Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Oral Lumicitabine Regimens in Hospitalized Adult Participants Infected With Human Metapneumovirus

Metapneumovirus Clinical Trial

— STEP  

Official title:

A Phase 2b, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Adult Subjects Infected With Human Metapneumovirus

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03502694
• Other study ID #: CR108378
• Secondary ID: 2017-001696-2264
• Status: Withdrawn
• Phase: Phase 2
• Start date: November 5, 2018
• Est. completion date: October 28, 2020

Study information

• Verified date: November 2018
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine in hospitalized adult participants infected with human metapneumovirus (hMPV - a virus closely related to respiratory syncytial virus (RSV) and has been identified as an important cause of acute respiratory infections, affecting all age groups) the dose-response relationship of multiple regimens of lumicitabine on antiviral activity based on nasal hMPV shedding using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay.

Description:

The study consists of 3 phases: screening phase, treatment phase (Day 1 to Day 5/6 [depending on timing of loading dose]), and follow-up phase of 28 days post randomization. Participants will have assessments at Days 7, 10, 14, and 28 to evaluate safety, efficacy, and pharmacokinetics (PK). The primary hypothesis of study is a positive dose-response relationship of active treatment on average hMPV viral load area under concentration versus time curve (AUC) over 7 days, meaning that either average AUC on pooled active treatments is lower than on placebo, or average AUC on high active dose is lower than average AUC on placebo using multiple contrast testing. Based on review of PK, efficacy and safety data, Independent Data Monitoring Committee (IDMC) may recommend modifications to study design that is changes in dose and treatment duration.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: October 28, 2020
• Est. primary completion date: April 30, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Participants 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

• Participants diagnosed with human metapneumovirus (hMPV) infection using a rapid polymerase chain reaction (PCR)-based molecular diagnostic assay, with or without coinfection with another respiratory pathogen (respiratory virus or bacteria)

• Participants with an acute respiratory illness with signs and symptoms consistent with a viral infection (for example, fever, cough, nasal congestion, runny nose, sore throat, myalgia, lethargy, shortness of breath, or wheezing) with onset less than or equal to (<=)5 days from the anticipated time of randomization

• With the exception of the symptoms related to hMPV infection, participants must be medically stable on the basis of physical examination, medical history, vital signs, and 12-lead electrocardiogram (ECG) performed at screening. If there are abnormalities, they must be consistent with the underlying illness in the study population, and/or the hMPV infection. This determination must be recorded in the participant's source documents and initialed by the investigator

• A woman must have a negative urine pregnancy test (beta-human chorionic gonadotropin [b-hCG]) at screening

Exclusion Criteria:

• Participants who are not expected to survive for more than 48 hours

• Participants who have had major thoracic or abdominal surgery in the 6 weeks prior to randomization

• Participants who are considered by the investigator to be immunocompromised within the past 12 months, whether due to underlying medical condition (for example, malignancy or genetic disorder) or medical therapy (for example, medications other than corticosteroids for the treatment of chronic obstructive pulmonary disease (COPD) or asthma exacerbations, chemotherapy, radiation, stem cell or solid organ transplant)

• Participants 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 milliliters per minute (mL/min) per 1.73 meter square (m^2)

• Participants with a known history of human immunodeficiency virus (HIV) or chronic viral hepatitis

Related Conditions & MeSH terms

• Metapneumovirus

Intervention

Drug:
• Lumicitabine
Participants will receive loading dose and maintenance dose of lumicitabine tablets orally.
• Placebo
Participants will receive matching placebo tablets orally.

