Study of the Transmission of Cytomegalovirus (CMV) Infection From Mother to Foetus

• ClinicalTrials.gov Identifier: NCT01251744
• Recruitment Status: Completed
• First Posted: December 2, 2010
• Results First Posted: January 2, 2020
• Last Update Posted: June 29, 2020
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

This study is designed to evaluate maternal virological and immunological parameters to determine their ability to predict congenital cytomegalovirus (CMV) infection. When a pregnant woman is infected with CMV, her immune system (which protects her from infection) is activated and the virus can be found in the woman's bodily fluids (blood, saliva, urine, vaginal secretions). The aim of this study is to find out if there is a link between either the pregnant woman's immune response or the presence of the virus in these bodily fluids and the child/foetus being infected with the virus.

Condition or disease	Intervention/treatment	Phase
Infections, Cytomegalovirus; Cytomegalovirus Infections	Procedure: Blood sample; Procedure: Cord blood sample; Procedure: Saliva swab; Procedure: Urine sampling; Procedure: Vaginal swab	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 160 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Study of Maternal-foetal Cytomegalovirus (CMV) Transmission
• Actual Study Start Date: December 9, 2010
• Actual Primary Completion Date: November 6, 2013
• Actual Study Completion Date: June 17, 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: CMV Mothers' Group; Pregnant subjects with confirmed primary CMV infection.	Procedure: Blood sample; Blood sample at study entry, every two months during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Cord blood sample; Cord blood sample taken at the time of delivery.; Procedure: Saliva swab; Saliva swab taken at study entry, every month during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Urine sampling; Approximately 10 mL of urine will be sampled at study entry, every month during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Vaginal swab; Vaginal swab taken at study entry, every month during pregnancy and one month after pregnancy conclusion.
Experimental: CMV Newborns' Group; Offsprings of the CMV Mothers' Group, also tested for CMV infection, comprising infants that were live born.	Procedure: Blood sample; Blood sample at study entry, every two months during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Cord blood sample; Cord blood sample taken at the time of delivery.; Procedure: Saliva swab; Saliva swab taken at study entry, every month during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Urine sampling; Approximately 10 mL of urine will be sampled at study entry, every month during pregnancy, at pregnancy conclusion and one month after pregnancy conclusion.; Procedure: Vaginal swab; Vaginal swab taken at study entry, every month during pregnancy and one month after pregnancy conclusion.

