a virus from the same virus-family as the challenge agent.

d) Prior participation in another human challenge study with a challenge agent in the preceding 3 months, taken from the date of challenge agent administration in the previous study to the date of expected challenge agent administration 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 PI/investigator, 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, including any medications known to be potent inducers or inhibitors of CYP450 enzymes, 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 of dosing with IMP has exceeded the maximum permissible 24-hour dose (e.g., ≥4 g paracetamol over the preceding week).
• Systemic antiviral administration within 4 weeks of the dosing with IMP.
• a) Confirmed positive test for drugs of misuse on first study visit (i.e., IMP administration visit). One repeat test is allowed at PI/investigator's discretion.

b) 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).

c) Excessive consumption of xanthine-containing substances (e.g., daily intake in excess of 5 cups of caffeinated drinks e.g., coffee, tea, cola).

d) Presence of significant signs and symptoms of nicotine withdrawal on entry to the clinical unit.

• A forced expiratory volume in 1 second (FEV1) < 80%.
• Positive HIV, hepatitis B, or hepatitis C test.
• Presence of fever, defined as participant presenting with a temperature reading of ≥37.9ºC on Day -2, Day -1, and/or pre-challenge on Day 0.
• Those employed or immediate relatives of those employed at hVIVO or the sponsor.
• Any other medical, psychiatric, social, or occupational condition and/or responsibility that, in the opinion of the PI/investigator, would interfere with, or serve as a contraindication to, protocol adherence or the assessment of safety (including reactogenicity) will deem the participant unsuitable for the study.

Any other reason that in the opinion of the PI/investigator raises a concern that the participant will not be able to cope with quarantine requirements.