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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

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ClinicalTrials.gov Identifier: NCT01995175
Recruitment Status : Active, not recruiting
First Posted : November 26, 2013
Results First Posted : February 15, 2019
Last Update Posted : August 28, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Respiratory Syncytial Virus Procedure: Nasal swab sampling Procedure: Blood sampling Other: Diary cards Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2409 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : December 12, 2013
Actual Primary Completion Date : October 3, 2017
Estimated Study Completion Date : October 22, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Prospective Cohort
Newborn subjects followed up for LRTI symptoms from birth until they are 2 years of age and for incidence of wheeze and asthma up to 6 years of age.
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.

Procedure: 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.




Primary Outcome Measures :
  1. Incidence Rates of First Episode of Respiratory Syncytial Virus (RSV) Respiratory Tract Infection (RTI) [ Time Frame: 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. 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.

  2. Number of Subjects Hospitalized for RSV [ Time Frame: 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.

  3. Incidence Rates of RSV Lower Respiratory Tract Infection (LRTI) or Severe LRTI as Defined by the LRTI Case Definition and Severity Scale [ Time Frame: 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 daignosed when an infant with RSV LRTI has oxygen saturation<93% or lower chest wall drawing.


  4. Number of RSV LRTI or Severe LRTI Episodes as Defined by the GlaxoSmithKline (GSK) LRTI Case Definition [ Time Frame: 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.

  5. Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (WHO [Modjarrad 2015]) [ Time Frame: 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 chest wall in-drawing.

  6. Number of RSV LRTI or Severe LRTI Episodes as Defined by the Existing Comparator LRTI Case Definition (Nokes et al.) [ Time Frame: 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 oxymetry 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 oxymetry or inability to feed (prostration or unconsciousness), when accompanied by a clinical diagnosis of LRTI or


Secondary Outcome Measures :
  1. Levels of RSV-A and B Neutralizing Antibodies in the Cord Blood [ Time Frame: At birth (Month 0) ]
    Levels of RSV A and B neutralizing antibodies were expressed as Geometric Mean Titers (GMTs) ad 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.

  2. Levels of RSV-A and B Neutralizing Antibodies in the Blood Serum [ Time Frame: 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.

  3. GMTs of RSV A and B Neutralizing Antibodies in the Cord Blood by Subjects Classified According to Non-overlapping Disease Severity Categories [ Time Frame: 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

  4. GMTs of RSV A and B Neutralizing Antibodies by Subjects Classified According to Non-overlapping Disease Severity Categories [ Time Frame: 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.

  5. Number of WHO LRTI Episodes by Age Categories [ Time Frame: 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.

  6. Number of WHO Severe LRTI Cases by Age Categories [ Time Frame: 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.

  7. Number of Subjects With Medically Attended Wheeze [ Time Frame: From 2 years of age up to 6 years of age. ]
    Medically attended wheeze, corresponds, in the extension phase, to a history from parents solicited by contact every 3 months, which may be supplemented by review of routine medical records or contact with health care provider.

  8. Number of Subjects With Wheeze or Asthma Requiring Admission [ Time Frame: From 2 years of age up to 6 years of age. ]
    Wheeze or asthma requiring admission corresponds to, in the extension phase, a history from parents, which may be supplemented by review of routine medical records or contact with health care provider.

  9. Number of Subjects With Medication Prescription for Wheeze or Asthma [ Time Frame: From 2 years of age up to 6 years of age. ]
    Prescription of medications for wheeze or asthma in the extension phase corresponds to a specific request for relevant medication from parents, which may be supplemented by review of routine medical records or contact with health care provider.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01995175


Locations
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United States, California
GSK Investigational Site
Oakland, California, United States, 94611
GSK Investigational Site
Sacramento, California, United States, 95815
GSK Investigational Site
Sacramento, California, United States, 95823
GSK Investigational Site
San Jose, California, United States, 95119
GSK Investigational Site
Santa Clara, California, United States, 95051
GSK Investigational Site
Walnut Creek, California, United States, 94596
United States, New York
GSK Investigational Site
Syracuse, New York, United States, 13210
United States, Utah
GSK Investigational Site
Roy, Utah, United States, 84067
GSK Investigational Site
Syracuse, Utah, United States, 84075
United States, Washington
GSK Investigational Site
Seattle, Washington, United States, 98105
Argentina
GSK Investigational Site
Ciudad de Buenos Aires, Buenos Aires, Argentina, C1431FWO
GSK Investigational Site
Rio Cuarto, Argentina, 5800
Bangladesh
GSK Investigational Site
Dhaka, Bangladesh, 1000
Canada, Nova Scotia
GSK Investigational Site
Halifax, Nova Scotia, Canada, B3K 6R8
Finland
GSK Investigational Site
Kokkola, Finland, 67100
GSK Investigational Site
Oulu, Finland, 90220
GSK Investigational Site
Pori, Finland, 28100
GSK Investigational Site
Seinajoki, Finland, 60100
Honduras
GSK Investigational Site
San Pedro Sula, Honduras
South Africa
GSK Investigational Site
Soweto, Gauteng, South Africa, 2013
Thailand
GSK Investigational Site
Bangkok, Thailand, 10330
GSK Investigational Site
Khon Kaen, Thailand, 40002
GSK Investigational Site
Pathum Thani, Thailand, 12120
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] December 15, 2017
Statistical Analysis Plan  [PDF] May 18, 2018

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01995175    
Other Study ID Numbers: 200150
First Posted: November 26, 2013    Key Record Dates
Results First Posted: February 15, 2019
Last Update Posted: August 28, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by GlaxoSmithKline:
Asthma
Respiratory Syncytial virus
Cohort study
Quarterly phone contacts
Wheeze
New born
Lower Respiratory Tract Infection
Additional relevant MeSH terms:
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Respiratory Tract Infections
Respiratory Tract Diseases
Infection