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Trial registered on ANZCTR


Registration number
ACTRN12623000787684
Ethics application status
Approved
Date submitted
30/06/2023
Date registered
19/07/2023
Date last updated
19/07/2023
Date data sharing statement initially provided
19/07/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the induction and resolution of hypophosphatemia following intravenous iron (ferric carboxymaltose) treatment of anaemic Malawian pregnant women in their second trimester
Scientific title
Kinetics of hypophosphatemia in Malawian pregnant women receiving intravenous iron administered during the second trimester in the management of anaemia
Secondary ID [1] 310010 0
None
Universal Trial Number (UTN)
U1111-1294-4802
Trial acronym
REVAMP Phase
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Anaemia 330515 0
Iron deficiency 330516 0
Hypophosphatemia 330517 0
Condition category
Condition code
Blood 327367 327367 0 0
Anaemia
Reproductive Health and Childbirth 327514 327514 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be assigned to receive the following: intravenous ferric carboxymaltose (1000 mg for body weight >50 kg, or 20 mg/kg for body weight <50 kg) once during the second trimester. The intervention is administered by a nurse at a health facility and it is recorded in the trial database as a condition of being enrolled in the trial. Therefore, the administration of the intervention will be directly observed.
Intervention code [1] 326433 0
Treatment: Drugs
Comparator / control treatment
This is a single arm interventional study with no control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335235 0
The nadir serum phosphate concentration following a single treatment dose of intravenous ferric carboxymaltose
Timepoint [1] 335235 0
The lowest serum phosphate concentration will be determined from sampling at 13 time points following the administration of ferric carboxymaltose. The time points are 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [1] 423568 0
The time course of changes in serum phosphate
Timepoint [1] 423568 0
Serum phosphate will be measured at 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks and 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [2] 423569 0
The proportion of women with biochemical hypophosphataemia at baseline, at study time points until delivery.
Timepoint [2] 423569 0
Biochemical hypophophataemia will be assessed by measuring phosphate levels in blood samples obtained at baseline (recruitment), 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [3] 423570 0
Haemoglobin concentrations following intervention over the study period measured using an automated haematology analyser.
Timepoint [3] 423570 0
Haemoglobin will be measured from blood samples obtained at 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks and 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [4] 423571 0
The effect of a single dose of ferric carboxymaltose on bone turnover as measured by bone turnover markers in the blood (i.e. alkaline phosphatase, ALP and bone turnover markers eg P1NP, CTX) measured in the serum using a biochemical assay.
Timepoint [4] 423571 0
The time points are baseline (recruitment), 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery
Secondary outcome [5] 423572 0
Timecourse of the effect of a single dose of ferric carboxymaltose on calcium, measured in the serum using a biochemical assay.
Timepoint [5] 423572 0
The time points are baseline (recruitment), 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [6] 423574 0
Proportion of women with at least one treatment related adverse effect (occurring immediately post-infusion, and within 7 days of commencement of treatment).
Timepoint [6] 423574 0
The time points are recruitment and within 7 days of receiving ferric carboxymaltose.
Any adverse events or adverse reactions will be collected. Immediately after infusion, participants will be asked whether they have experienced headache, dizziness, discolouration of the skin, nausea, vomiting, upper abdominal pain, dyspepsia, flushing, shortness of breath, chest pains, anaphylactic shock or any other event. All adverse events will be recorded in an adverse event form and all adverse events will be followed until resolution.
Secondary outcome [7] 423608 0
Serum ferritin levels following the intervention and over the course of the study period.
Timepoint [7] 423608 0
Serum ferritin will be measured in blood samples obtained at the study time points of 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [8] 423611 0
The effect of a single dose of ferric carboxymaltose on FGF23 measured in the serum using an ELISA based assay.
Timepoint [8] 423611 0
The time points are baseline (recruitment), 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.
Secondary outcome [9] 424146 0
The proportion of women with clinical hypophosphataemia at baseline, at study time points until delivery.
Timepoint [9] 424146 0
Clinical hypophosphataemia will be determined from records reporting physical features of hypophosphataemia at the study timepoints of recruitment, 3 days, 7 days, 10 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks and 10 weeks post-intervention, as well as 36 weeks’ gestation and delivery.

