| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Respiratory Syncytial Virus Infection |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 20.1 |
| 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 |
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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 |
| The primary objective is to determine in infants and children who are hospitalized with RSV infection the dose-response relationship of multiple regimens of ALS-008176 on antiviral activity based on nasal RSV shedding using quantitative real-time reverse transcriptase polymerase chain reaction [qRT-PCR] assay. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to determine in infants and children who are hospitalized with RSV infection:
• The impact of ALS-008176 on the clinical course of RSV infection including:
- Duration of hospital stay.
- Duration of supplemental oxygen.
- Clinical assessments (including clinician Clinical Outcome Assessment [COA]).
- Time to clinical stability.
• The time to cessation of nasal RSV shedding.
• The impact of ALS-008176 on the emergence of resistant strains of RSV.
• The safety and tolerability of ALS-008176.
• The PK of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in whole blood.
• The relationship between the PK and the PD (antiviral activity, clinical symptoms, and selected safety parameters) after single (LD) and repeated oral dosing (MD) of ALS 008176.
• The acceptability and palatability of the ALS-008176 formulation.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female infant who is ≥28 days to ≤36 months of age, inclusive, defined at the time of randomization.
2. Hospitalized (or in emergency room prior to hospitalization) at the time of randomization and unlikely to be discharged for the first 24 hours after randomization.
3. Diagnosed with RSV infection based on a PCR-based molecular diagnostic assay (Note: in cases where commercial PCR-based assays are not available at the site, the sponsor should be consulted for agreement on the assay to be used) with or without co-infection with another respiratory pathogen (eg, influenza, human metapneumovirus, or bacteria).
4. The time of onset of RSV symptoms to the time of randomization must be ≤5 days. Onset of symptoms is defined as the first time (within 1 hour) the parent(s)/caregiver(s) becomes aware of respiratory or systemic symptoms of RSV infection. At the recommendation of the IDMC, this duration may be decreased or increased to up to 7 days. If this occurs, the Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) will be notified promptly, without the need for a formal protocol amendment.
5. With the exception of the RSV-related illness or defined comorbid condition for severe RSV bronchiolitis (prematurity at birth [for infants <1 year old at randomization], bronchopulmonary dysplasia, congenital heart disease, other congenital diseases, Down Syndrome, neuromuscular impairment, or cystic fibrosis) the subject must be medically stable on the basis of physical examination, medical history, vital signs, and ECG performed at screening. If there are abnormalities, they must be consistent with the underlying condition in the study population. This determination must be recorded in the subject’s source documents and initialed by the investigator.
6. Medically stable on the basis of clinical laboratory tests performed at screening. If the results of the serum chemistry panel or hematology are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant or to be appropriate and reasonable for the population under study (RSV-related illness or defined comorbid conditions for severe RSV bronchiolitis). This determination must be recorded in the subject’s source documents and initialed by the investigator. A single repeat laboratory evaluation is allowed for eligibility determination.
7. Estimated glomerular filtration rate (GFR) is not below the lower limit of normal for the subject’s age (Schwartz equation calculation).
8. In the investigator’s opinion, the subject’s legally acceptable representative understands and is able to comply with protocol requirements, instructions, and protocol stated restrictions, and subject is likely to complete the study as planned.
9. Their legally acceptable representative must sign an ICF indicating that he or she understands the purpose of, and procedures required for, the study and is willing for the subject to participate in the study.
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| E.4 | Principal exclusion criteria |
1. Subject has known or suspected immunodeficiency (except immunoglobulin A [IgA] deficiency), such as known human immunodeficiency virus infection.
2. Receipt of (within the last 12 months) or currently on a waiting list for a bone marrow, stem cell or solid organ transplant, receipt of radiation or chemotherapy within 12 months prior to screening, or currently taking immunosuppressive medication.
3. Subjects who are anticipated to be treated with other agents with potential antiviral activity against RSV (eg, ribavirin, IV immunoglobulin, palivizumab).