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects With Any Cytomegalovirus (CMV) Congenital Infection [ Time Frame: At Month 0 ]
   The CMV congenital infections were assessed in newborns and foetuses of subjects who had a confirmed primary CMV infection during pregnancy.
2. Number of Subjects With CMV Presence in the Urine [ Time Frame: Within 10 days post-delivery (Days 0-9) ]
   Evidence of infection in urine was assessed by culture or by Polymerase Chain Reaction (PCR).
3. Number of Subjects With CMV Presence in the Amniotic Fluid [ Time Frame: Within 10 days post-delivery (Days 0-9) ]
   Evidence of infection in the amniotic fluid was assessed by culture or by Polymerase Chain Reaction (PCR).
4. Evidence of CMV DNA or CMV Inclusions in Tissues of an Aborted or Stillborn Foetus [ Time Frame: Within 10 days post-delivery (Days 0-9) ]
5. Number of CMV DNA Copies in Saliva, Urine, Blood or Vaginal Secretions [ Time Frame: At Month 0 ]
   The assessment focused on the presence of CMV DNA copies (by Quantitative Polymerase Chain Reaction [qPCR]) in saliva, urine, blood and vaginal secretions every month from study entry to, and including, pregnancy conclusion.
6. Number of CMV DNA Copies in Saliva, in Urine and in Blood or Vaginal Secretions [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
   The assessment focused on the presence of CMV DNA copies (by Quantitative Polymerase Chain Reaction [qPCR]) in saliva, urine and blood every month from study entry to, and including, pregnancy conclusion.
7. Descriptive Statistics of the Anti-CMV Immunoglobulin Type M (IgM) Status [ Time Frame: At Month 0 ]
   Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay [ELISA], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
8. Descriptive Statistics of the Anti-CMV IgM Status [ Time Frame: At Month 2 ]
   Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay [ELISA], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
9. Descriptive Statistics of the Anti-Cytomegalovirus (Anti-CMV) Immunoglobulin Type M (IgM) Status [ Time Frame: At Month 4 ]
   Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay [ELISA], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
10. Anti-CMV Immunoglobulin Type M (IgM) Status, Descriptive Statistics [ Time Frame: At Month 6 ]
    Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay [ELISA], with respect to positive and negative subjects.
11. Descriptive Statistics for the Anti-CMV IgM Status [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Anti-CMV IgM status was assessed by Enzyme-Linked Immunosorbent Assay [ELISA], with respect to positive and negative subjects. Grey Zone = optical density zone within 20% of cut-off value. When an optical density is within this grey zone, sample testing is repeated to confirm the result.
12. Anti-glycoprotein B (gB) Immunoglobulin Type G (IgG) Antibody Concentrations [ Time Frame: At Month 0 ]
    Anti-gB IgG concentrations were assessed by ELISA, presented as geometric mean concentrations (GMCs) and expressed in ELISA units per milliliter (EU/mL). The cut-off value was greater than or equal to (≥) 54 EU/mL.
13. Anti-gB IgG Antibody Concentrations [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Anti-gB IgG concentrations were assessed by ELISA, presented as geometric mean concentrations (GMCs) and expressed in ELISA units per milliliter (EU/mL). The cut-off value was greater than or equal to (≥) 54 EU/mL.
14. Descriptive Statistics of the Anti-glycoprotein B (gB) Immunoglobulin Type G (IgG) Avidity Index [ Time Frame: At Month 0 ]
    The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
15. Descriptive Statistics of the Anti-gB IgG Avidity Index [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
16. CMV-specific Cluster of Differentiation 4 (CD4) T-cell Frequencies [ Time Frame: At Month 0 ]
    Descriptive statistics of the frequency of CMV-specific CD4 T cells expressing at least two markers among: cluster of differentiation 40 ligand (CD40L), interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), as assessed by Intracellular Cytokine Staining [ICS], by stimulating agent (among Human Cytomegalovirus [HCMV] immediate-early gene [IE1] antigen, HCMV glicoprotein B [gB] antigen, HCMV lysate antigen and HCMV pp65 antigen).
17. CMV-specific CD4 T-cell Frequencies [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Descriptive statistics of the frequency of CMV-specific CD4 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining [ICS], by stimulating agent (among immediate-early gene [IE1] antigen, glicoprotein B [gB] antigen, CMV lysate antigen and CMV pp65 antigen).
18. CMV-specific Cluster of Differentiation 8 (CD8) T-cell Frequencies [ Time Frame: At Month 0 ]
    Descriptive statistics of the frequency of CMV-specific CD8 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining [ICS], by stimulating agent (among immediate-early gene [IE1] antigen, glicoprotein B [gB] antigen, CMV lysate antigen and CMV pp65 antigen).
19. CMV-specific CD8 T-cell Frequencies [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Descriptive statistics of the frequency of CMV-specific CD8 T cells expressing at least two markers among CD40L, IL-2, IFNg, TNFa, as assessed by Intracellular Cytokine Staining [ICS], by stimulating agent (among immediate-early gene [IE1] antigen, glicoprotein B [gB] antigen, CMV lysate antigen and CMV pp65 antigen).
20. CMV-specific Proliferating Cluster of Differentiation (CD4) T Cells Frequencies [ Time Frame: At Month 0 ]
    Labelled cells were quantified by flow cytometry, by stimulating agent (among immediate-early gene [IE1] antigen, glicoprotein B [gB] antigen, CMV lysate antigen and CMV pp65 antigen).
21. CMV-specific Proliferating CD4 T Cells Frequencies [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]

    Labelled cells were quantified by flow cytometry, by stimulating agent (among immediate-early gene [IE1] antigen, glicoprotein B [gB] antigen, CMV lysate antigen and CMV pp65 antigen).

    Note: Results were retrieved by subtracting the background without imputing the negative and zero values, this generated negative values.

