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Trial registered on ANZCTR


Registration number
ACTRN12619001322123
Ethics application status
Approved
Date submitted
27/08/2019
Date registered
27/09/2019
Date last updated
27/09/2019
Date data sharing statement initially provided
27/09/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Research to inform the impact of immunosuppressive medications taken during pregnancy on maternal and infant immune responses to vaccines
Scientific title
Research to inform the impact of immunosuppressive medications taken during pregnancy on maternal and infant immune responses to vaccines
Secondary ID [1] 298981 0
Nil known
Universal Trial Number (UTN)
Trial acronym
IMMUMUM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autoimmune disease 313972 0
Inflammatory bowel disease 313973 0
Lupus 314368 0
Condition category
Condition code
Inflammatory and Immune System 312373 312373 0 0
Autoimmune diseases
Oral and Gastrointestinal 312701 312701 0 0
Inflammatory bowel disease

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
This is an observational study assessing the safety and immunogenicity of influenza and pertussis vaccination in pregnant women exposed to biological disease-modifying anti-rheumatic drugs, and assessing immune responses to vaccines in their infants.

Exposures:
Group 1: Pregnant women with autoimmune disease exposed to biological disease-modifying anti-rheumatic drugs
Group 2: Pregnant women with autoimmune disease exposed to non-biological disease-modifying anti-rheumatic drugs
Group 3: Pregnant women with autoimmune disease who are not taking any immunosuppressive medications

What is required of participants:
* Consent to access records and share medical history
* Two blood tests for maternal participants
* Two blood tests for infant participants

Duration of observation for maternal participants is 5 months, and for infant participants is 7 months.

All pregnant women in Australia are routinely offered pertussis vaccination in each pregnancy, and influenza vaccination in each pregnancy where it is available (i.e. depending on seasonal availability of the vaccine). The women in our study would have been routinely offered these vaccines regardless of their involvement in this study.

Pertussis vaccine is given between 20 and 32 weeks gestation, in accordance with national guidelines. Influenza vaccine can be given at any time in pregnancy, and depends on availability of the vaccine. In this study, participants will receive the vaccine through their regular healthcare provider at the routine timepoints described above.
Intervention code [1] 315246 0
Not applicable
Comparator / control treatment
Group 4: Healthy control patients

What is required of participants:
* Consent to access records and share medical history
* Two blood tests for maternal participants
* Two blood tests for infant participants

Duration of observation for maternal participants is 5 months, and for infant participants is 7 months.

All pregnant women in Australia are routinely offered pertussis vaccination in each pregnancy, and influenza vaccination in each pregnancy where it is available (i.e. depending on seasonal availability of the vaccine). The women in our study would have been routinely offered these vaccines regardless of their involvement in this study.

Pertussis vaccine is given between 20 and 32 weeks gestation, in accordance with national guidelines. Influenza vaccine can be given at any time in pregnancy, and depends on availability of the vaccine. In this study, participants will receive the vaccine through their regular healthcare provider at the routine timepoints described above.
Control group
Active

Outcomes
Primary outcome [1] 321002 0
In the mothers: geometric mean concentrations (GMC) of IgG against pertussis toxin, filamentous haemagglutinin, pertactin, fimbriae agglutinogens 2-3 and influenza virus at the pre-vaccination visit, 4 weeks post vaccination and at delivery

This is a composite primary outcome.

The outcome will be assessed using serum multiplex assays for the vaccine specific antibodies listed above.

Timepoint [1] 321002 0
4 weeks post receipt of antenatal dTpa booster, given between 20 and 32 weeks of gestation
Primary outcome [2] 321003 0
In the infants: geometric mean concentrations (GMC) of IgG against pertussis toxin, filamentous haemagglutinin, pertactin, fimbriae agglutinogens 2-3, diphtheria toxoid, tetanus toxoid, Haemophilus influenza type B, pneumococcal 13 serotypes and hepatitis B virus

This is a composite primary outcome.

The outcome will be assessed using serum multiplex assays for the vaccine specific antibodies listed above.
Timepoint [2] 321003 0
At birth (cord blood) and 6 weeks: baseline measurements
At 7 months of age, 4 weeks after receipt of Infanrix Hexa (DTPa, IPV, hepatitis B, Hib)
Secondary outcome [1] 373664 0
Immunoglobulin levels in the infant (IgG, IgA, IgM) and IgG subclasses, lymphocyte and neutrophil counts,(lymphocyte subsets (T, B, and NK cell)

This is a composite secondary outcome, which will be measured by serum assay for immunoglobulins and flow cytometry for lymphocyte subsets.
Timepoint [1] 373664 0
At birth, 6 weeks and 7 months of age
Secondary outcome [2] 373665 0
Proportion of mothers with injection site reactions within 7 days of dTpa or influenza vaccine

Examples of known/possible adverse events include injection site redness, swelling or pain, as well as systemic symptoms such as fever and fatigue. Participants will be provided with 7 day diary cards and thermometers, and will be asked to record their temperature and symptoms daily. The diary cards include checkboxes for all symptoms being assessed, as well as a rating scale.
Timepoint [2] 373665 0
Within 7 days of receipt of dTpa vaccine, and within 7 days of receipt of influenza vaccine if given.
Secondary outcome [3] 373666 0
Serum drug levels for bDMARD in maternal blood
Timepoint [3] 373666 0
1. At the pre-vaccination visit
2. At delivery
Secondary outcome [4] 374942 0
Serum drug levels for bDMARD (infliximab or adalimumab) in infant blood (exploratory only)
Timepoint [4] 374942 0
Six weeks and seven months of age

