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Trial registered on ANZCTR


Registration number
ACTRN12613000661774
Ethics application status
Approved
Date submitted
7/06/2013
Date registered
17/06/2013
Date last updated
20/04/2017
Type of registration
Retrospectively registered

Titles & IDs
Public title
Detectability of Anti-D and Compliance in Two Regimens
Scientific title
Rhesus Negative Obstetric Population in Western Australia Receiving Treatment for the Prevention of Sensitisation to the D-Antigen: Comparison of Existing Australian Dosing Regime and a Single 1500IU Dose to Assess Protection from Sensitisation and Patient Compliance
Secondary ID [1] 282640 0
Nil
Universal Trial Number (UTN)
U1111-1144-1156
Trial acronym
DACTR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rhesus negative blood type
289341 0
Pregnancy
289342 0
Sensitisation to the D-Antigen 289343 0
Condition category
Condition code
Reproductive Health and Childbirth 289679 289679 0 0
Antenatal care

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Rh(D) Immunoglobulin-VF is a sterile, preservative-free solution containing human plasma proteins and 22.5 mg/mL glycine. The solution has a pH of 6.6. At least 98% of the protein is immunoglobulin (mainly IgG), with an anti-D (Rho) antibody content of 625 IU per vial/ =30 mg/mL human plasma proteins or 250 IU per vial/ =10 mg/mL human plasma proteins.Rh(D) Immunoglobulin-VF (Anti-D) is a human immunoglobulin preparation for intramuscular administration. Rh(D) Immunoglobulin-VF is prepared from blood obtained from voluntary and non-remunerated (unpaid) donors. Rh(D) Immunoglobulin-VF contains proteins called antibodies which help to suppress the unwanted immune response in an Rh(D) negative woman following her exposure to Rh(D) positive red cells. For example, if a pregnant woman has an Rh(D) negative blood group and her baby is Rh(D) positive, the baby's blood is incompatible with the mother’s. This could lead to reduced red blood cells, brain damage and other serious complications in the baby. This condition is known as Haemolytic Disease of the Newborn. Rh(D) Immunoglobulin-VF can be given to Rh(D) negative women during pregnancy and following birth of an Rh(D) positive baby to help prevent Haemolytic Disease of the Newborn. Rh(D) Immunoglobulin-VF is sometimes given on other occasions when a woman of child-bearing age may become exposed to Rh(D) positive blood: for example, after blood transfusion, amniocentesis (taking a sample of the fluid surrounding the unborn baby), miscarriage or stillbirth. Rh(D) Immunoglobulin-VF is available only with a doctor’s prescription.

Route for both control and intervention: Intra-muscular injection of Rh(D) Immunoglobulin-VF, produced by the Commonwealth Serum Laboratories (CSL), as per current practice

Control group: 625 IU Rh(D) Immunoglobulin-VF at 28 and 34 weeks gestation as per current KEMH practice.

Intervention group: 1500 IU Rh(D) Immunoglobulin-VF at 28 weeks gestation as approved in clinical guidelines for a single-dose regime.
Intervention code [1] 287307 0
Prevention
Comparator / control treatment
Standard Treatment
Control group: 625 IU Rh(D) Immunoglobulin-VF administered via intra-muscular injection at 28 and 34 weeks gestation as per current King Edward Memorial Hospital practice.
Control group
Dose comparison

Outcomes
Primary outcome [1] 289766 0
Detectability of anti-D at delivery via standard diagnostic practices employed at King Edward Memorial Hospital
Timepoint [1] 289766 0
Following delivery of each participant enrolled in this study
Primary outcome [2] 289767 0
Proportion of women receiving doses at correct gestation via analysis of number of enrolments compared with the number and timing of doses delivered in each arm of the study.
Timepoint [2] 289767 0
Following the delivery of all participants recruited to this study.
Secondary outcome [1] 303200 0
Risk factors for no detectable antibody at delivery via questionnaire and review of medical records
Timepoint [1] 303200 0
Following delivery of participant
Secondary outcome [2] 303201 0
Complication rates (obstetric and neonatal) via review of medical records.
Timepoint [2] 303201 0
Following delivery of participant
Secondary outcome [3] 303202 0
The total amount of anti-D used per participant:
The total amount of anti-D used per participant will be calculated by summing the amount of anti-D administered (International Units) during the trial period.

i.e. Participant in single dose arm 1500 = 1500 IU
Participant in two dose arm 625 + 625 =1250 IU
Non-compliant two dose participant 650 + 0 = 650IU
Timepoint [3] 303202 0
Following the delivery of all participants.

