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Trial registered on ANZCTR


Registration number
ACTRN12622001121752
Ethics application status
Approved
Date submitted
8/08/2022
Date registered
15/08/2022
Date last updated
20/07/2023
Date data sharing statement initially provided
15/08/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Lacosamide pharmacokinetics changes in blood and breast mild during and after pregnancy
Scientific title
A multicenter, open-label, longitudinal, prospective, pharmacokinetic phase 1b study in pregnant women with epilepsy treated with lacosamide: a substudy of the the Australian Pregnancy Register of Antiepileptic Drugs for Women in Pregnancy with Epilepsy and Allied Conditions.
Secondary ID [1] 307725 0
UP0121
Universal Trial Number (UTN)
U1111-1281-3877
Trial acronym
Linked study record
The Australian Pregnancy Register of Antiepileptic Drugs for Women in Pregnancy with Epilepsy and Allied Conditions - This is the parent study of this study (i.e. the participants to be enrolled in this trial will have enrolled in the Australian Pregnancy Register.

Health condition
Health condition(s) or problem(s) studied:
Epilepsy 327295 0
Condition category
Condition code
Neurological 324422 324422 0 0
Epilepsy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The objective of this Phase 1B, multicentre, longitudinal, prospective, PK, open label study is to assess any changes in lacosamide plasma concentrations that may result from physiological changes that occur during pregnancy in women with epilepsy. A change of PK during pregnancy will be assessed relative to postpartum lacosamide concentrations. In addition, if subjects give additional consent, this study will also measure lacosamide concentrations in mature breast-milk to estimate newborn lacosamide exposure. The study is interventional due to the additional collection of blood samples and breast milk from women which are exceeding medical practice. Blood samples will be taken by local pathology centres at four time points: 0-14 weeks, 15-28 weeks and 29-40 weeks antenatal, and 6-12 weeks post-natal. The breast milk samples will be taken by a local pathology centre at 6-12 weeks post-natal. Medical, socioeconomic, lifestyle, medication and obstetric data will also be collected by 30-60 minute telephone interviews at these timepoints. All other study assessments are part of routine clinical practice, and any decision to continue/discontinue or change LCM therapy during pregnancy and breastfeeding will be made between the participant and her treating physician, taking into account potential risks and benefits, and according to the local label.
Intervention code [1] 324201 0
Diagnosis / Prognosis
Intervention code [2] 324232 0
Early detection / Screening
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 332237 0
Primary outcome will be lacosamide plasma concentrations during pregnancy relative to the post-partum period.
Timepoint [1] 332237 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum
Secondary outcome [1] 412665 0
Secondary outcome will be the lacosamide concentration in mature breastmilk
Timepoint [1] 412665 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.
Secondary outcome [2] 412667 0
Treatment Emergent Adverse Effects (TEAEs)

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [2] 412667 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.
Secondary outcome [3] 412859 0
TEAEs leading to discontinuation

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [3] 412859 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.
Secondary outcome [4] 412860 0
Serious TEAEs

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [4] 412860 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.
Secondary outcome [5] 412863 0
Pregnancy outcomes (low birth weight).

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [5] 412863 0
6-12 weeks post-partum.
Secondary outcome [6] 412864 0
Seizure frequency per 28-days

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [6] 412864 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.
Secondary outcome [7] 412897 0
Pregnancy outcomes (preterm delivery)

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [7] 412897 0
6-12 weeks post-partum.
Secondary outcome [8] 412898 0
Pregnancy outcomes (live birth vs. still birth).

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [8] 412898 0
6-12 weeks post-partum.
Secondary outcome [9] 412899 0
Pregnancy outcomes (abortions [spontaneous, elective, medically indicated]).

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [9] 412899 0
6-12 weeks post-partum.
Secondary outcome [10] 412900 0
Pregnancy outcomes (small for gestational age [SGA]).

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [10] 412900 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery
Secondary outcome [11] 412902 0
Pregnancy outcomes (congenital abnormalities).

These data points will be collected on the telephone interviews at the time intervals below, and analysed individually and reported as descriptive outcomes.
Timepoint [11] 412902 0
1. 0-14 weeks antenatal; 2. 15-28 weeks antenatal; 3. 29 weeks antenatal - delivery; 4. 6-12 weeks post-partum.

