| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Respiratory Syncytial Virus (RSV) |
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| E.1.1.1 | Medical condition in easily understood language |
| Viral infection in the lungs |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10070358 |
| E.1.2 | Term | Human respiratory syncytial virus test positive |
| E.1.2 | System Organ Class | 100000109842 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the antiviral effect of inhaled PC786 compared to placebo in healthy adults who have received a clinical challenge strain of RSV (RSV-A Memphis 37b virus) inoculated via the intranasal route |
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| E.2.2 | Secondary objectives of the trial |
• To assess the safety and tolerability of repeat inhaled doses of PC786 in healthy adults inoculated with RSV-A Memphis 37b virus
• To obtain estimates of derived systemic pharmacokinetic parameters of PC786 and the potential circulating metabolite(s), if detectable, following the initial and repeat doses of inhaled PC786 for 5 days
• To determine the nasal concentrations of PC786 following facemask delivery
• To compare the effect of inhaled PC786 with that of placebo on mucus production in healthy adults inoculated with RSV-A Memphis 37b virus
• To compare the effect of inhaled PC786 with that of placebo on RSV symptoms in healthy adults inoculated with RSV-A Memphis 37b virus
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be male or female, aged between 18 and 55 years inclusive (at the time of consent) who fit one of the following criteria
Women of childbearing potential who have a documented menstrual period within 28 days prior to first dose.
Women of non-childbearing potential defined as being amenorrhoeic for >12 months with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms).
Men who are willing and able to use one of the contraception methods described in the protocol, from the time of the date of Viral Challenge, until 90 days after receipt of the final dose of study medication.
2. Sero-suitable to the challenge virus
3. In good health with no history of major medical conditions that will interfere with subject safety, as defined by medical history, physical examination, and routine laboratory tests and determined by the Investigator at a screening evaluation. The following conditions are deemed acceptable:
• Subjects with a history of rhinitis, currently inactive (within the last 30 days and not required nasal corticosteroids in this time) or with ongoing mild rhinitis may be included at the PI’s discretion
• Subjects with clinically mild atopic eczema/atopic dermatitis and clinically mild psoriasis may be included at the Investigator's discretion (e.g., use of low/mild potency regular topical steroids is acceptable. Eczema in the cubital fossa and/or use of medium to high potency dermal corticosteroids are exclusions)
• Subjects with a physician diagnosed underactive thyroid who have been controlled on treatment for at least 6 months with evidence of a normal thyroid function test (TFT) can be included at the discretion of the PI
• Subjects reporting physician diagnosed migraine can be included as long as there are no associated neurological symptoms such as hemiplegia or visual loss
• Subjects with physician diagnosed mild Irritable Bowel Syndrome (IBS) not requiring regular treatment can be included at the discretion of the PI
• Subjects who have experienced no more than one mild (mild is defined as having been treated with bronchodilators only) episode of wheeze after the age of 12, may be included at the Investigator’s discretion, providing the episode lasted no more than 2 weeks, and ended more than 1 year ago. A history of childhood asthma up to and including the age of 12 years is acceptable provided the subject is asymptomatic without treatment.
4. A total body weight ≥ 50 kg and Body Mass Index (BMI) ≥ 18 kg/m2 and ≤ 30kg/m2
5. Females must have a negative serum β human chorionic gonadotropin (β-hCG) at screening and a negative urinary pregnancy test at Day –2 or Day –1.
6. Subject must be willing and able to adhere to the restrictions and prohibitions required by this protocol.
7. An informed consent document signed and dated by the subject and the Investigator.
8. Subjects will have a documented medical history either prior to entering the study and/or following medical history review with the study physician at screening.