Eligibility
Key inclusion criteria
1. Meets criteria for one of the study groups:
a. Group 1: receiving any bDMARD at any time during pregnancy
b. Group 2: receiving a non-biological DMARD at any time during pregnancy
c. Group 3: has autoimmune disease and is not receiving any immunosuppressive in pregnancy
d. Group 4: pregnant women who are generally well or any medical conditions are stable and well-controlled

2. Has provided written informed consent and is willing and able to comply with the scheduled visits and study procedures

3. Aged 18 to greater than or equal to 45 years.

4. English speaking with a good understanding of English language.

5. Available for the entire study period
Minimum age
18 Years
Maximum age
45 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Has received or will receive immunoglobulins and/or any blood products during the study period
2. Allergy to a vaccine component
3. Any other significant acute or chronic medical condition that in the opinion of the investigator may interfere with the interpretation of study results or place the participant at increased risk if they participate in the study.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
This is primarily a descriptive study to provide information to design future research, thus the sample size has been based partly on practical considerations and the expected recruitment rate. An absolute reduction of 30% in the percentage of participants achieving protective antibody levels in group 1 (exposed to biological disease-modifying anti-rheumatic drugs) compared to group 4 (healthy controls) would be considered clinically important and would warrant further research. Assuming 95% of healthy mothers and infants achieve antibody levels above the relevant protective threshold, a sample size of 33 per group would allow us to detect a difference in proportions achieving protective thresholds >/= 30% at 80% power with a two-sided alpha level of 0.025 to account for comparisons on both mothers and infants. All antibody concentrations will be log transformed for statistical analysis as geometric mean concentrates (GMC). Comparisons of the proportion of moths and infants achieving protective antibody levels in group 1 versus group 4 will be performed using chi-square tests. Statistical analysis will include both comparisons of GMC (with 95% confidence intervals) as a continuous variable (t test) and categorical variable using known protective threshold measures of antibodies to vaccine antigens (chi-square). Other exploratory analyses will use standard statistical methods and regression models may be used to examine predictors of outcome.

Subgroup analysis will include:
1. Comparison of pertussis vaccine induced immunity between women exposed to biological disease-modifying anti-rheumatic drugs during pregnancy and healthy women, and their respective infants, based on GMC of IgG against pertussis toxin, filamentous haemagglutinin, pertactin and fimbriae agglutinogens 2-3
2. Comparison of primary endpoint data for mothers taking infliximab versus adalimumab (exploratory only)
3. Serum drug levels for infliximab or adalimumab in infant blood (exploratory only). Drug levels will only be performed for infants whose mothers took infliximab or adalimumab during pregnancy. Mothers will be asked during study visits which medications they have taken during their pregnancy.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
21/11/2018
Date of last participant enrolment
Anticipated
31/12/2020
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
100
Accrual to date
32
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 14476 0
Westmead Hospital - Westmead
Recruitment hospital [2] 14477 0
Westmead Private Hospital - Westmead
Recruitment hospital [3] 14478 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [4] 14479 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [5] 14480 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [6] 14481 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 27491 0
2145 - Westmead
Recruitment postcode(s) [2] 27492 0
2065 - St Leonards
Recruitment postcode(s) [3] 27493 0
2050 - Camperdown
Recruitment postcode(s) [4] 27494 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 303522 0
Other Collaborative groups
Name [1] 303522 0
Sydney Health Partners
Country [1] 303522 0
Australia
Primary sponsor type
Individual
Name
Associate Professor Nicholas Wood
Address
The National Centre for Immunisation Research and Surveillance
Kids Research
The Children's Hospital at Westmead
Corner Hawkesbury Road & Hainsworth Street NSW 2145
Country
Australia
Secondary sponsor category [1] 303584 0
None
Name [1] 303584 0
Address [1] 303584 0
Country [1] 303584 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304048 0
Sydney Children's Hospital Network Human Research Ethics Committee
Ethics committee address [1] 304048 0
Ethics committee country [1] 304048 0
Australia
Date submitted for ethics approval [1] 304048 0
Approval date [1] 304048 0
24/04/2018
Ethics approval number [1] 304048 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95642 0
A/Prof Nicholas Wood
Address 95642 0
National Centre for Immunisation Research and Surveillance
Kids Research
The Children's Hospital at Westmead
Corner Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 95642 0
Australia
Phone 95642 0
+61 2 9845 1429
Fax 95642 0
+61 2 9845 1418
Email 95642 0
nicholas.wood@health.nsw.gov.au
Contact person for public queries
Name 95643 0
Ketaki Sharma
Address 95643 0
National Centre for Immunisation Research and Surveillance
Kids Research
The Children's Hospital at Westmead
Corner Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 95643 0
Australia
Phone 95643 0
+61 2 9845 0038
Fax 95643 0
+61 2 9845 1418
Email 95643 0
ketaki.sharma@health.nsw.gov.au
Contact person for scientific queries
Name 95644 0
Ketaki Sharma
Address 95644 0
National Centre for Immunisation Research and Surveillance
Kids Research
The Children's Hospital at Westmead
Corner Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Country 95644 0
Australia
Phone 95644 0
+61 2 9845 0038
Fax 95644 0
+61 2 9845 1418
Email 95644 0
ketaki.sharma@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.