Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05694858 |
Other study ID # |
UKM/PPI/111/8/JEP-2022-736 |
Secondary ID |
FF-2022-401MOSTI |
Status |
Not yet recruiting |
Phase |
Phase 1/Phase 2
|
First received |
|
Last updated |
|
Start date |
October 1, 2024 |
Est. completion date |
July 31, 2027 |
Study information
Verified date |
March 2024 |
Source |
Universiti Kebangsaan Malaysia Medical Centre |
Contact |
MUHAMMAD IRFAN BIN ABDUL JALAL, MBChB BAO, PhD |
Phone |
+60172107299 |
Email |
irfan.abduljalal[@]ukm.edu.my |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Microneedle (MN) is a mimic of a hypodermic needle, composed of hundreds of micron-sized,
out-of-plane protrusions, typically arranged in arrays on a patch that can be applied onto
the skin. MN can be fabricated from a variety of materials, preferably biocompatible
polymers. Maltose, a natural carbohydrate, is a safe and biocompatible product that can be
fabricated into MNs that are biodegradable and soluble within several minutes. Besides, local
anaesthetic agents such as lignocaine can be impregnated within the MN matrix, facilitating
its transdermal delivery more efficiently which results in enhanced efficacy. So far, maltose
MN efficacy in enhancing the transdermal drug delivery (TDD) of lignocaine and thus reducing
the pain experienced by healthy patients requiring intravenous cannulation prior to routine
eye surgeries (phacoemulsification, trabeculectomy etc) has not been extensively studied.
Hence, the objectives of this research are: 1) To evaluate the safety profile of
lignocaine-embedded microneedle patch as a means of pain reduction in adult patients
requiring routine vein-puncturing procedures; 2) To assess the pharmacokinetic (PK)
parameters of lignocaine in the systemic circulation when the transdermal lignocaine delivery
is enhanced through microneedle usage; 3) To compare the efficacy of lignocaine-embedded
microneedle patch with standard 5% Eutectic Mixture of Local Anesthetics (EMLA) dermal patch
for pain reduction during venepuncture procedure based on mean changes in VAS scores and skin
algesimeter index (pharmacodynamic (PD) study).
Description:
This is a prospective, phase I/II, randomized, triple-blind (participants and care
providers), two-parallel group, active controlled trial.
This study is divided into two phases:
A) Phase I: Non-randomized single-centre open-label single group clinical trial to primarily
assess the safety and tolerability of lignocaine-impregnated microneedle in adult patients
undergoing routine vein-puncturing related procedures (pharmacokinetic (PK) study).
B) Phase II: A randomized single centre double blind two parallel group active controlled
clinical trial to assess the efficacy of lignocaine-impregnated microneedle compared to 5%
EMLA dermal patch (Pharmacodynamic (PD) study).
I) Phase I Study
For phase I of the research, the safety and tolerability of 12.5mg lignocaine-embedded
microneedle on a small number of adult patients (20 patients; 10 males and 10 females)
without hepatic or renal dysfunction will be assessed.All participants of this phase I will
be healthy patients who undergo cataract or glaucoma surgeries who will be recruited from the
Hospital Canselor Tuanku Muhriz (HCTM), Universiti Kebangsaan Malaysia (UKM) ophthalmology
outpatient clinic. Pre-treatment fasting is not required for all participants.
On the day of the study, each potential participant will be screened for study eligibility
based on our pre-specified inclusion and exclusion criteria. An interim abridged medical
history will be taken from each participant and their list of medications will be reviewed.
Vital signs (systolic and diastolic blood pressures, oral temperature, pulse and respiratory
rates) will be taken and targeted clinical examinations will be performed by the medical
officers to assess the overall health of the participants.
After the 12.5mg lignocaine-impregnated microneedles have been applied to the designated
sites, intravenous cannula will be placed on the dorsal aspect of the participant's right
hand. Approximately 3.0 ml venous blood samples will then be withdrawn from the antecubital
fossa at each t=0, 30, 60, 90, 120, 180 minutes and collected into separate 3.5-ml of plastic
blood collection tube with accelerator & separator gel (BD™, New Jersey, USA). Heparinized
saline will be periodically infused to ensure that the cannula lumen remains patent
throughout the sampling periods. The blood samples will then be sent to the Malaysian
Institute of Chemistry for lignocaine concentration measurements using the validated Gas
Chromatography Nitrogen Phosphorus Detector (GC-NPD) methodology.
The participants will be allowed to return home after the last blood sample is taken at
t=180. The participants will be further monitored for any adverse events (AEs) such as
redness, pain, itchiness, blistering, etc (local reactions) and light-headedness, euphoria,
tinnitus, diplopia etc. (systemic reactions), serious adverse events (SAEs) and suspected
unexpected serious adverse reactions (SUSARs) for up to 48 hours via telephone calls.
