Primary ObjectiveFor 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…
ID
Source
Brief title
Condition
- Viral infectious disorders
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 curve (AUC) from immediately
prior to first dose of study drug (baseline) until Day 7.
Secondary outcome
Secondary Endpoints
The secondary endpoints for part 1 and part 2 are:
* Safety/tolerability including adverse events (AEs), physical examinations,
vital signs, electrocardiograms (ECGs), and clinical laboratory results.
* 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 noninvasive 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 (IV) catheter/nasogastric tube.
- Time to clinical stability defined as the time at which the following
criteria are all met:
o normalization of blood oxygen level (return to baseline; by pulse oximetry)
without requirement of supplemental oxygen beyond baseline level
o normalization of oral feeding
o normalization of respiratory rate
o 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.
* Population-derived PK parameters of ALS-008112
Exploratory Endpoints
The exploratory endpoints for part 1 and part 2 are:
* The amount of:
- Supplemental oxygen above pre-RSV disease level (regardless of method used)
from study treatment initiation to Day 7.
NOTE: If the dosing duration is increased by the IDMC to up to 10 days,
supplemental oxygen above pre-RSV disease level will be measured from treatment
initiation until 1 day after the last dose of study drug.
- Oxygen delivered by noninvasive ventilator support (eg, continuous positive
airway pressure) and/or invasive ventilator support (eg,
endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy).
- Subjects (proportion) who started antibiotic use after the first dose of the
study drug.
* Disease status and presence of complications with onset after treatment
initiation:
- Bacterial superinfections reported as AEs (eg, pneumonia, acute otitis media,
sinusitis, bronchitis, bacteremia).
- Exacerbations of underlying pulmonary disease (eg, asthma, chronic
obstructive pulmonary disease).
- Cardiovascular and cerebrovascular events (eg, myocardial infarction,
congestive heart failure exacerbation, arrhythmia, stroke).
- Respiratory failure.
- Clostridium difficile associated diarrhea.
- Other RSV-related complications.
* Duration and severity of signs and symptoms of RSV infection as assessed by
the respiratory infection patient-reported outcome (RI-PRO) questionnaire and
additional questions about health and functioning completed by the subject in
the eCOA.
* HRQoL assessed by the EuroQoL 5 Dimension 5 Level version (EQ-5D-5L)
completed by the subject in the eCOA.
* Hospital readmission for respiratory reasons up to the Day 28 follow-up visit.
* Medical resource utilization.
* RSV RNA viral load (AUC) as measured by qRT-PCR of endotracheal samples in
intubated subjects.
* RSV RNA viral load (AUC) as measured by qRT-PCR of mid-turbinate nasal swabs
and endotracheal samples in intubated subjects.
* Lung function measured by the DLCO and spirometry test.
* RSV infectious viral load as measured using a quantitative viral culture
(plaque assay).
Background summary
ALS-008176 (also known as JNJ-64041575 or lumicitabine) is a 3*,5*-
bisisobutyrate prodrug, which is readily metabolized to the cytidine nucleoside
analog polymerase inhibitor ALS-008112. Subsequently, inside cells, ALS 008112
is efficiently converted to its nucleoside triphosphate (NTP), ALS-008136. This
NTP is a selective inhibitor of respiratory syncytial virus (RSV) ribonucleic
acid (RNA)-dependent RNA polymerase activity and works via a classic chain
termination mechanism. ALS-008144, the uridine analog metabolite of ALS-008112,
is the inactive major metabolite noted in systemic circulation.
For Part 1, no formal hypothesis is specified. Part 1 is intended to
characterize the PK in the low-dose arm of 750 mg LD/250 mg MD ALS-008176 and
to confirm the popPK model derived from healthy volunteers in hospitalized
adult subjects infected with RSV. Furthermore, the safety and tolerability of
this regimen will be investigated before proceeding to Part 2 of the study
which will include the high-dose arm of 1,000 mg LD/500 mg MD ALS-008176.
For Part 2, the primary hypothesis is that there is a positive dose-response
relationship of active treatment on the average RSV RNA viral load AUC with the
average AUC on at least 1 of the active treatments being lower than the average
AUC on placebo.
Study objective
Primary Objective
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 infection the dose-response relationship of multiple regimens of
ALS-008176 on antiviral activity based on nasal RSV shedding using quantitative
reverse transcriptase-polymerase chain reaction (qRT-PCR) assay.
Secondary Objectives
The secondary objectives for Part 1 and Part 2 are to determine in hospitalized
adults who are infected with RSV:
- The safety and tolerability of lumicitabine.
- The impact of lumicitabine 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 lumicitabine on the emergence of resistant strains of RSV.
- The 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.
Exploratory Objectives
The exploratory objectives for Part 1 and Part 2 are to evaluate in
hospitalized adults who are infected with RSV
* The relationship between viral kinetics and clinical outcome, including the
relationship between RSV RNA viral load and:
- Oxygen supplementation.
- Duration of hospitalization.
- Katz ADL score.
- Clinical stability.
* The impact of the baseline viral subtype and genotype on the antiviral
activity.