Locations

Country	Name	City	State
Argentina	Hospital Interzonal General de Agudos Dr. Jose Penna	Bahia Blanca
Argentina	Hospital Regional Español	Bahía Blanca
Argentina	Hospital Italiano de Buenos Aires	Buenos Aires
Argentina	CEMIC Saavedra	Ciudad De Buenos Aires
Argentina	Hospital Italiano de La Plata	Ciudad De La Plata
Argentina	Hospital Privado-Universitario de Cordoba	Cordoba
Argentina	Hospital Rawson	Cordoba
Argentina	Instituto Medico Platense	La Plata
Australia	Flinders Medical Centre	Adelaide
Australia	Queen Elizabeth Hospital	Adelaide
Australia	Princess Alexandra Hospital	Brisbane
Australia	Barwon Health - University Hospital Geelong	Geelong
Australia	Royal Melbourne Hospital	Melbourne
Australia	Mater Hospital Brisbane	South Brisbane
Australia	Westmead Hospital	Sydney
Brazil	Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul	Porto Alegre
Brazil	Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo	Ribeirao Preto
Brazil	Hospital Alemão Oswaldo Cruz	Sao Paulo
Brazil	Hospital Das Clinicas Da Faculdade De Medicina Da Universidade De Sao Paulo	Sao Paulo
Brazil	Hospital Sirio Libanes	São Paulo
Bulgaria	MHAT 'Sv. Ivan Rilski' Kozloduy EOOD	Kozloduy
Bulgaria	Specialized Hospital for Active Treatment of Pulmonary Diseases - Pernik	Pernik
Bulgaria	Specialized Hospital for Active Treatment of Pulmonary Diseases - Troyan EOOD	Troyan
Bulgaria	MHAT Dr Stefan Cherkezov	Veliko Tarnovo
France	CHU Rouen	Bois Guillaume
France	CHU caen	Caen
France	Hôpital Louis Mourier	Colombes
France	APHP - Hopital Henri Mondor	Créteil
France	CHU Dijon	Dijon
France	CHU Grenoble	La Tronche
France	CHU Nîmes	Nîmes
France	Hopital Saint-Louis	Paris
France	Hôpital Tenon	Paris
France	CHU la milétrie	Poitiers
France	CHU Saint-etienne	St Priest En Jarez
France	Hopital Foch	Suresnes
France	Centre Hospitalier Universitaire de Tours	Tours Cedex
Japan	Fukuoka University Hospital	Fukuoka
Japan	Ogaki Municipal Hospital	Gifu
Japan	National Hospital Organization Tenryu Hospital	Hamamatue
Japan	Japanese Red Cross Nagasaki Genbaku Isahaya Hospital	Isahaya
Japan	Shimane University Hospital	Izumo
Japan	Shinkomonji hospital	Kitakyusyu
Japan	Kobe City Medical Center General Hospital	Kobe-City
Japan	Japanese Red Cross Society Nagano Hospital	Nagano
Japan	Nagasaki University Hospital	Nagasaki
Japan	National Hospital Organization Higashinagoya National Hospital	Nagoya
Japan	Rinku General Medical Center	Osaka
Japan	SUBARU Health Insurance Society Ota Memorial Hospital	Ota
Japan	Tohoku Medical And Pharmaceutical University Hospital	Sendai
Japan	Saka General Hospital	Shiogama
Japan	National Hospital Organization Ibarakihigashi	Tokai-Mura
Japan	National Hospital Organization Tokyo National Hospital	Tokyo
Japan	Okinawa Prefectural Chubu Hospital	Uruma
Japan	Okitama Public General Hospital	Yamagata
Japan	Shimonoseki City Hospital	Yamaguchi
Japan	Shin Yukuhashi Hospital	Yukuhashi
Korea, Republic of	Soonchunhyang University Bucheon Hospital	Bucheon
Korea, Republic of	Yeungnam University Medical Center	Daegu
Korea, Republic of	Gachon University Gil Hospital	Incheon