22. Concentrations of Anti-CMV Tegument Protein Immunoglobulin G (IgG) Antibodies [ Time Frame: At Day 0 = study entry ]
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
23. Anti-CMV Tegument Protein Immunoglobulin G (IgG) Antibody Concentrations [ Time Frame: At Month 2 ]
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
24. Concentrations of Anti-CMV Tegument Protein IgG Antibodies [ Time Frame: At Month 4 ]
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
25. Anti-CMV Tegument Protein IgG Antibody Concentrations [ Time Frame: At Month 6 ]
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
26. Concentrations of Anti-CMV IgG Antibodies [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Antibody concentrations were expressed as Geometric Mean Concentrations (GMCs), measured in units per milliliter (U/mL). Concentrations of antibodies were assessed by the Enzyme-Linked Immunosorbent Assay (ELISA) for a cut-off greater than or equal to (≥) 0.668 U/mL.
27. Descriptive Statistics of the Anti-CMV Tegument Protein Globulin Type B (gB) Immunoglobulin G (IgG) Avidity, by Congenital Infection Status [ Time Frame: At Day 0 = study entry ]
    Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
28. Descriptive Statistics of the Anti-CMV Tegument Protein gB Immunoglobulin G (IgG) Avidity, by Congenital Infection Status [ Time Frame: At Month 2 ]
    Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
29. Descriptive Statistics of the Anti-CMV Tegument Protein gB IgG Avidity, by Congenital Infection Status [ Time Frame: At Month 4 ]
    Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
30. Descriptive Statistics of the Anti-CMV Tegument Protein Globulin Type B (gB) IgG Avidity, by Congenital Infection Status [ Time Frame: At Month 6 ]
    Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
31. Anti-CMV Tegument Protein Globulin Type B (gB) Immunoglobulin G (IgG) Avidity Descriptive Statistics, by Congenital Infection Status [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Avidity of anti-CMV tegument protein gB IgG was assessed by ELISA. The avidity index was calculated as the mean absorbance of reactions in which the immune complexes were exposed to urea divided by the mean absorbance of reactions in which the immune complexes were not exposed to urea, expressed as a percentage.
32. Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast) [ Time Frame: At Month 0 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
33. Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast) [ Time Frame: At Month 2 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
34. Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast) [ Time Frame: At Month 4 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
35. Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast) [ Time Frame: At Month 6 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
36. Anti-CMV Antibody Titers, by Neutralisation Assay (Fibroblast) [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.
37. Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells) [ Time Frame: At Month 0 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 15 ED50.
38. Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells) [ Time Frame: At Month 2 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 15 ED50.
39. Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells) [ Time Frame: At Month 4 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 15 ED50.
40. Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells) [ Time Frame: At Month 6 ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 15 ED50.
41. Anti-CMV Antibody Titers, by Neutralisation Assay (Epithelial Cells) [ Time Frame: At pregnancy conclusion (Day 0 to 5, Day 0 = day of delivery, stillbirth or termination) ]
    Antibody titers were expressed as Geometric Mean Titers (GMTs), for the seropositivity cut-off of ≥ 10 ED50.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects who the investigator believes that they can and will comply with the requirements of the protocol .
• A pregnant female, 18 years of age or older at the time of study enrolment.
• Women with confirmed primary CMV infection.
• Written informed consent obtained from the subject.

Exclusion Criteria:

• Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to study entry.
• Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational pharmaceutical product.
• Previous vaccination against CMV infection.
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history or physical examination
• Major congenital defects, serious chronic illness or organ transplantation.
• Administration of immunoglobulins and/or any blood products within the three months preceding study enrolment or during the pregnancy.
• Documented Human immunodeficiency virus (HIV)-positive subject.
• Gestational age of more than 34 weeks, as determined by foetal ultrasound.

Contacts and Locations

Locations

Belgium

GSK Investigational Site

Brussels, Belgium, 1000

GSK Investigational Site

Bruxelles, Belgium, 1050

GSK Investigational Site

Bruxelles, Belgium, 1070

GSK Investigational Site

Charleroi, Belgium, 6000

GSK Investigational Site

La Louvière, Belgium, 7100

GSK Investigational Site

Leuven, Belgium, 3000

GSK Investigational Site

Liège, Belgium, 4000

GSK Investigational Site

Mons, Belgium, 7000

GSK Investigational Site

Wilrijk, Belgium, 2610

Sponsors and Collaborators

GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials; GlaxoSmithKline

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Antoine P, Olislagers V, Huygens A, Lecomte S, Liesnard C, Donner C, Marchant A. Functional exhaustion of CD4+ T lymphocytes during primary cytomegalovirus infection. J Immunol. 2012 Sep 1;189(5):2665-72. doi: 10.4049/jimmunol.1101165. Epub 2012 Aug 3.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01251744
• Other Study ID Numbers: 113134
• First Posted: December 2, 2010
• Results First Posted: January 2, 2020
• Last Update Posted: June 29, 2020
• Last Verified: May 2020

Keywords provided by GlaxoSmithKline:

Pregnancy; Congenital; Cytomegalovirus infection

Additional relevant MeSH terms:

Infection; Communicable Diseases; Cytomegalovirus Infections; Herpesviridae Infections; DNA Virus Infections; Virus Diseases