Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001373965
Ethics application status
Approved
Date submitted
19/03/2020
Date registered
22/12/2020
Date last updated
22/12/2020
Date data sharing statement initially provided
22/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Determining the Pharmacokinetics of Oral Creatine in Human Pregnancy
Scientific title
Investigating the pharmacokinetic shifts of oral creatine supplementation in the third trimester of pregnancy compared to the non-pregnant state.
Secondary ID [1] 300828 0
NA
Universal Trial Number (UTN)
U1111-1250-0059
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
The pharmacokinetics of oral creatine monohydrate (CrM) dosing in pregnancy 316717 0
Metabolism of nutraceutical supplement (creatine monohydrate) in pregnancy 316718 0
Condition category
Condition code
Diet and Nutrition 314960 314960 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Creatine Monohydrate will be administered orally in a liquid to all participants (pregnant and non-pregnant) by a research midwife after cannulation and collection of baseline samples and observations. The liquid will be consumed within 15 minutes and the time taken to consume the liquid will be recorded. Blood samples will be collected at nine subsequent time points over the course of ten hours post-administration. Subsequent urine samples will be collected at four-time points.

Stage [1]. Participants will receive a 5-gram oral creatine monohydrate as a one-off dose reconstituted from powder and delivered in a suitable beverage for the women.
An interim report will be presented to HREC to review the safety and PK profile data from Stage 1. Once the interim report is approved (within a month) Stage 2 will commence.
Stage [2]. Participants will receive a 10-gram oral of creatine monohydrate as a one-off dose reconstituted from powder and delivered in a suitable beverage for the women.
An interim report will be presented to HREC to review the safety and PK profile data from Stage 2. Once the interim report is approved (within a month) Stage 3 will commence.
Stage [3]. This stage of the trial will only involve pregnant women. Participants will receive 4 days of intervention (dose and regimen to be advised after the analysis of Stage 1 and 2 PK profiling). Based on the lag time between stages each stage group will be new participants with no previous exposure to creatine monohydrate.
Intervention code [1] 317158 0
Treatment: Other
Comparator / control treatment
Healthy non-pregnant women of reproductive age will receive an identical one-off dose of creatine monohydrate. This will be either a 5-gram or 10-gram dose (based on enrolment to Stage 1 or 2 of the trial), Reconstituted creatine monohydrate powder will be delivered in a suitable beverage for women to consume.
This is a multi-stage open-label dose-escalating trial. Eight non-pregnant and eight pregnant women will be assessed in Stages 1 & 2 with identical doses of creatine monohydrate. No comparator group will be required for Stage 3.
Control group
Active

Outcomes
Primary outcome [1] 323272 0
Quantitative analysis of plasma creatine concentrations.
Timepoint [1] 323272 0
Blood samples will be taken at baseline (0), 30 mins, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, and 10 hours after oral administration of creatine monohydrate in Stage 1 & Stage 2.
Primary outcome [2] 323273 0
Tolerability profile and safety
Timepoint [2] 323273 0
Participants will be assessed at the same intervals as sample collection over the 10 hour period post-intervention for any changes from baseline, including polydipsia, headache, swelling, stomach discomfort, muscle cramps, blurry vision or nausea. These will be changes identified in the participant, either reported by the participant, or observed by the researcher. Any change will be documented and acted upon appropriately. For Stage 1 and 2, participants will be phoned within a 24-hour period (one day post-intervention) to determine if any changes occurred over the subsequent 12-14-hour period post-study completion. Participants will be reviewed in person on each day of the Stage 3 trial intervention.
Secondary outcome [1] 381382 0
Blood and urine samples will be examined for Cmax, Tmax and AUC parameters.
Timepoint [1] 381382 0
Blood samples will be collected at baseline (0), and then at 30 minutes, 1 hour (hr), 1.5 hr, 2 hr, 3 hr, 4 hrs, 6 and 8 and 10 hours post-ingestion of creatine dose in both stages 1, & 2. Stage 3 blood samples will be collected at baseline (T0), pre-intervention (day 1) and then post-intervention at anticipated Cmax time. This blood collection process will be repeated on days 2, 3, and 4 of intervention.
Urine samples will be collected at baseline (0) and then at 2, 4, and 8 hours post-intervention in both stages 1 & 2. Stage 3 urine samples will be collected at baseline (T0) and on the final day post-intervention (day 4).
Secondary outcome [2] 381383 0
Assessment of blood pressure by a digital sphygmomanometer
Timepoint [2] 381383 0
Baseline (0), 2, 4 and 8 hours post-intervention.
Secondary outcome [3] 382092 0
Assessment of Cardiotocography (CTG) as a parameter of fetal well being, post-intervention.
Timepoint [3] 382092 0
Baseline (0), and 1.5-2 hours post-intervention, in line with anticipated peak maternal serum creatine levels.
Secondary outcome [4] 388977 0
Pulse rate by a (digital) readout.
Timepoint [4] 388977 0
Baseline (0), 2, 4, and 8 hours post-intervention
Secondary outcome [5] 388978 0
pulse oximetry
Timepoint [5] 388978 0
Baseline (0), 2, 4 and 8 hours post intervention

Eligibility
Key inclusion criteria
=/>18 years of age.
English speaking and able to give written informed consent
No known renal, hepatic, or cardiovascular symptoms.
No known gastrointestinal (GIT) disorders affecting absorption from GIT
Not consuming known dietary or nutritional supplements containing creatine or protein-based powders
BMI <35
Pregnant women only; between 30-34 weeks gestation birthing at the tertiary centre where the trial is being conducted so birthing outcomes can be assessed
Minimum age
18 Years
Maximum age
40 Years
Sex
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
<18 years of age
Poor English skills or not proficient in reading English
Diabetes Type 1 or 2
Known renal disease/hepatic disease
Known cardiovascular disease or risk factors for cardiovascular disorders
No colitis or any disease affecting absorption and function of the GIT system
Taking supplements that may contain creatine or other amino acids
BMI >35
Different model of care (not birthing at tertiary centre)