* Onset of complications after initiation of treatment.
* The impact of ALS-008176 on the clinical course of RSV during and following
hospitalization as assessed by the subject in the electronic Clinical Outcome
Assessment (eCOA) using various scoring systems.
* The impact of RSV and its treatment on health-related quality of life (HRQoL)
as assessed by the subject in the eCOA.
* The relationship between the Katz ADL and the subject eCOA responses.
* Medical resource utilization to manage subjects.
* The comparison of the RSV RNA viral loads measured in mid-turbinate
nasal swabs and endotracheal samples from intubated subjects.
* The comparison of the RSV RNA viral loads measured in mid-turbinate nasal
swabs and endotracheal samples from intubated subjects.
* To explore the evolution of diffusing capacity of the lung for carbon
monoxide (DLCO) and spirometry in subjects hospitalized with an RSV infection.
Additionally, the impact of ALS-008176 on the infectious viral load may be
evaluated using a quantitative culture of RSV (plaque assay) on a selected
number of subjects and samples (mid-turbinate nasal swabs [if non-intubated] or
mid turbinate nasal swabs and endotracheal samples [if intubated] at the
sponsor"s discretion.
Study design
This is a randomized, double-blind, placebo-controlled, parallel-group,
multicenter, dose-finding study of lumicitabine in hospitalized adults of *18
years of age (or the legal age of consent in the jurisdiction in which the
study is taking place) who are infected with RSV. The study will be performed
in 2 parts.
Part 1
A target of approximately 24 subjects with a maximum of 36 subjects will be
randomized in a 1:2 ratio to Regimen A or B:
* Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10)
of matching placebo, administered twice daily.
* Regimen B (low-dose lumicitabine): a single 750 mg LD (Dose 1) followed by
nine 250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
The IDMC will review the safety and PK data after approximately 12 subjects
have completed treatment as per the IDMC charter. When approximately 24
subjects have completed the Day 14 follow-up visit, an unblinded primary
analysis will be performed by the sponsor, for review by the IDMC. Further
enrollment in this part of the study up to 36 subjects may continue while the
data are being analyzed. Once all data for Part 1 are collected and the
database locked, the sponsor may perform an unblinded, secondary analysis on
the full dataset of Part 1, to support clinical development.
Part 2
A target of approximately 90 subjects will be randomized in a 1:1:1 ratio to
Regimen A, B, or C with approximately 30 subjects planned per treatment regimen:
* Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10)
of matching placebo, administered twice daily.
* Regimen B (low-dose ALS-008176): a single 750 mg LD (Dose 1) followed by nine
250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
* Regimen C (high-dose ALS-008176): a single 1,000 mg LD (Dose 1) followed by
nine 500 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
Each part of the study will be conducted in 3 phases: a screening phase, a
treatment phase from Day 1 to Day 5/6 (depending on the timing of the LD
administration), and a follow-up phase for a total of 28 days post
randomization. Subjects will have assessments completed during hospitalization
and at the Day 7, Day 10, Day 14, and Day 28 visits. Depending on discharge
date, assessments will be completed either while hospitalized or during
outpatient visits. For hospitalized subjects additional assessments are done as
per the Time and Events Schedule. The duration of the subject*s participation
will be approximately 28 days, screening period not included.
Pharmacokinetic assessments will be performed using a popPK model. Intensive PK
sampling in Part 1 of this study will be used to update and confirm the popPK
model that was developed based on the data from healthy volunteers. Based on
the PK data from hospitalized adult subjects infected with RSV from Part 1 of
this study, the PK sampling for Part 2 was optimized. The popPK model may be
further modified or adapted as needed.
An unblinded IDMC will be commissioned for this study and a Sponsor Committee
will be established. For Part 1, the IDMC will review the safety and PK data as
described above. In Part 2, based on the reviews of PK, efficacy, and safety
data, changes to enrollment in the treatment arms, dose regimen adjustments, or
an increase in dose duration to up to 10 days may be implemented. In Part 2, a
maximum of 2 formal interim analyses are planned to assess the primary endpoint
for early superiority and futility. The first formal interim analysis will be
performed when at least 45 subjects have completed treatment to ensure that
adequate data is available for interim analysis review, preferably after the
end of a hemispheric RSV season. If the study is considered underpowered, a
sample size increase may be suggested to a maximum of 180 subjects.
Intervention
Part 1
A target of approximately 24 subjects with a maximum of 36 subjects will be
randomized in a 1:2 ratio to Regimen A or B:
* Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10)
of matching placebo, administered twice daily.
* Regimen B (low-dose lumicitabine): a single 750 mg LD (Dose 1) followed by
nine 250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
Part 2
A target of approximately 90 subjects will be randomized in a 1:1:1 ratio to
Regimen A, B, or C with approximately 30 subjects planned per treatment regimen:
- Regimen A (placebo): a single LD (Dose 1) followed by 9 MDs (Doses 2 to 10)
of matching placebo, administered twice daily.