4. History of or concurrent illness (beyond a defined comorbid condition for severe RSV bronchiolitis) that in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject or that could prevent, limit, or confound the protocol-specified assessments such as liver or renal insufficiency; significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, metabolic disturbances, or genetic diseases that result in immunosuppression. These may include, but are not limited to bacteremia, organ dysfunction, or other severe comorbidities.
5. Poorly functioning gastrointestinal tract (ie, unable to absorb drugs or nutrition via enteral route). Note: the use of IV fluids is not exclusionary so long as the investigator believes the subject’s gastrointestinal tract still functions properly (ie, is able to absorb drugs or nutrition).
6. Subject is being treated with extracorporeal membrane oxygenation.
7. Subject receiving chronic oxygen therapy at home prior to admission.
8. Taking any disallowed therapies before the planned first dose of study drug.
9. Received an investigational drug, an investigational vaccine, or used an invasive investigational medical device within 30 days or 5 half-lives (whichever is longer) before the planned first dose of study drug or is currently enrolled in an investigational study.
10. Planned or current participation in another interventional clinical study during this study.
11. Known allergies, hypersensitivity, or intolerance to ALS-008176 or its excipients.
12. Being breastfed by a mother taking any of the excluded medications.
13. Subject’s legally acceptable representative ie, parent(s)/legal guardian/caregiver(s), is not able to communicate reliably with the investigator.
14. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is RSV RNA viral load (measured by qRT-PCR in mid-turbinate nasal swab specimens) AUC from immediately prior to first dose of study drug (baseline) until Day 7.
NOTE: If the dosing duration is increased by the IDMC to up to 10 days, the RSV RNA viral load AUC in subjects assigned to the longer dose duration will be measured from baseline until 1 day (+2 days) after the last dose of study drug.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Immediately prior to first dose of study drug (baseline) until 1 day (+2 days) after the last dose of study drug.
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| E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• RSV clinical course endpoints:
- Length of hospital stay from admission to discharge and from study treatment initiation to discharge.
- Length of hospital stay from admission to readiness for discharge and from study treatment initiation to readiness for discharge, with readiness for discharge defined by the investigator.
- Need for and duration of intensive care unit (ICU) stay.
- Need for and duration of supplemental oxygen (regardless of method used).
- Respiratory rate, peripheral capillary oxygen saturation (SpO2), and body temperature return to pre-RSV disease level.
- Number of hours until SpO2 ≥93% on room air among subjects who were not on supplemental oxygen prior to current hospitalization.
- Need for and duration of noninvasive ventilator support (eg, continuous positive airway pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation).
- Evolution of signs and symptoms of RSV disease as assessed by the clinician COA.
- Amount of food intake, hydration, and feeding by IV administration/enteral tube.
- Time to clinical stability defined as the time at which the following criteria are all met:
- normalization of blood oxygen level (return to baseline, by pulse oximetry) without requirement of supplemental oxygen beyond baseline level
- intravenous or enteral tube feeding/hydration no longer required
- normalization of respiratory rate
- normalization of heart rate
• RSV RNA viral load as measured by qRT-PCR in the mid-turbinate nasal swab specimens, which will be used to determine the following:
- Viral load over time.
- Peak viral load, time to peak viral load. rate of decline of viral load, and time to RSV RNA being undetectable.
- Proportion of subjects with undetectable viral load at each timepoint.
- RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) until Day 10 and until Day 14.
• Sequence changes (postbaseline) in the RSV large (L)-polymerase gene and other regions (only if no mutations are seen in the L gene) of the RSV genome compared with baseline sequences.
• Safety/tolerability including AEs, physical examinations, vital signs, ECGs, and clinical laboratory results.
• Population-derived PK parameters of ALS-008112 and ALS-008144 (and other metabolites if applicable).
• Acceptability and palatability of the ALS-008176 formulation as assessed by the parent(s)/caregiver(s) COA.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As described in end points. |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| 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 | No |
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| Chile |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Hungary |
| Ireland |
| Israel |
| Japan |
| Korea, Democratic People's Republic of |
| Malaysia |
| New Zealand |
| Panama |
| Poland |
| Portugal |
| Singapore |
| Slovakia |
| Spain |
| Taiwan |
| Thailand |
| Ukraine |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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