Primary ObjectiveThe primary objective is to evaluate superiority of pimodivir in combination with SOC treatment compared to placebo in combination with SOC treatment on Day 6, with respect to the clinical outcome on the hospital recovery scale.
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
The primary endpoint is the hospital recovery scale as assessed on Day 6.
Secondary outcome
1. Safety and tolerability based on assessment of adverse events (AEs),
clinical laboratory assessments, 12-lead electrocardiograms (ECGs), vital
signs, and peripheral capillary oxygen saturation.
2. Time from start of study drug to hospital discharge and total length of
hospital stay.
3. Time from ICU admission to ICU discharge and total time in ICU.
4. Time from start to end of mechanical ventilation and total time on
mechanical ventilation.
5. The hospital recovery scale as assessed each separate day from Days 2 to 14
(excluding the primary time point).
6. Time to return to daily activities.
7. Incidence of complications associated with influenza after the start of
study treatment.
8. All-cause mortality.
9. Incidence and duration of antibiotic treatment.
10. The number (proportion) of subjects needing extended treatment.
11. The number (proportion) of subjects requiring re-hospitalization.
12. The number (proportion) of subjects not hospitalized at Day 6.
13. Time to clinical response.
14. Time to respiratory response.
15. PK parameters of pimodivir (ie, plasma concentration just prior to the
beginning or at the end of a dosing interval [Ctrough], Cmax, tmax,
and AUC12h), as determined by population PK analysis.
16. The acceptability of the pimodivir formulation in adolescents, as measured
by a taste and swallowability questionnaire.
17. Time to viral negativity by qRT-PCR and viral culture.
18. Viral load over time by qRT-PCR and viral culture.
19. The emergence of viral resistance against pimodivir detected by genotyping
and/or phenotyping.
Background summary
Both seasonal and pandemic influenza are a significant cause of morbidity and
mortality worldwide. Because the efficacy of the current annual
hemagglutinin-based or modified live influenza virus vaccines depends on
accurately predicting the viral strains prior to each influenza season or
pandemic and because vaccines are not provided universally, there remains
annually a significant burden of disease due to influenza. Several antiviral
drugs have been developed for the treatment of influenza. The 2 main classes of
antiviral drugs used against influenza are the neuraminidase inhibitors (NAIs)
and the viral matrix 2 (M2) protein inhibitors. Unfortunately, these drugs have
several limitations and there remains a need for better therapeutic options for
the treatment of influenza.
A desired profile of a novel influenza antiviral includes: (1) rapid onset of
protective effects leading to an expanded treatment window; (2) better activity
in patients with high viral load; (3) inhibition of both production and release
of virus; (4) maintenance of potency against neuraminidase and M2 inhibitor
resistant viral strains; (5) safe and well tolerated. Pimodivir, an inhibitor
of the viral replication complex, potentially meets all of these criteria.
Study objective
Primary Objective
The primary objective is to evaluate superiority of pimodivir in combination
with SOC treatment compared to placebo in combination with SOC treatment on Day
6, with respect to the clinical outcome on the hospital recovery scale.
Study design
This is a Phase 3 randomized, double-blind, placebo-controlled, multicenter
study to evaluate the efficacy and safety of pimodivir in combination with SOC
treatment vs placebo in combination with SOC treatment in adolescent (13 to 17
years), adult (18 to 65 years), and elderly (>65 to *85 years) hospitalized
subjects with influenza A infection.
A target of 600 hospitalized influenza infected subjects will be randomly
assigned in a 1:1 ratio to receive 1 of the following treatments in this study
with 300 subjects planned per treatment arm. The aim is to enroll a minimum of
approximately 60 adolescent subjects in this study in selected countries and
study sites consistent with local regulations. The randomization will be
stratified for baseline NEWS2 (4-5 or >5), type of baseline SOC (including or
not including influenza antiviral treatment), and time since onset of influenza
symptoms (first administration of study drug within 72 hours or between 72 and
96 hours since onset of influenza symptoms). The study population should
contain at least 75% of subjects (75% of the total planned sample size of 600
subjects) with first administration of study drug *72 hours since onset of
influenza symptoms and the remaining subjects should have first administration
of study drug between 72 and 96 hours since onset of influenza symptoms.
* Treatment Arm 1: pimodivir 600 mg twice daily (bid) for 5 days + SOC
treatment*
* Treatment Arm 2: pimodivir placebo bid for 5 days + SOC treatment*
*SOC treatment is determined by the investigator based on local practice, and
may include influenza antivirals and/or supportive care only. An influenza
antiviral as part of the SOC cannot be changed (eg, switching one influenza
antiviral for another) or started during either the treatment period or
extension phase, with the exception that an influenza antiviral may be
discontinued in the case of a suspected adverse event.
Study drug will be taken orally. During hospitalization, in case of medical
need, study drug tablets may be dispersed in water before intake (in case of
administration via a nasogastric tube or if the subject has difficulties
swallowing the tablets).