- Regimen B (low-dose lumicitabine): a single 750 mg LD (Dose 1) followed by
nine 250 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
- Regimen C (high-dose lumicitabine): a single 1,000 mg LD (Dose 1) followed
by nine 500 mg MDs (Doses 2 to 10) of lumicitabine, administered twice daily.
Each part of the study will be conducted in 3 phases: a screening phase, a
treatment phase from Day 1 to Day 5/6 (depending on the timing of the LD), and
a follow-up phase for a total of 28 days post randomization.
Subjects will have assessments completed during hospitalization and at the Day
7, Day 10, Day 14, and Day 28 visits. Depending on discharge date, assessments
will be completed either while hospitalized or during outpatient visits. For
hospitalized subjects additional assessments are done as per the Time and
Events Schedule. The duration of the subject*s participation will be
approximately 28 days, screening period not included.
The study drug lumicitabine will be provided as tablets for oral
administration. Study drug administration should start as soon as possible, but
no later than 4 hours after randomization in order to maximize the opportunity
for the compound to inhibit viral replication and potentially improve outcomes.
Subjects will be dosed with a single LD followed by 9 MDs twice daily (at least
8 hours apart and with no more than 2 doses per calendar day) during Day 1 to
Day 5/6 (depending on the timing of the LD). Subjects will receive study drug
in a 1:1:1 ratio in 1 of the 3 treatment regimens shown in the table below.
Study burden and risks
Adverse events standards of care, adverse events from ALS-008176 of
lumicitabine, side effects from testing, unknown risks
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Listed location countries
Age
Inclusion criteria
1. 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. Diagnosed with RSV infection based on PCR-based assay with or without co-infection with another respiratory pathogen (eg, influenza,human metapneumovirus, or bacteria).
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. ;4. 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.;NOTE: The viral infection may present in any way as long as the underlying precipitant of the illness is considered by the investigator to be due to RSV infection. Examples of such an illness include:
* An upper or lower viral respiratory tract infection (eg, *flu-like illness*)
* Pneumonia
* Respiratory distress
* Asthma exacerbation
* Chronic obstructive pulmonary disease (COPD) exacerbation;5. 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 the 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, hematology, 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. A woman must have a negative urine ß-human chorionic gonadotropin at screening.;9. 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)
Examples of highly effective contraceptives include
- User-independent methods:
implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormone- releasing system; vasectomized partner; sexual abstinence.;- User-dependent methods:
combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable.
Typical use failure rates may differ from those 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.
Note: If the childbearing potential changes after start of the study or the risk of pregnancy changes (eg, a woman who is not heterosexually active becomes active) a woman must begin a highly effective method of contraception, as described throughout the inclusion criteria.;10. 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 (eg, 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. 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. A woman must agree not to donate eggs (ova, oocytes) during the study and for at least 44 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.
Exclusion criteria
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. Subjects who are considered by the investigator to be immunocompromised within the past 12 months, whether due to underlying medical condition (eg, malignancy or genetic disorder) or medical therapy (eg, 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. Subjects undergoing peritoneal dialysis, hemodialysis, or hemofiltration or with an estimated glomerular filtration rate (GFR, determined by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) of <60 mL/min.
GFR= 140 * min (Scr/k,1)* * max (Scr/k,1)-1.209 * 0.993Age * sex * race
Legend:
Min minimum of Scr/* or 1
Max maximum of Scr/* or 1
Scr serum creatinine measured in mg/dL
* 0.7 for women, 0.9 for men
* -0.329 for women, -0.411 for men
Age measured in years
Sex 1.018 for women, 1 for men
Race 1.159 for black, 1 for white and other;NOTE: The IDMC may recommend to lower the exclusionary GFR limit to <30 or <15 mL/min/1.73m2 if any available emerging PK data in subjects with GFR *60 mL/min/1.73m2 suggest that ALS-008112 exposure in the setting of moderate (ie, GFR *30 to <60 mL/min/1.73m2) or severe (ie, GFR *15 to <30 mL/min) renal impairment are projected to remain within an acceptable range.;In the event a local site is unable to perform a CKD-EPI determination, an alternative methodology for determining GFR is permissible if discussed with and approved by the sponsor.;7. Known allergies, hypersensitivity, or intolerance to lumicitabine/ALS-008176 or its excipients (refer to the IB).;8. Subjects unwilling to undergo mid-turbinate nasal swab procedures or with any physical abnormality which limits the ability to collect regular nasal specimens.;9. 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.;10. Women who are pregnant or breastfeeding.;11. Men who plan to father a child while enrolled in this study or within 104 days after the last dose of study drug.;12. Subjects taking any disallowed therapies as noted in Section 8 before the planned first dose of study drug.;13. 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.;14. Subjects with 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.;15. 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.;16. Subject is being treated with extracorporeal membrane oxygenation.;17. 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
NOTE: Retesting of abnormal laboratory values that may lead to exclusion will be allowed once without asking prior approval from the sponsor. Retesting will be performed once within the screening window. Subjects with a normal value at retest may be included.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001653-40-NL |
| ClinicalTrials.gov | NCT02935673 |
| CCMO | NL59053.056.16 |