A Prospective, Epidemiological Study to Assess the Disease Burden of Respiratory Syncytial Virus Associated, Suspected Lower Respiratory Tract Infections in Newborns, From 0 to 2 Years of Age and Risk of Development of Wheeze and Asthma From 0 to 6 Years of Age

Respiratory Syncytial Virus Clinical Trial

Official title:

A Prospective, Epidemiological Study to Assess the Disease Burden of RSV Associated, Suspected LRTIs From 0 to 2 Years and Population Attributable Risk Percent of RSV LRTI on the Development of Recurrent Wheeze and Asthma From 0 to 6 Years

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01995175
• Other study ID #: 200150
• Status: Completed
• Phase: N/A
• Start date: December 12, 2013
• Est. completion date: November 3, 2021

Study information

• Verified date: November 2022
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the incidence and associated healthcare utilization of RSV-associated, suspected LRTI in a general population of infants from birth up to 2 years of age, and also to assess the accuracy of a newly developed LRTI case definition and severity scale compared to two existing definitions. The study will also assess the population attributable risk percent of RSV LRTI on the development of wheeze and asthma from 0 to 6 years of age.

Description:

New born infants from various countries over the world will be followed up for up to two years for the occurrence of Lower Respiratory Tract Infections. Through active and passive surveillance, any suspected case will be identified, assessed during an examination visit and followed up until completion through a diary card. Full symptomology will be assessed during the examination visit. The disease course and all healthcare utilization will be subsequently collected through a two-week diary card and contact with ay healthcare providers involved in management of the disease. RSV detection will occur through quantitative PCR of collected nasal swabs. A baseline cord blood serum sample of all subjects and a follow-up blood serum sample from a sub-cohort will also be collected to assess antibody levels at various points in time and in relation to risk of RSV LRTI. For extension period, pertaining to wheeze and asthma (Epoch 002): Subjects' parent(s)/LAR(s) will be asked to re-consent and subjects will be followed up through quarterly contacts up to the age of 6 years. Data collection will also occur from medical charts retrospectively for those who have a gap period between the end of the primary study and providing re-consent for the extension. The extension involves enrolment visit (at 2nd birthday [on completion of primary study or as soon as possible thereafter]) and quarterly surveillance contacts.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2409
• Est. completion date: November 3, 2021
• Est. primary completion date: October 3, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A to 6 Years

Eligibility

Inclusion Criteria:

Before birth:

• Subject whose parent(s)/Legally Acceptable Representative(s) (LARs), in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written informed consent (including consent to obtain a cord blood sample at birth) obtained from the parent(s)/LAR(s) of the subject.

After Birth:

• Subject for whom updated and re-signed informed consent and confirmation of eligibility is available not later than 5 working days after birth.
• Cord blood sample collection of at least 3 mL, at birth.

For extension period:

• Subject is enrolled at a study site that is participating in the extension period follow-up.
• Subject whose parent(s)/LAR(s), in the opinion of the investigator, can and will comply with the requirements of the protocol.
• Written informed consent (or witnessed thumb printed consent in case of an illiterate subject) obtained from the parent(s)/LAR(s) of the subject.
• Previous participation in the primary study (from birth up to the age of 2 years). Exclusion Criteria:

Before birth:

• Subject expected to become Child in care
• Subjects whose parent(s)/LAR(s) are below the age of 18 or the legal consenting age of the respective country if this is higher.

After Birth:

• Child in care
• Newborn with a gestational age of less than 28 weeks.
• Subjects with any congenital condition that will require an expected postnatal stay in hospital of more than 12 consecutive weeks.
• Subjects with major congenital defects or serious chronic illness limiting life expectancy to less than 5 years.
• Subjects with any confirmed or suspected immunosuppressive or immunodeficient condition (including positive infection with human immunodeficiency virus [HIV]), based on medical history, physical examination or positive test result.

For extension period:

• Child in care.

Related Conditions & MeSH terms

• Respiratory Syncytial Virus
• Respiratory Tract Infections

Intervention

Procedure:
• Nasal swab sampling
Nasal swab samples will be collected from subjects at each examination visit, if they develop respiratory tract infection symptoms with difficulty in breathing and are called for an examination visit in the study.
• Blood sampling
A single blood sample will be collected from a sub-cohort consisting of the first 2000 enrolled subjects when they are either 2, 4, 6, 12, 18 or 24 months old.