Eligibility
Key inclusion criteria
Female, pregnant, aged over 18 years, with a negative antibody screen and no contraindications for anti-D intramuscular injection, such as previous anaphylaxis to immunoglobulin, isolated Immunoglobulin A (IgA) deficiency, or previously recorded endogenous anti-D antibodies
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Age less than 18 years at recruitment, Non-pregnant, Rhesus positive, allergy/adverse drug reaction to constituents of Anti-D as per product information

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed Opaque Envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted Block Randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A summary table of relevant baseline information will be produced. This table will include descriptive statistics e.g. mean, range and standard deviation and enable the comparison of control and single-dose groups.

Intention-to-treat analysis will be performed. The proportion of women without sufficient levels of anti-D antibody in single-dose and control groups will be compared with the Chi-squared test. The proportion of women not receiving their doses at the correct gestation will be compared with Fisher’s exact test.

Logistic regression will be performed to:
-determine the impact of the single-dose regime compared to control regime
-examine the effect of possible risk factors for lack of detectable antibody at delivery, such as BMI, baby’s blood group and gestation at delivery
-adjust for baseline differences between participants of both groups

A second analysis based on dosed participants will also be performed.

No interim analyses are planned due to the short duration and low risk of the study.

Basis of Sample Size Selection

Estimates for power calculation were derived from data published by MacKenzie et. al (2011) that evaluated compliance rates comparing a two dose regime (500IU Anti-D at 28 and 34 weeks) and a one dose regime (1500IU at 28 weeks).

With two doses of 500IU anti-D at 28-34 weeks, in women with 100% compliance, 61% of women had circulating anti-D at the time of delivery. Based on data published by MacKenzie et al (2011), compliance rates with the two- dose regime is 67%. Taking these two observations together, we estimate that 40% of women will have circulating anti-D at the time of delivery with a two-dose regime using 500IU of Anti-D. Therefore, using the Australian regime of two doses of 625IU, we estimate that in this study at least 40% of women will have circulating Anti-D at the time of delivery.
MacKenzie IZ, Dutton S, Roseman F. Evidence to support the single-dose over the two-dose protocol for routine antenatal anti-D Rhesus prophylaxis: a prospective observational study. Eur J Obstet Gynecol Reprod Biol. 2011 Sep;158(1):42-6. doi: 10.1016/j.ejogrb.2011.04.033.

A single dose regime of 1500IU of Anti-D at 28 weeks has a reported compliance rate of 78% in the United Kingdom with 22% of the compliant women having detectable antibody at the time of delivery. Taking these data together, we estimate that 17% of women using the one dose regime in this study will have circulating anti-D at delivery.


Power calculation for primary aim – circulating anti-D at delivery

To provide an alpha value of 0.05 with a 90% power to detect a 50% reduction in the number of women with circulating anti-D at the time of delivery, a sample size of 218 (109 single dose and 109 two doses) will be required to compare the two-dose regime with a single dose regime.

Power calculation for secondary aim – compliance rate

To provide an alpha value of 0.05 with a 90% power to detect a 50% reduction in the number of women who were non-compliant with their anti-D prophylaxis regime, a sample size of 284 (142 single dose, 142 two doses) will be required to compare the two-dose regime with a single dose regime.

Assuming a 10% drop out rate after randomization of the 300 women in this study, 270 women would complete the study providing us with 95% power for the primary aim and 91% power for the secondary aim.
Assuming a 15% drop out rate after randomization of the 300 women in this study, 255 women would complete the study providing us with 94% power for the primary aim and 89% power for the secondary aim.
Based on estimates from previous studies, we predict that women who have one or two dose regimes will have circulating antibody at 17% and 40% respectively; hence our sample size should be adequate to detect this difference. The haematologists involved with this study have advised that detecting a difference of this magnitude has clinically and scientifically utility.


Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 1097 0
King Edward Memorial Hospital - Subiaco
Recruitment postcode(s) [1] 6954 0
6008 - Subiaco

Funding & Sponsors
Funding source category [1] 287419 0
Hospital
Name [1] 287419 0
King Edward Memorial Hospital
Address [1] 287419 0
King Edward Memorial Hospital
374 Bagot Rd
Subiaco 6008
Western Australia
Country [1] 287419 0
Australia
Funding source category [2] 287420 0
Charities/Societies/Foundations
Name [2] 287420 0
Women and Infants Research Foundation (WIRF)
Address [2] 287420 0
Women and Infants Research Foundation (WIRF)
374 Bagot Rd
Subiaco 6008
Western Australia
Country [2] 287420 0
Australia
Primary sponsor type
University
Name
Associate Professor Craig E Pennell
Address
School of Women's and Infants' Health (M550)
The University of Western Australia
35 Stirling Highway
Crawley 6009
Western Australia
Country
Australia
Secondary sponsor category [1] 286168 0
None
Name [1] 286168 0
Address [1] 286168 0
Country [1] 286168 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289395 0
Women and Newborn Health Service
Ethics committee address [1] 289395 0
Level 1, Children's Clinical
Research Facility (CCRF)
Princess Margaret Hospital
GPO Box D184
Perth WA 6840
Ethics committee country [1] 289395 0
Australia
Date submitted for ethics approval [1] 289395 0
09/04/2013
Approval date [1] 289395 0
03/05/2013
Ethics approval number [1] 289395 0
2013039-EW