9. Serosuitable to the challenge virus, the serology result obtained suggests that the subject is appropriately sensitive to RSV (RSV-A Memphis 37b virus). |
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| E.4 | Principal exclusion criteria |
1. 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
2. Any clinically significant history of epistaxis within the last 3 months and/or history of being hospitalised due to epistaxis on any previous occasion
3. Any nasal or sinus surgery within six months of inoculation
4. Subjects who have smoked ≥ 10 pack years at any time
5. Subjects who have smoked < 10 pack years at any time if in the month prior to admission to the Quarantine Unit they have used tobacco in any form or other nicotine-containing products in any form or e-cigarettes
6. History or evidence of any clinically significant or currently active cardiovascular, respiratory, dermatological, gastrointestinal, endocrinological, haematological, hepatic, immunological, metabolic, urological, renal, neurological, psychiatric illness
• Psychiatric illness includes subjects with a history of depression and/or anxiety with associated severe psychiatric comorbidities, for example psychosis
• Subjects with a history of depression of any severity within the last 2 years will be excluded if the PHQ-9 score is ≥ 4
• Subjects with history of anxiety-related symptoms of any severity within the last two years will be excluded if the GAD-7 score is ≥ 4
7. Other major disease that, in the opinion of the Investigator, may interfere with a subject completing the study and necessary investigations. The following apply:
• Clinically active rhinitis (including hay fever) 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
• Any concurrent serious illness including history of malignancy that may interfere with the aims of the study or a subject completing the study. Basal cell carcinoma within 5 years of treatment or with evidence of recurrence is an exclusion
• Cluster headache/migraine or prophylactic treatment for migraine is an exclusion
8. A forced expiratory volume in 1 second (FEV1) < 80% of predicted value (using NHANES reference equations)
9. Subjects with any history of physician diagnosed and/or objective test confirmed asthma (except as stated in inclusion criterion 3), chronic obstructive pulmonary disease, pulmonary hypertension, reactive airway disease, or chronic lung condition of any aetiology
10. Twelve-lead ECG recording with clinically relevant abnormalities as judged by the study physician/PI
11. Positive human immunodeficiency virus, active hepatitis A, B, or C test
12. Confirmed positive test for drugs of abuse or urinary cotinine at screening or on admission
13. Venous access deemed inadequate for the phlebotomy and cannulation demands of the study
14. Presence of cold like symptoms and/or fever, defined as subject presenting with a temperature reading of > 37.5oC on Day -2, Day -1, and/or pre-Challenge on Day 0
15. Evidence of vaccinations within the 4 weeks prior to the planned date of Viral Challenge (VC), or intention to receive any vaccination(s) before the last day of follow-up
16. Receipt of blood or blood products, or loss (including blood donations) of 470 mL or more of blood during the 3 months prior to the planned date of VC, or planned during the 3 months after the final visit
17. Use of any medication or product (prescription or over-the-counter), for symptoms of hay fever, dermatitis, nasal congestion or respiratory tract infections including the use of regular nasal or medium-high potency dermal corticosteroids, antibiotics and First Defence™ (or generic equivalents) within 7 days prior to the planned date of VC apart from those described and allowed in exclusion criterion 7
18. Receipt of any investigational drug within 3 months prior to the planned date of VC
19. Receipt of three or more investigational drugs within the previous 12 months prior to the planned date of VC
20. Prior inoculation with a virus from the same virus-family as the Challenge Virus
21. Prior participation in another Human VC study with a respiratory virus in the preceding 12 months taken from the date of VC/first dosing with IP (whichever occurred first) in the previous study to the date of expected VC in this study
22. Receipt of systemic glucocorticoids or systemic antiviral drugs within 6 months prior to the planned date of VC
23. History or currently active symptoms suggestive of upper or lower respiratory tract infection within 6 weeks prior to VC
24. Use or anticipated use during the conduct of the study of concomitant medications, including vitamins or herbal and dietary supplements within the specified windows, unless in the opinion of the PI, the medication will not interfere with the study procedures or compromise subject safety |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The area under the curve (AUC 0-t) for RSV viral load measured in nasal washes by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in subjects with confirmed infection with RSV-A Memphis 37b |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AUC 0-t for RSV viral load from nasal washes (NW): Screening (S); Admit to Quarantine (A); Days 2-11, twice daily (12 hours between assessments), Days 12 and 28
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| E.5.2 | Secondary end point(s) |
• Safety data including, but not limited to, tabulation of adverse events (AEs), physical examinations, spirometry, vital signs, 12- lead ECGs and clinical laboratory results
• Derived pharmacokinetic parameters of PC786 and the potential circulating metabolite(s) if detectable, including AUC, Cmax, t1/2, tmax, accumulation ratio and metabolite(s) to parent AUC ratio, following repeat doses
• PC786 concentration determination in mucosal lining fluid (MLF) collected using synthetic absorptive matrix (SAM)
• Reduction in total weight of mucus produced post viral inoculation through to last administration of PC786 and until Day 12 post inoculation
• Relationship between various PK parameters (e.g., Cmax, Cmin, and AUC) and antiviral endpoints (e.g., viral load AUC, duration of shedding, symptom scores)
• Additional antiviral endpoints (as determined by RT-qPCR of nasal wash) including:
- change in viral load from baseline (prior to first dose of PC786) to Day 12 change in AUC0-t over different time periods
- time to non-detectability of virus from commencement of study medication
- peak viral load and time to peak viral load from baseline (prior to first dose of PC786)
- proportion of subjects with detectable virus by time following commencement of study medication
• Change in total RSV-A symptoms after challenge until Day 12 post inoculation (using a composite of 10 self-reported symptoms on the symptom diary card (SDC)) analysis includes, but not limited to, AUC total symptoms from baseline (prior to first dose of PC786) to Day 12 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AEs: Screening (S); Admit to Quarantine (A); Day (D) -2-12; D28
Physical Exam: S; A; D0 (pre & post Viral Challenge (VC)); D1-12; D28
Spirometry: S; A; D0 (pre VC); D1-12 (additional assessment will be performed at 30 minutes post the 2nd and 10th dose received by each subject); D28
Vital signs: S; A; D0-11 (TDS); D12; D28
ECG: S; A; D2, 5, 11, 28
Clinical labs: S; A; D2, 5, 8-11 (pre-last dose); D28
PK: D2-12
SAM: D2-10 (twice daily); D11-12; D28
Mucus weight: D-2; D0 (Pre VC); D1-12
NW: S; A; Days 2-11, (twice daily, 12 hours between assessments), Days 12 and 28
SDC: D-2, -1; D0-11 (TDS); D12
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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