Eligibility
Key inclusion criteria
Participants meeting the following criteria will be included in the trial:
1. Confirmed singleton pregnancy in the second trimester (13-26) weeks of gestation, dated by ultrasound
2. Moderate to severe anaemia as measured by capillary haemoglobin on HemoCue instrument, not requiring an immediate blood transfusion (Hb <10g/dl)
3. Negative malaria parasitaemia measured by rapid diagnostic test
4. Currently afebrile with no evidence of septicaemia
5. Written informed consent (including assent if <18 years old)
Minimum age
No limit
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous enrolment in REVAMP trial, REVAMP-TT trial or REVAMP-OBS trial
2. Actively participating in another interventional trial
3. Known hypersensitivity to the study drugs
4. Clinical symptoms of malaria or other infection
5. Any condition requiring hospitalisation in the next seven days of serious concomitant illness
6. Known history of sickle cell or sickle-haemoglobin C anaemia
7. Clinically low haemoglobin level requiring a blood transfusion (usually Hb<5g/dl)
8. Preeclampsia
9. HIV positive

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
NA
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
NA
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint/s
Safety
Statistical methods / analysis
We plan to recruit 55 women in total. A sample size of 44 participants with complete data at
nadir will have 90% power to demonstrate that the nadir of phosphate is statistically
significantly higher than the threshold of moderate hypophosphatemia (i.e. > 2 mg/dL),
assuming a mean phosphate of 2.5 mg/dL with standard deviation of 1 mg/dL 94 and two-sided 5% level of significance. In addition, this sample size will allow estimating the mean phosphate at nadir with a precision of +/-0.3 mg/dL (i.e. two-sided 95% confidence interval 2.2 to 2.8 mg/dL) if the sample mean and standard deviation are equal to our assumptions. Using a conservative assumption of 20% drop-out due to the burden of involvement in this study, 55
women are required to be enrolled.

A detailed statistical analysis plan for the final analysis will be drawn up during the course of the study and finalised before the start of data analysis. Serum phosphate, maternal haemoglobin, iron parameters, key bone metabolic parameters (e.g. calcium), and bone turnover markers in the blood (e.g., alkaline phosphatase, ALP), will be analysed using mixed effects regression models to describe longitudinal changes following a single dose of intravenous iron over the study period. Appropriate transformation of the outcome may be applied before fitting the statistical model. Safety including adverse events (occurring immediately post-infusion, and within 7 days of commencement of treatment) and hypophosphatemia (clinical and biochemical) at baseline and during the study period will be summarised.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/08/2023
Actual
Date of last participant enrolment
Anticipated
8/01/2024
Actual
Date of last data collection
Anticipated
2/08/2024
Actual
Sample size
Target
55
Accrual to date
Final
Recruitment outside Australia
Country [1] 25618 0
Malawi
State/province [1] 25618 0
Zomba district

Funding & Sponsors
Funding source category [1] 314188 0
Charities/Societies/Foundations
Name [1] 314188 0
Bill and Melinda Gates Foundation
Country [1] 314188 0
United States of America
Primary sponsor type
Other
Name
Training and Research Unit of Excellence (TRUE), Malawi
Address
1 Kufa Road, Mandala P.O. Box 30538 Chichiri, Blantyre 3
Country
Malawi
Secondary sponsor category [1] 316107 0
None
Name [1] 316107 0
Address [1] 316107 0
Country [1] 316107 0
Other collaborator category [1] 282724 0
Other
Name [1] 282724 0
The Walter and Eliza Hall Institute of Medical Research
Address [1] 282724 0
1G Royal Parade, Parkville VIC 3052
Country [1] 282724 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313314 0
National Health Sciences Research Committee, Ministry of Health, Malawi
Ethics committee address [1] 313314 0
P.O. Box 30377 Lilongwe 3
Ethics committee country [1] 313314 0
Malawi
Date submitted for ethics approval [1] 313314 0
29/11/2022
Approval date [1] 313314 0
21/02/2023
Ethics approval number [1] 313314 0
3018
Ethics committee name [2] 313316 0
The Walter and Eliza Hall Institute of Medical Research Human Research Ethics Committtee
Ethics committee address [2] 313316 0
1G Royal Pde Parkville VIC 3052 Australia
Ethics committee country [2] 313316 0
Australia
Date submitted for ethics approval [2] 313316 0
31/05/2023
Approval date [2] 313316 0
20/06/2023
Ethics approval number [2] 313316 0
22/22