Summary
Brief summary
Background, aims & objectives:
In some pregnancies, the blood types of mother and baby are not the same – this may cause problems for the baby. The mother’s immune system may ‘see’ the baby’s blood type as a threat, a process called sensitisation. This is called Rhesus disease and can cause anaemia, jaundice, and possibly serious consequences. Ways of preventing Rhesus disease are both safe and well-established, and used as part of regular antenatal care at KEMH. This involves an injection of anti-D antibody to maintain a protective level of this antibody in the blood. This dampens the body’s immune response to the baby’s blood, and greatly reduces the risk of Rhesus disease. With current prevention methods, the risk of Rhesus disease is less than 1%. There are two main approved dosing regimes, 1) the single-dose regime and 2) the double-dose regime. Both have advantages and disadvantages. Currently, Australia uses a double-dose regime, but is considering moving to a single-dose regime. Although widely used in the UK, Europe and USA, the single dose has not been studied locally in Australia. At present, women at KEMH receive two doses of anti-D during their pregnancy. This study will investigate both regimes to identify any difference in protection that lasts up to the time of delivery. A smaller study will review all women with evidence of sensitisation in the last 3 years to identify the possible causes. The results of the studies will help doctors optimise the preventive treatment, and help reduce the impact of Rhesus disease.
Study population:
Anti-D Dosage Study: We will recruit 300 Rhesus-negative pregnant women who have a negative antibody screen, and have no history of adverse reactions to anti-D injections.
Anti-D Sensitization Review: We will recruit women with evidence of sensitisation to the Rhesus-D antigen in the last 3 years. Based on population estimates, there will be up to 30 eligible women for this study in WA.
Study design & methods:
Anti-D Dosage Study: Three hundred women will be recruited from antenatal clinics in KEMH at <28 weeks of pregnancy. Women will be allocated to one of two groups. The control group will receive standard antenatal care, which includes two injections of anti-D antibody, six weeks apart (at 28 and 34 weeks of gestation). The single-dose group will receive one, larger dose injection of anti-D at 28 weeks. At delivery, all participants will have a blood test which checks for anti-D antibody. All participants will otherwise receive standard care for the prevention of sensitisation, including a) receiving additional anti-D injections after any potential sensitizing events during pregnancy and b) receiving an injection of anti-D antibody after delivery if their baby is Rhesus-positive. Relevant medical information will be extracted from medical records.
Anti-D Sensitization Review: All women with evidence of sensitisation to the Rhesus-D antigen in the last 3 years will be interviewed and their medical records reviewed to identify, if possible, the timing and potential contributing factors for sensitisation.
Outcomes:
This study will provide unique data for the National Blood Authority and Australian clinicians. It will provide information about the proportion of women that still have circulating anti-D at the time of delivery using the Australian two-dose (625IU) regime. This will enable a direct comparison to that achieved by the one-dose (1500IU) regime that is currently being proposed for Australian pregnant women. The sensitization review will also provide information to further advance Rhesus disease prevention in Australia by identifying potential targets for education campaigns.
Potential ethical issues:
There is minimal risk to participants as the intervention (a single dose of anti-D antibody) is an approved regime used in routine clinical practice in Europe and the USA.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40618 0
A/Prof Craig E Pennell
Address 40618 0
School of Women's and Infants' Health (M550)
The University of Western Australia
35 Stirling Highway
Crawley 6009
Western Australia
Country 40618 0
Australia
Phone 40618 0
+61893401326
Fax 40618 0
Email 40618 0
craig.pennell@uwa.edu.au
Contact person for public queries
Name 40619 0
A/Prof Craig E Pennell
Address 40619 0
School of Women's and Infants' Health (M550)
The University of Western Australia
35 Stirling Highway
Crawley 6009
Western Australia
Country 40619 0
Australia
Phone 40619 0
+61893401326
Fax 40619 0
Email 40619 0
craig.pennell@uwa.edu.au
Contact person for scientific queries
Name 40620 0
A/Prof Craig E Pennell
Address 40620 0
School of Women's and Infants' Health (M550)
The University of Western Australia
35 Stirling Highway
Crawley 6009
Western Australia
Country 40620 0
Australia
Phone 40620 0
+61893401326
Fax 40620 0
Email 40620 0
craig.pennell@uwa.edu.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary