| 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 |
For Part 1:
The primary objective is to characterize the pharmacokinetics (PK) and to confirm the population PK (popPK) model derived from healthy volunteers in hospitalized adults who are infected with RSV.
For Part 2:
The primary objective is to determine in hospitalized adults who are infected with RSV 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 impact of ALS-008176 on the clinical course of RSV infection including:
− Duration of hospital stay.
− Duration of supplemental oxygen.
− Evolution of Activities of Daily Living (ADL) as assessed by Katz ADL score.
− Time to clinical stability.
− Improvement on the ordinal scale.
− Rate of mortality and complications.
• The antiviral activity based on nasal RSV shedding using qRT-PCR assay (secondary for Part 1 only) and 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 pharmacokinetics (PK) of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in plasma.
• The relationship between the PK and pharmacodynamics (PD; antiviral activity, clinical symptoms, and selected safety parameters) after single (loading dose [LD]) and repeated oral dosing (maintenance dose [MD]) of ALS-008176. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. Criterion modified per Amendment 2:
1.1 Criterion modified per Amendment 3:
1.2 Men or women ≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place), 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. Criterion modified per Amendment 2:
3.1 Diagnosed with RSV infection based on polymerase chain reaction (PCR)-based assay with or without co-infection with another respiratory pathogen (eg, influenza, human metapneumovirus, or bacteria).
4. Criterion modified per Amendment 2:
4.1 Has an acute respiratory illness with signs and symptoms consistent with a viral infection (eg, fever, cough, nasal congestion, runny nose, sore throat, myalgia, lethargy, shortness of breath, or wheezing) with onset ≤5 days from the anticipated time of randomization.
5. Criterion modified per Amendment 2:
5.1 With the exception of the RSV disease, medically stable on the basis of medical history, physical examination, vital signs, and 12-lead ECG performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population and/or RSV infection. 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, haematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the investigator judges the abnormalities or deviations from normal do not pose an unacceptable risk to the subject, are not clinically significant, or are appropriate and reasonable for the population under study. 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. Must sign an ICF (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
8. Criterion modified per Amendment 2:
8.1 A woman must have a negative urine β-human chorionic gonadotropin at screening.
9. Criterion modified per Amendment 2:
9.1 Contraceptive use by women should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
Before randomization, a woman must be either:
a. Not of childbearing potential defined as:
• Postmenopausal: a postmenopausal state is defined as >45 years and no menses for 12 consecutive months without an alternative medical cause, OR
• Permanently sterile: permanent sterilization methods include hysterectomy, bilateral salpingectomy, bilateral tubal occlusion/ligation procedures (without reversal operation), and bilateral oophorectomy.
b. Of childbearing potential and, if heterosexually active,
• Practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
• Agrees to remain on a highly effective method throughout the study and for at least 44 days after the last dose of study drug.
10. Criterion modified per Amendment 2:
10.1 Contraceptive use by men should be consistent with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.
During the study and until the end of relevant systemic exposure, plus a minimum of 1 spermatogenesis cycle (ie. 104 days in total) after receiving the last dose of study drug, a man:
• Who is sexually active with a woman of childbearing potential must agree to use a barrier method of contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository)
• Who is sexually active with a pregnant woman must use a condom
• Must agree not to donate sperm
11. Criterion modified per Amendment 2:
11.1 Female partners of men must either be surgically sterilized, postmenopausal (amenorrhea for a minimum of 1 year) or, if of childbearing potential, must agree to practice a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) during the study and for 104 days following the last dose of study drug.
12. Criterion modified per Amendment 2:
12.1 A woman must agree not to donate eggs (ova, oocytes) during the study and for at least 104 days after receiving the last dose of study drug.
13. Willing and able to adhere to the prohibitions and restrictions specified in this protocol.
14. Subject must have a body weight ≥50.0 kg, at screening. |
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| E.4 | Principal exclusion criteria |
4.2. Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
1. Subjects who are not expected to survive for more than 48 hours.
2. Subjects who have had major thoracic or abdominal surgery in the 6 weeks prior to randomization.
3. Criterion modified per Amendment 2:
3.1 Subjects who are considered by the investigator to be immunocompromised within the past 12 months, whether due to underlying medical condition (e.g., malignancy or genetic disorder) or medical therapy (e.g., medications other than corticosteroids for the treatment of COPD or asthma exacerbations, chemotherapy, radiation, stem cell or solid organ transplant).