Other:
• Diary cards
Diary cards will be provided to parents or LARs of the subjects to record RTI/LRTI, wheeze and asthma symptoms.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Ciudad de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Rio Cuarto
Bangladesh	GSK Investigational Site	Dhaka
Canada	GSK Investigational Site	Halifax	Nova Scotia
Finland	GSK Investigational Site	Kokkola
Finland	GSK Investigational Site	Oulu
Finland	GSK Investigational Site	Pori
Finland	GSK Investigational Site	Seinajoki
Honduras	GSK Investigational Site	San Pedro Sula
Honduras	GSK Investigational Site	San Pedro Sula
South Africa	GSK Investigational Site	Soweto	Gauteng
Thailand	GSK Investigational Site	Bangkok
Thailand	GSK Investigational Site	Khon Kaen
Thailand	GSK Investigational Site	Pathum Thani
United States	GSK Investigational Site	Oakland	California
United States	GSK Investigational Site	Roy	Utah
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Santa Clara	California
United States	GSK Investigational Site	Seattle	Washington
United States	GSK Investigational Site	Syracuse	New York
United States	GSK Investigational Site	Syracuse	Utah
United States	GSK Investigational Site	Walnut Creek	California

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Bangladesh,  Canada,  Finland,  Honduras,  South Africa,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence Rates of First Episode of Respiratory Syncytial Virus (RSV) Respiratory Tract Infection (RTI) [Period 1]	The incidence rate was calculated by dividing the number of subjects reporting first episode over the follow-up period, to the total person-years. Detection of the RSV-infection was performed by reverse transcription quantitative real time polymerase chain reaction (RT-qPCR ) assay on ribonucleic acids (RNA) extracted from nasal swabs. Number of suspected RSV RTI cases were tabulated.	From birth up to 2 years of age
Primary	Number of Subjects Hospitalized for RSV [Period 1]	Healthcare utilization included primary, secondary and tertiary care settings such as self-care with Over-The-Counter [OTC] drugs, general practitioner [GP] visits, emergency room [ER] visits, hospital visits, etc. Note: This outcome measure presents results only for the more severe events of healthcare utilization - RSV hospitalization. Results for other causes (non-RSV) hospitalization and healthcare utilization for other settings were not calculated, as data were not available.	From birth up to 2 years of age
Primary	Incidence Rates of RSV Lower Respiratory Tract Infection (LRTI) or Severe LRTI as Defined by the LRTI Case Definition and Severity Scale [Period 1]	The incidence rate was calculated by dividing the number of subjects reporting first episodes over the follow-up period, to the total person-years. LRTI Case definition by WHO (Modjarrad 2015): LRTI is diagnosed when a child <5 years presents with cough and/or difficulty in breathing has the following symptoms: Fast breathing, (>60 per minute in a child <2 m, >50 per minute in a child 2 to 11 m and >40 per minute in a child 12 to 59 m) or Oxygen saturation <95% by pulse oximetry.; Severe LRTI is diagnosed when an infant with RSV LRTI has oxygen saturation<93% or lower chest wall drawing.	From birth up to 2 years of age
Primary	Number of RSV LRTI or Severe LRTI Episodes as Defined by the GlaxoSmithKline (GSK) LRTI Case Definition [Period 1]	LRTI Case definition by GSK: LRTI is diagnosed when a child <5 years presents with cough or runny or blocked nose and oxygen saturation <95% with a respiratory rate = 60/minute (< 2 months of age); = 50/minute (2 to 11 months of age); = 40/minute (12 to 24 months of age) and has RSV infection, confirmed on nasal swab positive for RSV A or B by quantitative polymerase chain reaction (qPCR).; Severe LRTI case definition by GSK: Child with LRTI and oxygen saturation < 92%, OR Difficulty breathing leading to: Irritability/agitation, or Lethargy/sleepiness, or Severe chest indrawing, or Reduced/no vocalization, or Apnoea > 20 sec, or Cyanosis, or Stop feeding well/dehydration.	From birth up to 2 years of age
Primary	Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (WHO [Modjarrad 2015]) [Period 1]	LRTI is diagnosed when a child <5 years presents with cough and/or difficulty in breathing has the following symptoms: Fast breathing, (>60 per minute in a child <2 m, >50 per minute in a child 2 to 11 m and >40 per minute in a child 12 to 59 m) or Oxygen saturation <95% by pulse oximetry. Severe LRTI is diagnosed when a child has LRTI and Oxygen saturation <93% by pulse oximetry and/or lower chest wall in-drawing.	From birth up to 2 years of age
Primary	Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (Nokes et al.) [Period 1]	LRTI is diagnosed when a child has a history of acute cough or difficulty in breathing and greater than or equal to (=) 1 of the following: Fast breathing for age (= 60 breaths/minimum if the child is < 2 m = 50 breaths/minimum if the child is 2-11 m). Indrawing, or Low oxygen saturation (< 90%) by pulse oximetry or inability to feed (prostration or unconsciousness), when accompanied by a clinical diagnosis of LRTI or bronchiolitis. Severe LRTI is diagnosed when a child has Indrawing, or Low oxygen saturation (< 90%) by pulse oximetry or inability to feed (prostration or unconsciousness), when accompanied by a clinical diagnosis of LRTI or bronchiolitis.	From birth up to 2 years of age
Secondary	Levels of RSV-A and B Neutralizing Antibodies in the Cord Blood [Period 1]	Levels of RSV A and B neutralizing antibodies were expressed as Geometric Mean Titers (GMTs) and the cut off for the neutralization assay was 8 End Point Dilution 60 percent (ED60) for RSV-A antibodies and 6 ED60 for RSV-B antibodies. Infant baseline blood sample serum was tested for detection of RSV neutralizing antibodies level.	At birth (Month 0)
Secondary	Levels of RSV-A and B Neutralizing Antibodies in the Blood Serum [Period 1]	Levels of RSV A and B neutralizing antibodies were expressed as GMTs and the cut off for the neutralization assay was 8 End Point Dilution 60 percent (ED60) for RSV-A antibodies and 6 ED60 for RSV-B antibodies. Infant blood sample serum was tested for RSV neutralizing antibodies level detection.	At 2, 4, 6, 12, 18 and 24 months of age
Secondary	GMTs of RSV A and B Neutralizing Antibodies in the Cord Blood by Subjects Classified According to Non-overlapping Disease Severity Categories [Period 1]	The association between RSV LRTI, RSV severe LRTI and RSV A and B neutralizing antibodies were assessed by calculating the GMTs of RSV A and B neutralizing antibodies in the cord blood by subjects classified according to non-overlapping disease severity categories: Non case (defined as subject not reporting RSV LRTI or RSV severe LRTI), WHO RSV LRTI (excluding WHO RSV severe LRTI) and WHO RSV severe LRTI.	At Month 0
Secondary	GMTs of RSV A and B Neutralizing Antibodies by Subjects Classified According to Non-overlapping Disease Severity Categories [Period 1]	The association between RSV LRTI, RSV severe LRTI and RSV A and B neutralizing antibodies were assessed by calculating the GMTs of RSV A and B neutralizing antibodies by subjects classified according to non-overlapping disease severity categories: Non case (defined as subject not reporting RSV LRTI or RSV severe LRTI), RSV LTRI and RSV severe LRTI.	During the first 6 months of life
Secondary	Number of WHO LRTI Episodes by Age Categories [Period 1]	LRTI refers to Child with RTI AND Blood Oxygen Saturation (SaO2) lower than (<) 95 percent (%), OR respiratory rate (RR) increase: higher than (>) 60/min < 2 months (m) of age; > 50/min 2-11m of age, 40/min 12-24m of age. Severe LRTI refers to Child with LRTI AND SaO2 < 92%, OR Difficulty breathing leading to: Irritability/agitation, OR Lethargy/sleepiness, OR Severe chest indrawing, OR Reduced/no vocalization, OR Apnoea > 20 sec, OR Cyanosis, OR Stop feeding well/dehydration. The number of WHO LRTI cases were assessed for the following age groups: 0-2, 3-5, 6-11 and 12-23 months of age. Occurrence of LRTI/severe LRTI cases as classified by the LRTI case definitions and severity scale, was not limited to the subgroups of subjects recruited from Months 1-6 and 13-18 but was provided for subjects in all age intervals: 0-2 months, 3-5 months, 6-11 months and 12-23 months.	From birth up to 2 years of life
Secondary	Number of WHO Severe LRTI Cases by Age Categories [Period 1]	LRTI refers to Child with RTI AND Blood Oxygen Saturation (SaO2) lower than (<) 95 percent (%), OR respiratory rate (RR) increase: higher than (>) 60/min < 2 months (m) of age; > 50/min 2-11m of age, 40/min 12-24m of age. Severe LRTI refers to Child with LRTI AND SaO2 < 92%, OR Difficulty breathing leading to: Irritability/agitation, OR Lethargy/sleepiness, OR Severe chest indrawing, OR Reduced/no vocalization, OR Apnoea > 20 sec, OR Cyanosis, OR Stop feeding well/dehydration. The number of WHO severe LRTI cases were assessed for the following age groups: 0-2, 3-5, 6-11 and 12-23 months of age.	From birth up to 2 years of life
Secondary	Incidence Rates of First Episode of Medically Attended Wheeze [Period 2]	The incidence rate was calculated by dividing the number of subjects reporting first episode of medically attended wheeze over the follow-up period, to the total person-years. Medically attended wheeze = an episode of health care provider confirmed wheeze. Medically attended wheeze, in the extension phase, was collected via a history from parents solicited by contact every 3 months, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.	From 2 years of age up to 6 years of age
Secondary	Incidence Rates of First Episode of Wheeze or Asthma Requiring Hospital Admission [Period 2]	The incidence rate was calculated by dividing the number of subjects reporting first episode of wheeze or asthma requiring hospital admission over the follow-up period, to the total person-years. Wheeze or asthma requiring hospital admission = an episode of health care provider confirmed wheeze or asthma requiring hospital admission. Wheeze or asthma requiring hospital admission, in the extension phase, was collected via a history from parents, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.	From 2 years of age up to 6 years of age
Secondary	Incidence Rates of First Episode of Reported Wheeze With Use of Any Medication [Period 2]	The incidence rate was calculated by dividing the number of subjects reporting first episode of reported wheeze with use of any medication over the follow-up period, to the total person-years. Reported wheeze = parents report a whistling sound associated with labored breathing. Prescription of medications for wheeze, in the extension phase, was collected via a specific request for relevant medication from parents, which was supplemented by the review of routine medical records or contact with health care provider. Incidence rate was assessed for the following categories: All subjects, Non-case (defined as subject not reporting RSV LRTI or RSV severe LRTI) and WHO RSV LRTI.	From 2 years of age up to 6 years of age