Eligibility
Key inclusion criteria
Age
1. Participant must be [18] to [50] years of age inclusive, at the time of signing the informed consent.
Type of participant and disease characteristics
2. Participant is capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
3. Participant must be considered reliable and capable of adhering to the protocol and visit schedule according to the judgment of the investigator.
4. Participant is currently treated with lacosamide as part their medical treatment.
5. Participant is a pregnant female.
6. Participant expects to continue lacosamide therapy throughout pregnancy and for at least 12 weeks postpartum.
Minimum age
18 Years
Maximum age
50 Years
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Women under age of 18 years at the time of signing the ICF.
2. Women with significant intellectual disability who, in the opinion of the investigator, are not able to understand the nature of the study.
3. Women with any medical or psychiatric condition that, in the opinion of the investigator, could jeopardize or would compromise the study participant's ability to participate in this study.
4. Women with severe alterations of renal (ClCr <30 mL/min) and/or hepatic (liver function tests > 3x upper limit of normal) function.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
1. Definition of Analysis Sets
The Enrolled Set (ES) will include all study participants who are confirmed as having signed the ICF to participate in the study and have provided the first blood sample.
The Safety Set (SS) will include all enrolled study participants who received at least 1 dose of LCM after Screening.
The Pregnancy Set (PS) will consist of all study participants in the SS who have a confirmed pregnancy (based on ultrasound, pregnancy test, or clinical assessement).
The Pharmacokinetic Per-Protocol Set (PK-PPS) is a subset of the PS, consisting of those study participants for whom a sufficient number of samples are available.

2. General Considerations
In general, summary statistics (n [number of available measurements], arithmetic mean, standard deviation [SD], median, minimum, and maximum) for quantitative variables and frequency tables for qualitative data will be presented. The arithmetic mean and SD will be replaced by the geometric mean and coefficient of variation (CV), respectively, for quantitative PK data. Any further deviations from this general approach will be outlined in the SAP.

3. Planned Outcome Analyses

3.1 Analysis of the Primary Outcome
All PK analyses on LCM plasma concentrations will be performed on the PK-PPS. The individual plasma concentrations of LCM will be summarized over the course of pregnancy by trimester and dosing time point (predose or postdose) using graphs and descriptive statistics (number of observations [n], geometric mean, lower and upper 95% confidence intervals [CI], geometric CV, arithmetic mean, SD, CV, median, minimum, and maximum values).
For the calculation of descriptive statistics, a plasma concentration below the lower limit of quantification (LLOQ) will be substituted by LLOQ/2. The geometric and arithmetic means and associated SD, lower and upper limits of 95% CI, and CV will be calculated only if at least two thirds of the individual data at a specific trimester are measured, are above or equal to LLOQ, and n=3.
For summaries of plasma concentration data, baseline will be defined as the predose measurement 6-12 weeks postpartum.
Pharmacokinetic analyses
The LCM plasma concentrations will be analyzed using a non-linear mixed effect model to evaluate the effect of pregnancy on the PK of LCM. For this analysis the pre- and post-dose samples will be used. Covariates to be included are (but not limited to): age, weight, stage of pregnancy, use of CYP450 inducing comedication.
The details of the analysis will be described in a dedicated analysis plan and will be separately reported.

3.2 Analysis of the Secondary Outcomes
Estimated Daily Infant Dose will be calculated using the standardized mean milk consumption for a fully breastfed 2-month old infant of 150mL/kg/day as the assumed infant consumption volume and multiplied by the concentration measured in the collected sample to derive and estimated daily infant dose using the formula: Estimated Daily Infant Dosage (mg/kg/day) = Cmilk (Day X) x 150mL/kg/day where Cmilk is the LCM concentration in breast milk.

Lacosamide breastmilk concentrations will be summarized in a similar fashion using graphs and descriptive statistics (number of observations [n], geometric mean, lower and upper 95% confidence intervals [CI], geometric CV, arithmetic mean, SD, CV, median, minimum, and maximum values).

4 Analyses of Safety and Other Outcomes
4.1 Safety analyses
All safety analyses will be performed using the SS. All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) with the current version at the end of the study and characterized as treatment-emergent according to the intake of LCM.
The occurrence and incidence of treatment-emergent adverse events (TEAEs) will be summarized by MedDRA system organ class and preferred term. The occurrence and incidence of TEAEs will also be summarized by intensity and by relationship to LCM. Adverse events leading to discontinuation and SAEs will also be summarized.
Measured values of vital signs (blood pressure [systolic and diastolic], respiratory rate, pulse rate, and peripheral body temperature) at Screening will be summarized descriptively.
Physical examination abnormalities will be listed.

4.2 Analysis of Other Outcomes
Pregnancy outcomes will be summarized and listed based on the PS.
Disposition characteristics will be summarized based on the ES and baseline characteristics will be summarized based on the PS. Analyses include descriptive summaries and will be detailed in the SAP.
Seizure frequency (per 28 days) will be summarized by drug exposure.

5 Handling of Missing Data
There will be no special procedures for handling missing data. All imputation of missing or partial dates for safety assessments, as well as handling values below the LLOQ in the PK data, will be detailed in the SAP.