Summary
Brief summary
Anaemia in pregnancy remains a critical global health problem, affecting 46% of pregnant women in Africa. Antenatal anaemia causes significant risks for both mother and child and can result in serious complications (including maternal mortality, low birth weight and premature delivery). In pregnancy, anaemia is commonly due to iron deficiency. Across Africa, few women receive or take the full recommended course of antenatal oral iron and may present for their initial visit far into the second trimester. This late presentation limits opportunities to treat antenatal anaemia, exposing women and their babies to its consequences. New intravenous iron products provide a chance to give high doses of iron in a single rapid infusion, thus eliminating the difficulties in monitoring oral iron compliance and allowing for a quick recovery to normal iron levels.

Ferric Carboxymaltose is an intravenous iron formulation that is commonly used to treat anaemia. One noted side effect of Ferric Carboxymaltose infusion is a transient low phosphate in the blood (hypophosphatemia). Although the use of Ferric Carboxymaltose as a single treatment of anaemia in pregnancy has not been associated with significant clinical outcomes, there is limited data examining phosphate levels in pregnant women receiving this treatment in general, as well as within the African setting, where nutritional deficiencies may be more common.

Our study is designed to accurately track the level and duration of any changes in serum phosphate following the use of Ferric Carboxymaltose to treat anaemia in pregnant Malawian women in their second trimester. Our study also aims to measure phosphate-related bone health markers and bone turnover markers in study participants following administration of Ferric Carboxymaltose. Our study will clarify the safety profile of Ferric Carboxymaltose when used to treat anaemia in pregnant women in Malawi and similar settings worldwide.
Trial website
N/A
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 127706 0
Prof Sant-Rayn Pasricha
Address 127706 0
Population Health and Immunity/Infection and Immunity Division
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052 Australia
Country 127706 0
Australia
Phone 127706 0
+61 393452618
Fax 127706 0
Email 127706 0
pasricha.s@wehi.edu.au
Contact person for public queries
Name 127707 0
Prof Sant-Rayn Pasricha
Address 127707 0
Population Health and Immunity/Infection and Immunity Division
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052 Australia
Country 127707 0
Australia
Phone 127707 0
+61 393452618
Fax 127707 0
Email 127707 0
pasricha.s@wehi.edu.au
Contact person for scientific queries
Name 127708 0
Prof Sant-Rayn Pasricha
Address 127708 0
Population Health and Immunity/Infection and Immunity Division
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade, Parkville VIC 3052 Australia
Country 127708 0
Australia
Phone 127708 0
+61 393452618
Fax 127708 0
Email 127708 0
pasricha.s@wehi.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only
When will data be available (start and end dates)?
IPD available from 31st December 2025 onwards (no end date)
Available to whom?
This will be determined on a case-by-case basis at the discretion of Principal Investigator
Available for what types of analyses?
To achieve the aims in an approved proposal, for IPD meta-analyses
How or where can data be obtained?
Access subject to approvals by Principal Investigator (email pasricha.s@wehi.edu.au)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
19578Study protocol  pasricha.s@wehi.edu.au Will be made available at the time of datasharing.... [More Details]



Results publications and other study-related documents

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