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

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

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01995175

Enrollment

2409

Registered

2013-11-26

Start date

2013-12-12

Completion date

2021-11-03

Last updated

2022-11-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Respiratory Syncytial Virus

Keywords

Asthma, Respiratory Syncytial virus, Cohort study, Quarterly phone contacts, Wheeze, New born, Lower Respiratory Tract Infection

Brief 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.

Detailed 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.

Interventions

PROCEDURENasal 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.

PROCEDUREBlood 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.

OTHERDiary cards

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

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 6 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of RSV LRTI or Severe LRTI Episodes as Defined by the GlaxoSmithKline (GSK) LRTI Case Definition [Period 1]	From birth up to 2 years of age	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.
Incidence Rates of First Episode of Respiratory Syncytial Virus (RSV) Respiratory Tract Infection (RTI) [Period 1]	From birth up to 2 years of age	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.
Number of Subjects Hospitalized for RSV [Period 1]	From birth up to 2 years of age	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.
Incidence Rates of RSV Lower Respiratory Tract Infection (LRTI) or Severe LRTI as Defined by the LRTI Case Definition and Severity Scale [Period 1]	From birth up to 2 years of age	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.
Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (WHO [Modjarrad 2015]) [Period 1]	From birth up to 2 years of age	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.
Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (Nokes et al.) [Period 1]	From birth up to 2 years of age	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.

Secondary

Measure	Time frame	Description
Incidence Rates of First Episode of Medically Attended Wheeze [Period 2]	From 2 years of age up to 6 years of age	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.
Levels of RSV-A and B Neutralizing Antibodies in the Cord Blood [Period 1]	At birth (Month 0)	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.
Incidence Rates of First Episode of Reported Wheeze With Use of Any Medication [Period 2]	From 2 years of age up to 6 years of age	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.
Incidence Rates of First Episode of Wheeze or Asthma Requiring Hospital Admission [Period 2]	From 2 years of age up to 6 years of age	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.
Levels of RSV-A and B Neutralizing Antibodies in the Blood Serum [Period 1]	At 2, 4, 6, 12, 18 and 24 months of age	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.
GMTs of RSV A and B Neutralizing Antibodies in the Cord Blood by Subjects Classified According to Non-overlapping Disease Severity Categories [Period 1]	At Month 0	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.
GMTs of RSV A and B Neutralizing Antibodies by Subjects Classified According to Non-overlapping Disease Severity Categories [Period 1]	During the first 6 months of life	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.
Number of WHO LRTI Episodes by Age Categories [Period 1]	From birth up to 2 years of life	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.
Number of WHO Severe LRTI Cases by Age Categories [Period 1]	From birth up to 2 years of life	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.

Countries

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

Participant flow

Recruitment details

2409 subjects were enrolled in the primary study and followed-up from birth up to 2 years of age (Period 1 - from 0 up to 2 years of age). 1395 subjects from primary study were enrolled in the extension study and followed-up from 2 up to 6 years of age (Period 2 - from 2 up to 6 years of age).

Pre-assignment details

Out of 2409 subjects enrolled in the primary study, 7 subjects did not sign the re-consent for study participation after delivery (birth), leaving 2402 subjects enrolled. 1 subject was excluded due to protocol violation, hence 2401 subjects formed the Per Protocol Set-Primary Study. Out of 2148 subjects who completed the primary study, 10 subjects were excluded due to invalid ICF/fraudulent data, 743 did not further participate, and therefore, 1395 subjects were enrolled in the extension study.

Participants by arm

Arm	Count
Overall Group Newborn subjects followed up for Lower Respiratory Tract Infections (LRTI) symptoms from birth until they are 2 years of age and for incidence of wheeze and asthma up to 6 years of age.	2,401
Total	2,401

Withdrawals & dropouts

Period	Reason	FG000
Period 1 - From 0 up to 2 Years of Age	Lost to Follow-up	102
Period 1 - From 0 up to 2 Years of Age	Migrated / moved from the study area	49
Period 1 - From 0 up to 2 Years of Age	Other	67
Period 1 - From 0 up to 2 Years of Age	Withdrawal by Subject	35
Period 2 - From 2 up to 6 Years of Age	Consent withdrawal, not due to a Serious Adverse Event	7
Period 2 - From 2 up to 6 Years of Age	Lost to Follow-up	22
Period 2 - From 2 up to 6 Years of Age	Migrated/moved from the study area	6
Period 2 - From 2 up to 6 Years of Age	Other	21
Period 2 - From 2 up to 6 Years of Age	Protocol Violation	1

Baseline characteristics

Characteristic	Overall Group
Age, Customized 24 to 36 months of age	1395 Participants
Age, Customized Gestational age at birth ≤28 weeks	0 Participants
Age, Customized Gestational age at birth 29-32 weeks	26 Participants
Age, Customized Gestational age at birth 33-36 weeks	154 Participants
Age, Customized Gestational age at birth ≥37 weeks	2221 Participants
Race/Ethnicity, Customized Geographic ancestry African Heritage / African American	632 Participants
Race/Ethnicity, Customized Geographic ancestry American Indian or Alaskan Native	4 Participants
Race/Ethnicity, Customized Geographic ancestry Asian - Central/South Asian Heritage	5 Participants
Race/Ethnicity, Customized Geographic ancestry Asian - East Asian Heritage	4 Participants
Race/Ethnicity, Customized Geographic ancestry Asian - Japanese Heritage	1 Participants
Race/Ethnicity, Customized Geographic ancestry Asian - South East Asian Heritage	271 Participants
Race/Ethnicity, Customized Geographic ancestry Latino/Mestizo	103 Participants
Race/Ethnicity, Customized Geographic ancestry Native Hawaiian or Other Pacific Islander	2 Participants
Race/Ethnicity, Customized Geographic ancestry Not specified	117 Participants
Race/Ethnicity, Customized Geographic ancestry White - Arabic / North African Heritage	2 Participants
Race/Ethnicity, Customized Geographic ancestry White - Caucasian / European Heritage	549 Participants
Sex/Gender, Customized Female	708 Participants
Sex/Gender, Customized Male	704 Participants
Sex/Gender, Customized Missing	968 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 0
other Total, other adverse events	0 / 0
serious Total, serious adverse events	0 / 0

Outcome results

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.