6 Planned Interim Analysis and Data Monitoring
No interim-analysis or data monitoring is planned.

7 Determination of Sample Size
Because no formal hypothesis testing will be conducted, the sample size of 30 study participants is deemed sufficient for a small exploratory Phase 1B study. It is expected that up to 30 women will need to be screened to ensure that approximately 20 evaluable study participants (as defined by at least one pre- and post-dose sample during and after pregnancy) yielding a clinically meaningful pharmacokinetic outcome.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/09/2022
Actual
11/11/2022
Date of last participant enrolment
Anticipated
2/09/2024
Actual
Date of last data collection
Anticipated
1/09/2025
Actual
Sample size
Target
30
Accrual to date
3
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 22934 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment postcode(s) [1] 38240 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 311998 0
Commercial sector/Industry
Name [1] 311998 0
UCB BIOPHARMA SRL
Country [1] 311998 0
Belgium
Primary sponsor type
Hospital
Name
Melbourne Health trading as The Royal Melbourne Hospital
Address
Level 8 South, 300 Grattan Street, Parkville 3050, in the state of Victoria, Australia
Country
Australia
Secondary sponsor category [1] 313522 0
None
Name [1] 313522 0
Address [1] 313522 0
Country [1] 313522 0
Other collaborator category [1] 282394 0
University
Name [1] 282394 0
Monash University
Address [1] 282394 0
The Department of Neuroscience, Monash University, The Alfred Centre, 99 Commercial Road, Melbourne, Victoria, 3004, Australia
Country [1] 282394 0
Australia
Other collaborator category [2] 282395 0
Charities/Societies/Foundations
Name [2] 282395 0
Epilepsy Society of Australia
Address [2] 282395 0
PO Box 2137
Glenelg SA 5045
Country [2] 282395 0
Australia
Other collaborator category [3] 282396 0
Charities/Societies/Foundations
Name [3] 282396 0
The Raoul Wallenberg Australian Pregnancy Register (RWAPR)
Address [3] 282396 0
PO Box 2116
Royal Melbourne Hospital VIC 3050
Country [3] 282396 0
Australia
Other collaborator category [4] 282397 0
Charities/Societies/Foundations
Name [4] 282397 0
RMH Neuroscience Foundation
Address [4] 282397 0
PO Box 2116
Royal Melbourne Hospital VIC 3050
Country [4] 282397 0
Australia
Other collaborator category [5] 282398 0
Charities/Societies/Foundations
Name [5] 282398 0
Epilepsy Action Australia
Address [5] 282398 0
PO Box 384
NORTH RYDE BC NSW 1670
Country [5] 282398 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311420 0
Royal Melbourne Hospital HREC
Ethics committee address [1] 311420 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 311420 0
Australia
Date submitted for ethics approval [1] 311420 0
13/07/2022
Approval date [1] 311420 0
02/08/2022
Ethics approval number [1] 311420 0
2015.211 - HREC/11/MH/282

Summary
Brief summary
The objective of this Phase 1B, multicentre, longitudinal, prospective, PK, open label study is to assess any changes in LCM plasma concentrations that may result from physiological changes that occur during pregnancy in women with epilepsy. A change of PK during pregnancy will be assessed relative to postpartum LCM concentrations. In addition, if subjects give additional consent, this study will also measure LCM concentrations in mature breast-milk to estimate newborn LCM exposure.
This collaborative study will be conducted as a sub-study of The Raoul Wallenberg Australian Pregnancy Register (RWAPR), which is an observational, prospective, longitudinal study of pregnancies in women taking ASMs, and also women with epilepsy not taking ASMs.
The study is interventional due to the additional collection of blood samples and breast milk from women which are exceeding medical practice. However, all other study assessments are part of routine clinical practice, and any decision to continue/discontinue or change LCM therapy during pregnancy and breastfeeding will be made between the participant and her treating physician, taking into account potential risks and benefits, and according to the local label.
Trial website
https://www.neuroscience.org.au/australian-epilepsy-pregnancy-register
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 121034 0
Prof Frank Vajda
Address 121034 0
PO Box 2146, The Royal Melbourne Hospital, Gratton Street, Parkville, Victoria, Australia, 3050
Country 121034 0
Australia
Phone 121034 0
+61 0418370566
Fax 121034 0
Email 121034 0
vajda@netspace.net.au
Contact person for public queries
Name 121035 0
Mrs Janet Graham
Address 121035 0
PO Box 2146, The Royal Melbourne Hospital, Gratton Street, Parkville, Victoria, Australia, 3050
Country 121035 0
Australia
Phone 121035 0
+61 1800 069 722
Fax 121035 0
Email 121035 0
Janet.Graham@mh.org.au
Contact person for scientific queries
Name 121036 0
Mrs Janet Graham
Address 121036 0
PO Box 2146, The Royal Melbourne Hospital, Gratton Street, Parkville, Victoria, Australia, 3050
Country 121036 0
Australia
Phone 121036 0
+61 1800 069 722
Fax 121036 0
Email 121036 0
Janet.Graham@mh.org.au

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


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.