The study will consist of a screening/baseline visit, a double-blind treatment
period of 5 days (with the possibility to extend the treatment period), and a
follow-up period of 23 days after the last dosing day. The entire study
duration for each subject will be 28 days, except for subjects receiving
extended treatment, for whom the study will last 33 days. The study is
considered complete with the completion of the last study assessment for the
last subject participating in the study.
An Independent Data Monitoring Committee (IDMC) will be commissioned for this
study to monitor efficacy and safety data on a regular basis.
Intervention
Patients should take their prescribed doses of IP.
There are two treatment groups in this study:
* Pimodivir 600 mg, 2 tablets, twice per day for 5 days plus standard of care
treatment
* Placebo, 2 tablets, twice per day for 5 days plus standard of care treatment
*
This may be extended by PI for up to 5 additional days
Furthermore, their data of Medical history (including status of influenza
vaccinations) and demographic data will be collected They must undergo physical
and vital
signs examinations. Female participants will have a pregnancy test. An
electrocardiogram will be made. Blood, nasal swap sample and urine will be
collected
.
Study burden and risks
Although generally a self-limited disease, infection with influenza A can cause
significant morbidity and mortality and may result in hospitalization,
especially in certain patient populations such as those at the extremes of age.
Pimodivir is being developed for the treatment of patients who are hospitalized
due to or at high risk of complications from influenza A, and who have the
highest unmet medical need. As a therapeutic option intended for global use,
studying pimodivir in combination with the SOC accounts for worldwide
differences in the treatment of this population. In the instances where
pimodivir is administered with a NAI SOC option, an additive effect of
pimodivir over NAI administration alone will be explored in high-risk and
hospitalized subjects. Further, the FLZ3001 study design is based on a
recognition that local SOC approaches, particularly NAI, may have some benefit
to patients even if used off label, as was noted above. Accordingly, the study
design allows subjects to gain any potential benefits of the current SOC
therapies, while also assessing the benefit of pimodivir.
Pimodivir has been studied in healthy subjects, in subjects infected with a
challenge dose of influenza A and in in subjects naturally infected with
influenza. Pimodivir was generally safe and well tolerated.
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Listed location countries
Age
Inclusion criteria
* Male or female, 13 to 85 years of age, inclusive. Note: Adolescent subjects
(13-17 years) will be enrolled in selected countries and study sites consistent
with local regulations.
* Tested positive for influenza A infection after the onset of symptoms using a
polymerase chain reaction (PCR)-based or other rapid molecular diagnostic
assay.
* Requires hospitalization to treat influenza infection and/or to treat
complications of influenza infection (eg, radiological signs of lower
respiratory tract disease, septic shock, central nervous system [CNS]
involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney
disease, severe dehydration, myocarditis, pericarditis, ischemic heart disease,
exacerbation of underlying chronic pulmonary disease, including asthma, chronic
obstructive pulmonary disease [COPD], decompensation of previously controlled
diabetes mellitus), including subjects admitted to the intensive care unit
(ICU). Note: For the purpose of the protocol, subjects admitted under
*observation* status with an anticipated length of stay beyond 24 hours are
eligible for enrollment.
* Enrollment and initiation of study drug treatment *96 hours after onset of
influenza symptoms.
* Being on invasive mechanical ventilation or having an SpO2 <94% on
room air during screening. Subjects with known pre influenza SpO2 <94% must
have an SpO2 decline *3% from pre-influenza SpO2.
* Having a screening/baseline National Early Warning Score (NEWS2) of *4.
For a full list of inclusion criteria please refer to the protocol.
Exclusion criteria
* Received more than 3 doses of influenza antiviral medication (eg, oseltamivir
[OST] or zanamivir), or any dose of ribavirin within 2 weeks, prior to first
study drug intake. Received intravenous (IV) peramivir more than one day prior
to screening.
* Unwilling to undergo regular nasal mid-turbinate (MT) swabs or has any
physical abnormality which limits the ability to collect regular nasal MT
specimens.
* Unstable angina pectoris or myocardial infarction within 30 days prior to
screening (inclusive).
* Presence of clinically significant heart arrhythmias, uncontrolled, unstable
atrial arrhythmia, or sustained ventricular arrhythmia, or risk factors for
Torsade de Pointes syndrome.
* Known severe hepatic impairment (Child Pugh C cirrhosis) or chronic
hepatitis C infection undergoing hepatitis C antiviral therapy.
* Severely immunocompromised in the opinion of the investigator (eg,
known cluster of differentiation 4+ [CD4+] count <200 cells/mm3, absolute
neutrophil count <750/mm3, first course of chemotherapy completed within 2
weeks prior to screening, history of stem cell transplant within 1 year prior
to screening, any history of a lung transplant).
For a full list of exclusion criteria please refer to the protocol.
Design
Recruitment
Medical products/devices used
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 | EUCTR2017-002156-84-NL |
| ClinicalTrials.gov | NCTO3376321 |
| CCMO | NL62660.056.18 |