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Kangnam Sacred Heart Hospital	Seoul
Korea, Republic of	Korea University Guro Hospital	Seoul
Malaysia	Hospital Sultanah Bahiyah	Alor Setar
Malaysia	Hospital Pulau Pinang	George Town
Malaysia	Hospital Raja Perempuan Zainab Ii	Kota Bharu
Malaysia	University Malaya Medical Centre	Kuala Lumpur
Malaysia	Sarawak General Hospital	Kuching
Malaysia	Hospital Miri	Miri
Malaysia	Hospital Taiping	Taiping
Netherlands	UMCG	Groningen
Netherlands	UMC Utrecht	Utrecht
Netherlands	Gelre Ziekenhuizen Zutphen	Zutphen
Poland	10 Wojskowy Szpital Kliniczny z Poliklinika	Bydgoszcz
Poland	Wojewódzki Szpital Specjalistyczny im. sw. Rafala w Czerwonej Górze	Checiny
Poland	SSZZOZ im. dr Teodora Dunina w Rudce	Mrozy
Poland	Samodzielny Publiczny Zespol Gruzlicy i Chorob Pluc w Olsztynie	Olsztyn
Poland	Samodzielny Publiczny Zespól Opieki Zdrowotnej w Proszowicach	Proszowice
Russian Federation	State Health Care Institution 'Engels city hospital #2'	Engels
Russian Federation	Regional State Health Care Institution 'Clinical Hospital #1'	Smolensk
Russian Federation	Clinical Infectious Diseases Hospital n. a. S.P. Botkin	St. Petersburg
Russian Federation	Saint-Petersburg State Health Care Institution 'Vvedenskaya Hospital'	St. Petersburg
Russian Federation	Saint-Petersburg State Public Health Organization City Clinical Hospital #26	St. Petersburg
Russian Federation	Siberian State Medical University	Tomsk
Russian Federation	State Health Care Institution of Voronezh region 'Voronezh regional clinical infectious hospital'	Voronezh
Russian Federation	Clinical Emergency Hospital n.a. N.V. Solovyev	Yaroslavl
Spain	Hosp. Gral. Univ. de Elche	Elche
Spain	Hosp. Univ. 12 de Octubre	Madrid
Spain	Hosp. Univ. de La Princesa	Madrid
Spain	Hosp. Univ. La Paz	Madrid
Spain	Hosp. Clinico Univ. de Santiago	Santiago De Compostela
Spain	Hosp. Alvaro Cunqueiro	Vigo
Sweden	Sahlgrenska University Hospital	Göteborg
Sweden	Skanes universitetssjukhus	Malmö
Sweden	Norrlands Universitetssjukhus	Umeå
Sweden	Akademiska Sjukhuset	Uppsala
Taiwan	Kaohsiung Veterans General Hospital	Kaohsiung
Taiwan	Far Eastern Memorial Hospital	New Taipei
Taiwan	Taipei Medical University Shuang Ho Hospital	New Taipei
Taiwan	China Medical University Hospital	Taichung
Taiwan	Taipei Municipal Wanfang Hospital	Taipei
Ukraine	Bukovian State Medical University, Dept. of Infectious Disease and Epidemiology	Chernivtsi
Ukraine	Ivano-Frankivsk Regional Clinical Hospital	Ivano-Frankivsk
Ukraine	Kharkiv National Medical University, Regional Clinical Infectious Hospital	Kharkiv
Ukraine	Vinnytsia City Clinical Hospital #1, Department of Infectious Diseases #1	Vinnytsya
United States	Northwestern University - Northwestern Memorial Hospital - Infectious Disease Center	Chicago	Illinois
United States	Lake Internal Medicine Associates	Eustis	Florida
United States	UCSF Fresno	Fresno	California
United States	MemorialCare Research Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	St Michaels Medical Center	Newark	New Jersey
United States	SUNY Upstate Medical University	Syracuse	New York