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)
No allocation concealment. This is an open-label pharmacokinetic study
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Population PK Modelling: Concentration to time data for creatine in plasma samples will be fitted to one-, two-, or three-compartment models by nonlinear mixed-effects modelling (NONMEM version 6.1; Globomax LLC, Hanover, MD). Data will be analysed using the first-order conditional estimation method with interaction and ADVAN6 to solve the differential equations. Between-subject variability will be calculated using an exponential variability model. Residual unexplained variability will be modelled using an exponential, additive or combined random error. Visual inspection of diagnostic scatter plots and the NONMEM objective function value (OBJ) will be used to evaluate goodness of fit. Statistical comparison of nested models will be undertaken using the NONMEM program on the basis of a X2 test of the difference in OBJ. A decrease in the OBJ of 3.84 units (P< 0.05) will be considered statistically significant. Covariates that are biologically relevant, including age and BMI will be built into the model. Visual Predictive Checks will be undertaken to evaluate the final model.
Dosing Simulations: Monte Carlo simulations for oral creatine supplementation will be undertaken using NONMEM. Simulations will test the doses (5g and 10g) and the potential effects of multiple dosing (1, 2 or 3 times a day). For each dose and schedule, the Monte Carlo simulation will generate concentration-time profiles (AUC0-24) values for 1000 subjects, based on parameters determined in the PK model.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
11/01/2021
Actual
Date of last participant enrolment
Anticipated
11/05/2022
Actual
Date of last data collection
Anticipated
28/06/2022
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 16149 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 29678 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 305287 0
University
Name [1] 305287 0
Monash University Health Practitioner Research Fellowship
Country [1] 305287 0
Australia
Funding source category [2] 305494 0
Government body
Name [2] 305494 0
NHMRC Early Career Research Fellowship
Country [2] 305494 0
Australia
Funding source category [3] 306908 0
Charities/Societies/Foundations
Name [3] 306908 0
Andrea Logan Trust
Country [3] 306908 0
Australia
Primary sponsor type
Hospital
Name
Monash Medical Centre
Address
246 Clayton Rd,
Clayton, 3168
Victoria,
Australia
Country
Australia
Secondary sponsor category [1] 305646 0
Other
Name [1] 305646 0
Hudson Institute of Medical Research
Address [1] 305646 0
27-31 Wright St, Clayton, 3168
Victoria, Australia
Country [1] 305646 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305626 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 305626 0
HREC Coordinator
Research Support Services
Level 2 , I Block
Monash Medical Centre
246 Clayton Road
Clayton, Victoria, 3168
Ethics committee country [1] 305626 0
Australia
Date submitted for ethics approval [1] 305626 0
19/02/2020
Approval date [1] 305626 0
17/07/2020
Ethics approval number [1] 305626 0
RES-20-0000-138A

Summary
Brief summary
Creatine monohydrate (CrM) is widely available as a nutritional supplement in Australia that mainly used as an ergogenic aid for sportsmen and women. Pre-clinical studies suggest dietary creatine supplementation during pregnancy may protect the fetus from acute in utero hypoxic events. While there is evidence to support the safety of creatine use in non-pregnant women of reproductive age, there is limited evidence on the pharmacokinetics (PK) of CrM in women of reproductive age and no information on the PK of CrM in pregnancy. To address these knowledge gaps safely, we have designed an open-label parallel-arm pharmacokinetic trial that will occur in three stages; where the first two stages will trial different CrM doses, starting with the lowest anticipated therapeutic dose. The third stage will trial the optimum dose (to be confirmed) over a multi-day period in the third trimester of pregnancy. Overall, This study will inform the optimum dosing of creatine monohydrate in late pregnancy (3rd trimester). This dosing regimen could be used in subsequent studies assessing the efficacy of maternal dietary creatine supplementation to improve pregnancy outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101002 0
Dr Kirsten Palmer
Address 101002 0
Monash Medical Centre
Department of Obstetrics & Gynaecology
Level 5 B Block
246 Clayton Road
Clayton 3168
Victoria
Country 101002 0
Australia
Phone 101002 0
+61 3 9594 5145
Fax 101002 0
Email 101002 0
[email protected]
Contact person for public queries
Name 101003 0
Dr Kirsten Palmer
Address 101003 0
Monash Medical Centre
Department of Obstetrics & Gynaecology
Level 5 B Block
246 Clayton Road
Clayton 3168
Victoria
Country 101003 0
Australia
Phone 101003 0
+61 3 9594 5145
Fax 101003 0
Email 101003 0
[email protected]
Contact person for scientific queries
Name 101004 0
Dr Stacey Ellery
Address 101004 0
Hudson Institute of Medical Research,
The Ritchie Centre.
27 - 31 Wright Street, Clayton 3168,
Victoria
Country 101004 0
Australia
Phone 101004 0
+61 3 8572 2870
Fax 101004 0
Email 101004 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a PK trial only. We are not collecting data for other research purposes that would require long term storage of samples. We have not applied for Ethics approval to use the samples we collect here for future studies.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
7411Informed consent form    379486-(Uploaded-17-10-2020-16-58-08)-Study-related document.pdf
7654Ethical approval    379486-(Uploaded-17-10-2020-16-56-59)-Study-related document.pdf



Results publications and other study-related documents

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

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA no brainer: intervening early to protect against perinatal brain injury.2022https://dx.doi.org/10.1113/JP283559
N.B. These documents automatically identified may not have been verified by the study sponsor.