| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Respiratory Syncytial Virus Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| RSV is a common virus that can cause severe chest infections in small children, adults with heart, lung and immune system conditions and elderly people. |
|
| 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 | PT |
| E.1.2 | Classification code | 10061603 |
| E.1.2 | Term | Respiratory syncytial virus infection |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 activity of RV521 compared to placebo in healthy adult subjects inoculated with RSV-A Memphis 37b. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate RV521 compared to placebo in healthy adult subjects inoculated with RSV in terms of:
o Safety and tolerability
o Antiviral effect assessed by:
Clinical symptom-related endpoints
Viral-load related endpoints
o To characterise the pharmacokinetics
(PK) profile of multiple oral doses of RV521 in healthy subjects inoculated with RSV |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Aged 18 to 45 years from the day prior to signing the consent form.
2. 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, as determined by the Investigator at a screening evaluation.
3. A documented medical history either prior to entering the study and/or following medical history review with the study physician at screening.
4. A total body weight ≥ 50 kg and BMI ≥ 18 kg/m2 and ≤ 30 kg/m2.
5. The following inclusion criteria are applicable to subjects undergoing viral challenge who are in a heterosexual relationship and female subjects in a same sex relationship (i.e., the criteria do not apply to those in a male same sex relationship unless otherwise stated):
a) True abstinence - when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
Or
b) Two forms of effective contraceptive methods among (between) the couple, which are defined as:
• For males:
i. Condom with spermicidal foam/gel/film/cream, sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. This applies only to males participating in the study) .
• For females:
i. Women no longer of child bearing potential (post-menopausal females are defined as having a history of amenorrhea for ≥2 years with no alternative medical cause , otherwise they should have documented status as being surgically sterile or post hysterectomy. The latter applies only to females participating in the study ).
ii. If of childbearing potential, acceptable forms of contraception include:
o Established (a minimum of 2 weeks prior to admission) use of oral, injected or implanted hormonal methods of contraception.
o Placement of an intrauterine device (IUD) or intrauterine system (IUS).
o Barrier methods of contraception or occlusive cap (diaphragm or cervical/vault caps), both with one of the following - spermicidal foam/gel/film/cream/suppository.
• The longevity of contraception is as follows:
i. Male subjects (including those in a same sex relationship) must comply with agreed contraception at entry to quarantine, and continuing until 90 days after the date of last dosing with IMP ().
ii. Male subjects must not donate sperm following discharge from quarantine until 90 days after the date of Viral Challenge/last dosing with IMP (whichever occurs last).
Female subjects of childbearing potential must have a negative pregnancy test at screening and just prior to the date of Viral Challenge and must be using contraception consisting of two forms of birth control (one of which must be a barrier method) starting from ≥2 weeks prior to entry to quarantine and continuing until 90 days after the date of Viral Challenge/last dosing with IMP (whichever occurs last).
6. An informed consent document signed and dated by the subject and the Investigator or designee.
7. Sero-suitable to the Challenge virus.
• The serology result obtained suggests that the subject is sensitive to RSV infection , i.e. they are likely to be infected following inoculation with the challenge virus.
8. A history of childhood asthma before the age of 12 years is acceptable provided the subject is asymptomatic without treatment. Subjects who have experienced no more than one mild episode of wheeze (mild is defined as having been treated with bronchodilators only), may be included at the Investigator’s discretion, providing the episode lasted no more than 2 weeks, and ended more than 1 year ago. |
|
| E.4 | Principal exclusion criteria |
1) For information on smoking and how it effects participation in the trial, please see Protocol Section 7.4 - Exclusion Criteria #1
2) Females who:
a) Are breastfeeding, or
b) Have been pregnant within 6 months prior to the study, or
c) Have a positive pregnancy test at any point during screening or prior to Viral Challenge.
3) A history or evidence of medically documented significant medical condition and its effect on participation in the trial. For more detailed information, please see Protocol Section 7.4 - Exclusion Criteria #3
4) A forced expiratory volume in 1 second (FEV1) < 80%.
5) Subjects with any history of physician diagnosed and/or objective test confirmed asthma, COPD, pulmonary hypertension, or chronic lung condition of any aetiology (see inclusion criteria number [8] for asthma).