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Bulgaria,  France,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  Poland,  Russian Federation,  Spain,  Sweden,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Concentration-Time Curve (AUC) of Human Metapneumovirus (hMPV) Viral Load	The AUC of hMPV ribonucleic acid (RNA) logarithm base 10 (log10) viral load (measured by quantitative real time reverse transcriptase polymerase chain reaction [qRT-PCR] in the mid-turbinate nasal swab specimens) is estimated by analyzing mean log10 viral load values over time using a restricted maximum likelihood based repeated measures approach.	Baseline up to Day 7
Secondary	Number of Participants with Adverse Events as a Measure of Safety and Tolerability	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.	Up to 28 days
Secondary	Number of Participants with an Abnormal Physical Examination Findings (Height, Body Weight, Respiratory System, Nose, Ear, Throat, Facial and Neck Lymph Nodes, and Skin Examination) as a Measure of Safety and Tolerability	Number of participants with an abnormal physical examination will be reported. A complete physical examination (including all body systems, height [only at screening], and body weight measurement) or a directed physical examination including respiratory system, nose, ear, throat, facial and neck lymph nodes, and skin examination will be performed.	Up to 28 days
Secondary	Number of Participants with an Abnormal Vital Signs/Peripheral Capillary Oxygen Saturation (SpO2) Reading as a Measure of Safety and Tolerability	Number of participants with abnormal vital signs (including body temperature, heart rate, respiratory rate, systolic blood pressure [SBP], diastolic blood pressure [DBP]), and SpO2 measurements will be reported.	Up to 28 days
Secondary	Number of Participants with an Abnormal Electrocardiogram (ECG) Reading as a Measure of Safety and Tolerability	Number of participants with abnormal twelve-lead ECG will be reported.	Up to 28 days
Secondary	Number of Participants with Clinical Laboratory Abnormalities as a Measure of Safety and Tolerability	Number of participants with clinical laboratory abnormalities (clinical laboratory tests include the following: hematology panel, serum chemistry panel, urinalysis, estimated glomerular filtration rate (GFR), urine pregnancy test (women only), and serum procalcitonin levels) will be reported.	Up to 28 days
Secondary	Maximum Observed Plasma Concentration (Cmax) of JNJ-63549109	The Cmax is the maximum observed plasma concentration of JNJ-63549109. JNJ-63549109 is the metabolite of lumicitabine.	Dose 1: 0.5 to 1 hour postdose, and 2 to 3 hours postdose; Dose 2: predose, and 3 to 6 hours postdose; Dose 3 and 10: predose
Secondary	Concentration at 12 Hours Postdose (C12h) of JNJ-63549109	The C12h is the predicted concentration of JNJ-63549109 at 12 hours postdose.	Days 1, 2, and 5/6: 12 hours postdose
Secondary	Area Under the Plasma Concentration-Time Curve (AUC) of JNJ-63549109	AUC is defined as area under plasma concentration-time curve.	Dose 1: 0.5 to 1 hour postdose, and 2 to 3 hours postdose; Dose 2: predose, and 3 to 6 hours postdose; Dose 3 and 10: predose
Secondary	Ordinal Scale	The ordinal scale will be used to assess participant's status and consists of 6 categories that are exhaustive, mutually exclusive, and ordered, where: 1) Death, 2) Admitted to intensive care unit (ICU), 3) Non-ICU hospitalization requiring supplemental oxygen, 4) Non-ICU hospitalization not requiring supplemental oxygen, 5) Not hospitalized, unable to resume normal activities, 6) Not hospitalized, resumption of normal activities.	Day of last dose (Day 5 or Day 6)
Secondary	Length of Hospital Stay from Admission to Discharge	The length of hospital stay from admission to discharge will be reported.	From admission to discharge (Up to 28 days)
Secondary	Length of Hospital Stay from Admission to Readiness for Discharge	The length of hospital stay from admission to readiness for discharge will be reported.	From admission to readiness for discharge discharge (Up to 28 days)
Secondary	Length of Hospital Stay from Study Treatment Initiation to Discharge	The length of hospital stay from study treatment initiation to discharge will be reported.	From study treatment initiation to discharge (Up to 28 days)
Secondary	Length of Hospital Stay from Study Treatment Initiation to Readiness for Discharge	The length of hospital stay from study treatment initiation to readiness for discharge will be reported.	From study treatment initiation to readiness for discharge (Up to 28 days)
Secondary	Percentage of Participants Requiring Admission to the Intensive Care Unit (ICU)	The percentage of enrolled participants requiring admission to the ICU will be reported.	Up to 28 days
Secondary	Duration of ICU Stay	In the event that a participant requires admission to the ICU, the duration for how long the participant remained in the ICU will be measured.	Up to 28 days
Secondary	Percentage of Participants Requiring Oxygen Supplementation/Noninvasive Mechanical Ventilation Support	The percentage of enrolled participants requiring oxygen supplementation/noninvasive mechanical ventilation support (for example [eg], nasal cannula, face mask, continuous positive airway pressure, bilevel positive airway pressure) above pre-hMPV infection status will be reported.	Up to 28 days
Secondary	Duration of Oxygen Supplementation/Noninvasive Mechanical Ventilation Support	The duration of oxygen supplementation/noninvasive mechanical ventilation support (eg, nasal cannula, face mask, continuous positive airway pressure, bilevel positive airway pressure) above pre-hMPV infection status will be measured.	Up to 28 days
Secondary	Percentage of Participants Requiring Invasive Mechanical Ventilation Support	The percentage of enrolled participants requiring invasive mechanical ventilation support (eg, endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy) above pre-hMPV infection status will be reported.	Up to 28 days