4. Subjects with a known history of human immunodeficiency virus (HIV) or chronic viral hepatitis.
5. Subjects with ALT ≥3 times the upper limit of normal (ULN) AND bilirubin ≥2×ULN (direct >35%) OR ALT ≥5×ULN at screening.
6. Criterion modified per Amendment 2:
6.1 Subjects undergoing peritoneal dialysis, haemodialysis, or hemofiltration or with an estimated glomerular filtration rate (GFR, determined by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) of <60 mL/min/1.73m2.
7. Known allergies, hypersensitivity, or intolerance to ALS-008176 or its excipients (refer to the IB).
8. Criterion deleted per Amendment 2
9. Subjects unwilling to undergo mid-turbinate nasal swab procedures or with any physical abnormality which limits the ability to collect regular nasal specimens.
10. Subjects unable to take medications enterally or with a known gastrointestinal-related condition that is considered by the sponsor or investigator to be likely to interfere with study drug absorption.
11. Women who are pregnant or breastfeeding.
12. Criterion modified per Amendment 2:
12.1 Men who plan to father a child while enrolled in this study or within 104 days after the last dose of study drug.
13. Subjects taking any disallowed therapies as noted in Section 8 before the planned first dose of study drug.
14. Criterion modified per Amendment 2:
Subjects who received prescription medications intended to prevent or treat the RSV infection itself (eg, ribavirin, IV immunoglobulin, palivizumab), 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.
15. Subjects with any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
16. Subjects who have used systemic corticosteroids for >7 consecutive days immediately prior to randomization at doses higher than 20 mg/day of prednisone or equivalent.
17. Subject is being treated with extracorporeal membrane oxygenation.
18. Subjects with 1 or more of the following laboratory abnormalities at screening as defined by the Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity Table:
- Hemoglobin <9.5 g/dL
- Platelet count <75,000/mm³
- White blood cell count <1,000/mm³
- Absolute neutrophil count <1,000/mm³
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For Part 1:
The primary endpoint is the PK of ALS-008112 and ALS-008144 (and other metabolites, if applicable) in plasma.
For Part 2:
The primary endpoint is RSV RNA viral load (measured by qRT-PCR in the mid-turbinate nasal swab specimens) area under the concentration-time curve (AUC) from immediately prior to first dose of study drug (baseline) until Day 7.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: PK samples should be collected at:
Dose 1 (LD): 0.5 to 1 hour postdose, 2 to 3 hours postdose, and 4 to 6 hours postdose
Dose 2: predose, 0.5 to 1.5 hour postdose, and 3 to 6 hours postdose
Dose 3: if patient has not been discharged, predose (preferable), or random sample
Day of discharge if still on study drug: random sample
Dose 10: if patient has not been discharged, predose (preferable) or random sample
Day 7: random sample at visit
Day 10: random sample at visit
If >10 doses are administered upon IDMC recommendation: prior to the last dose (if feasible)
Part 2: Immediately prior to first dose of study drug (baseline) until Day 7 |
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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).
− Number of hours until peripheral capillary oxygen saturation (SpO2) ≥93% on room air among subjects who were not on supplemental oxygen prior to the onset of respiratory symptoms.
− Respiratory rate, SpO2, and body temperature return to pre-RSV disease level.
− Need for and duration of non-invasive ventilator support (eg, continuous positive airway pressure) and/or invasive ventilator support (eg, endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy).
− Time to return to pre-RSV functional status (Katz ADL score).
− Need for hydration and feeding by intravenous catheter/nasogastric 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
• normalization of oral feeding
• normalization of respiratory rate
• normalization of heart rate
− Improvement on the ordinal scale.
− All-cause mortality.
• RSV RNA viral load as measured by qRT-PCR of 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 time point.
− The RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) until Day 7 (secondary for Part 1 only).
− RSV RNA viral load AUC from immediately prior to first dose of study drug (baseline) until Day 10 and until Day 14.
− RSV RNA viral load AUC in subjects assigned to a longer dosing duration, if dosing duration is increased by the Independent Data Monitoring Committee (IDMC), from baseline until 1 day after the last dose of study drug (Part 2 only).
• Sequence changes (postbaseline) in the RSV polymerase L-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 adverse events (AEs), physical examinations, vital signs, electrocardiograms (ECGs), and clinical laboratory results.
• Population-derived PK parameters of ALS-008112
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As described in the endpoints |
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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 | Yes |
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| France |
| Germany |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Sweden |
| Taiwan |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 25 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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