6) Positive human immunodeficiency virus (HIV), active hepatitis A (HAV), B (HBV), or C (HCV) test.
7) Any significant abnormality altering the anatomy of the nose or nasopharynx in a substantial way that may interfere with the aims of the study and in particular any of the nasal assessments or viral challenge, (subjects with historical nasal polyps can be included, but large nasal polyps causing current and significant symptoms and/or requiring regular treatments in the last month are an exclusion).
8) Any clinically significant history of epistaxis (large nosebleeds) within the last 3 months and/or history of being hospitalized due to epistaxis on any previous occasion.
9) Any nasal or sinus surgery within 3 months of the date of Viral Challenge.
10) Twelve-lead ECG recording with clinically relevant abnormalities as judged by the study physician/PI.
11) Confirmed positive test for drugs of abuse or cotinine on admission.
12) Venous access deemed inadequate for the phlebotomy and cannulation demands of the study.
13) Presence of fever, defined as subject presenting with a temperature reading of ≥ 37.9oC on Day -2, Day -1, and/or pre-Challenge on Day 0.
14) Evidence of vaccinations within the 4 weeks prior to the planned date of Viral Challenge. Intention to receive any vaccination(s) before the Follow-up visit (Day 28). (NB. No travel restrictions will apply after the Follow-up visit).
15) Those employed or immediate relatives of those employed at hVIVO or the Sponsor.
16) Receipt of blood or blood products, or blood loss (including blood donations) of a maximum of 470 mL during the 3 months prior to the planned date of Viral Challenge or planned during the 3 months after the final visit.
17) For the use of medications their effect on study participation please see Protocol Section 7.4 - Exclusion Criteria # 17 & 21
18) For the participation in past clinical trials and their effect on study participation please see Protocol Section 7.4 - Exclusion Criteria #18
19) Receipt of systemic (intravenous and/or oral) glucocorticoids or systemic antiviral drugs within 3 months prior to the planned date of Viral Challenge.
20) History or currently active symptoms suggestive of upper or lower respiratory tract infection within 6 weeks prior to Viral Challenge.
21) History of anaphylaxis-and/or a history of severe allergic reaction or significant intolerance to any food or drug, as assessed by the PI.
22) History or presence of alcohol addiction, or excessive use of alcohol (weekly intake > 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 >5 cups of caffeinated drinks e.g. coffee, tea, cola).
23) Any other finding that, in the opinion of the Investigator, deems the subject unsuitable for the study.
24) Subjects of Japanese ethnicity, as determined by the following criteria being met; subjects must have lived outside of Japan for ≤ 5 years in total and be first generation Japanese, defined as born in Japan and having 4 biologic grandparents who are ethnic Japanese. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The area under the curve (AUC) for RSV viral load measured in nasal washes by quantitative Reverse transcription polymerase chain reaction (RT-qPCR), in subjects inoculated with RSV-A Memphis 37b. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints relating to efficacy include, but not limited to: Viral Load:
• AUC of RSV-A Memphis 37b as determined by cell based infectivity assay (cell based infectivity assay e.g. ‘plaque assay’) of nasal wash
• Additional viral load endpoints calculated separately using data from both RT-qPCR and cell based infectivity assay of nasal wash comparing placebo and RV521 treated including:
o peak viral load
o time to peak viral load
o time to resolution from peak
o time to cessation of virus detection post first dosing.
Clinical Symptoms:
• Effect of RV521 compared to placebo on RSV symptoms, with endpoints including:
o Peak total symptom scores over the duration of quarantine
o AUC of total symptom scores
o total symptom score (10 item diary card)
o time to peak symptom score after virus inoculation
o time to resolution.
• Total weight of nasal mucus produced (via weighed paper tissues) and total tissue count.
Secondary endpoints relating to safety include, but are not limited to:
• Adverse Events (AEs)
• Physical examinations
• Vital signs
• 12-lead electrocardiograms (ECGs)
• Spirometry
• Clinical laboratory results (including biochemistry, haematology, coagulation, cardiac enzymes and urine analysis).
Secondary endpoints related to PK include, but are not limited to:
• Time to maximum plasma concentration (tmax), terminal half-life (t½), maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) and area under the plasma concentration-time curve from time zero to infinity (AUC0-inf)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 |
|
| 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 | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| 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
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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