Secondary	Duration of Invasive Mechanical Ventilation Support	The duration of invasive mechanical ventilation support (eg, endotracheal-mechanical ventilation or mechanical ventilation via tracheostomy) above pre-hMPV infection status will be measured.	Up to 28 days
Secondary	Time to no Longer Requiring Supplemental Oxygen	The time to which a participant no longer requires supplemental oxygen will be measured.	Up to 28 days
Secondary	Time to Clinical Stability	Time to clinical stability is 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 and normalization of heart rate.	Up to 28 days
Secondary	Number of Hours from Initiation of Study Treatment Until SpO2 is Greater Than or equal to (>=) 93 Percent (%) on Room air	The number of hours until SpO2 is >= 93% on room air among participants who were not on supplemental oxygen prior to onset of respiratory symptoms will be recorded.	Up to 28 days
Secondary	Time for Respiratory Rate to Return to Pre-hMPV Infection Status	The time for respiratory rate to return to pre-hMPV infection status will be recorded.	Up to 28 days
Secondary	Time for Peripheral Capillary Oxygen Saturation (SpO2) Return to Pre-hMPV Infection Status	The time for SpO2 to return to pre-hMPV infection status will be recorded.	Up to 28 days
Secondary	Time for Body Temperature to Return to Pre-hMPV Infection Status	The time for body temperature to return to pre-hMPV infection status will be recorded.	Up to 28 days
Secondary	Percentage of Enrolled Participants Who Require Hydration and/or Feeding by Intravenous (IV) Catheter or Nasogastric Tube	The percentage of enrolled participants who require hydration and/or feeding by intravenous (IV) catheter or nasogastric tube will be reported.	Up to 28 days
Secondary	Number of Participants With Bacterial Superinfections Reported as AEs	The number of participants with bacterial superinfections, as defined by the investigator based on clinical judgment and/or increasing procalcitonin levels, reported as AEs will be reported.	Up to 28 days
Secondary	Number of Participants With Treatment-Emergent Complications	The number of participants with treatment-emergent complications, including cardiovascular events and cerebrovascular events (for example, myocardial infarction, congestive heart failure exacerbation, arrhythmia, stroke) or Clostridium difficile-associated diarrhea, will be reported.	Up to 28 days
Secondary	Change From Baseline in the National Early Warning Score (NEWS) Over Time	The NEWS scoring system measures acute-illness severity using 7 physiological parameters (respiration rate, oxygen saturation, supplementary oxygen requirement, temperature, systolic blood pressure, heart rate, and level of consciousness). Each parameter is scored between 0 and 3 compared to normal ranges, with higher scores indicating greater severity. The total score is the sum of the individual physiological parameter values and ranges between 0 (least severe) and 21 (most severe).	Baseline up to 28 days
Secondary	Number of Participants With All-Cause Mortality	Number of participants will be assessed for all-cause mortality.	Up to 28 days
Secondary	Time to Return to Pre-hMPV Infection Functional Status (Katz Activities of Daily Living [ADL] score)	Katz activities of daily living will assess questions related to Bathing, Dressing, Toileting, Transferring, Continence and Feeding. For the six individual activities, a score of 1 indicates independence, and a score of 0 indicates dependence. Total score will be calculated by adding the scores of all six activities and ranges from 0 high (participant independent) to 6 low (participant very dependent).	Up to 28 Days
Secondary	hMPV Viral Load Over Time	Viral load over time will be measured in mid-turbinate nasal swabs (obtained from non-intubated participants) or in mid-turbinate nasal swabs and endotracheal samples (obtained from intubated participants or via suction through tracheostomy or other sampling methods) by qRT-PCR.	Up to 28 days
Secondary	Peak hMPV Viral Load	Peak viral load over time will be measured by qRT-PCR.	Up to 28 days
Secondary	Time to Peak hMPV Viral Load	Time to peak viral load as measured by qRT-PCR will be reported.	Up to 28 days
Secondary	Rate of Decline of hMPV Viral Load	Rate of decline in hMPV viral load during treatment as measured by qRT-PCR will be reported.	Up to 28 days
Secondary	Time to hMPV Ribonucleic Acid (RNA) Being Undetectable	Time to hMPV RNA being undetectable as measured by qRT-PCR.	Up to 28 days
Secondary	Percentage of Participants With Undetectable hMPV Viral Load at Each Timepoint	Percentage of participants with undetectable viral load at each time point will be reported.	From Day 1 to Day 7 and on Day 10, Day 14, and Day 28
Secondary	AUC of hMPV Viral Load From Baseline up to Day 10	The AUC of hMPV RNA log10 viral load (measured by qRT-PCR in the mid-turbinate nasal swab specimens) is estimated by analyzing mean log10 viral load values over time using a restricted maximum likelihood based repeated measures approach.	Baseline up to Day 10
Secondary	AUC of hMPV Viral Load from Baseline up to Day 14	The AUC of hMPV RNA log10 viral load (measured by qRT-PCR in the mid-turbinate nasal swab specimens) is estimated by analyzing mean log10 viral load values over time using a restricted maximum likelihood based repeated measures approach.	Baseline up to Day 14
Secondary	AUC of hMPV Viral Load in Participants Assigned to a Longer Dosing Duration From Baseline Until 1 day After the Last Dose of Study Drug	If dosing duration is increased by the Independent Data Monitoring Committee (IDMC), the AUC of hMPV viral load (measured by qRT-PCR in the mid-turbinate nasal swab specimens) will be estimated by analyzing mean log10 viral load values over time using a restricted maximum likelihood based repeated measures approach.	Baseline Until 1 day After the Last Dose of Study Drug (approximately up to 12 days)
Secondary	Number of Participants With Postbaseline Changes in the hMPV Polymerase Lgene and Other Regions of the hMPV Genome Compared With Baseline Sequences	Number of participants will be assessed for postbaseline changes in the hMPV polymerase Lgene (only if no mutations are seen in the Lgene) and other regions of the hMPV genome compared with baseline sequences.	Up to 28 days