The pharmacokinetic data will be first summarized in mean / standard deviation or median /
interquartile range for continuous data and count and percentage for categorical data. The
pharmacokinetic parameters (Area under the curve until time = infinity (AUCinf), Area under
the curve until time t (AUCt), Cmax, Cmin, tmax, t1/2, volume of distribution (Vd), Clearance
(Cl)) of lignocaine will be evaluated using blood samples obtained at times t=0, 30, 60, 90,
120, and 180 minutes after the application of lignocaine-impregnated MN patch. The
intraindividual and interindividual variations of the pharmacokinetic parameters will be
evaluated using coefficient of variation (CV) and these will be classified as low (CV≤10%),
moderate (CV ≈ 25%) and high (CV>40%).63 The pharmacokinetic data will be analysed using the
non-linear mixed effect models based on two-compartmental model which will be implemented on
NONMEM® version VI (Icon Development Solutions, Ellicott City, Maryland, USA). The influence
of clinically relevant covariates such as participant's age, gender, BMI and others on
pharmacokinetic parameters will be evaluated in a stepwise fashion. First-order conditional
likelihood (FOCE INTER on NONMEM) will be used to fit the data and model selection will be
dependent upon the likelihood ratio test, the estimates of pharmacokinetic parameters and
their 95% confidence intervals and goodness-of fit measures.
II) Phase II Study
For phase II of the research lidocaine-impregnated microneedle patch will be used as the
experimental agent under study (i.e. studied agent). As a comparator, the standard EMLA patch
which is a eutectic emulsion mixture of lidocaine and prilocaine at 1:1 ratio (i.e. each gram
of EMLA cream contains lidocaine and prilocaine, 25 mg each). A eutectic mixture has a lower
melting temperature than each constituent's melting temperature. The anaesthetic efficacy of
EMLA cream will be assessed via pain induced by intravenous (IV) cannulation and the primary
endpoint are the participant's VAS score and skin algesimeter index measured 30 minutes after
either lignocaine-impregnated patch or EMLA patch application.
1. Randomization Procedure and Blinding (Masking) of Trial Participants
For random allocation, block randomization procedure with varying block size (permuted
block) will be utilized to guarantee that both intervention groups will have an equal
number of trial participants. This will be carried out by the trial statistician using
the R package, blockrand version 1.50 which will be implemented on R platform. The list
of generated random numbers will be used to allocate the study participants to either
intervention or control branch. The allocation sequence generated will be kept in a
password-protected document that is only accessible to the statistician to maintain
allocation concealment. To further ensure the adequacy of allocation concealment,
randomisation code will not be revealed until the potential trial participants have been
definitively enrolled into the trial, which will be after all baseline measurements are
made and all eligibility criteria are deemed fulfilled by the study recruiters. In
addition, allocation concealment is further safeguarded by ensuring identity of the
allotted treatment is only revealed to the interventionist (i.e. the person who will be
administering the intervention) via secured telephone calls (central randomization).
Consecutive recruitments will be made until the final intended sample size is achieved.
For this study, the outcome assessors and care providers (may be the same individual)
will be masked to the identity of interventions (single blinding / single masking). Only
the statistician and interventionist/procedurist will be unmasked to the study
interventions. Furthermore, unique ID code to indicate each treatment sequence
assignment will be generated and utilised to ensure that the unintentional / intentional
unmasking of one trial participant will not compromise the integrity of blinding for the
rest of study participants. The primary unblinded trial persons (subjects, the
statistician and the procedurist/interventionist) are instructed not to divulge the
identity of the allotted treatments to other blinded trial personnel. The success of
blinding will be determined by asking the blinded trial persons to guess the identity of
interventions received and then compare the results obtained with what would be
anticipated by chance. Blinding indices such as James' Blinding Index or Bang's blinding
Index could also be calculated to objectively assess whether blinding has been
successfully achieved in this trial.
2. Administration of Lignocaine-embedded Microneedle (intervention) and EMLA (control)
patches
Prior to the administration of intervention/control, relevant clinic-demographic
profiles (age, gender, ethnicity, anthropometric measurements, presence of
comorbidities, the types of eye surgeries received etc.) will be recorded and entered in
the case report forms (CRFs) that are specifically designed for this study. This
research study uses lignocaine embedded microneedles. The comparison of pharmacodynamic
properties (i.e. efficacy) between 12.5 mg lignocaine delivered through direct embedment
within the microneedle matrix and standard 5% EMLA dermal patch containing 1 finger-tip-
unit (FTU=0.5g) of 12.5mg lignocaine and 12.5mg prilocaine will be assessed via VAS
score and skin algesimeter index for the pain induced by venepuncture.
The window period given to lignocaine for it to be effective will be based on the usual
clinical practice observation where it is usually applied for 30 minutes prior to
venepuncture. The rationale behind it is due to logistical issues and for the day care's
operational convenience. Nevertheless, in a busy clinical setting, the application time
is sometimes shortened to 15 minutes for a slight anaesthetic effect. Thus, we postulate
that, with the aid of microneedle, the time to onset of action for lignocaine could be
greatly reduced resulting in a much more reduced pain sensation when the clinical
assessment is carried out 30 minutes after treatment application.
The administrator of interventions (procedurist) will identify and draw a grid of 1cm ×
1cm at the dorsum hand, which will serve as an ideal site for cannulation. The
procedurist will then apply the lignocaine-impregnated microneedle patch. After a
30-minute application time, the attending medical officer will perform venepuncture line
using a 21-gauge (G) hypodermic needle inserted into the vein in the dorsal aspect of
the participant's hand.
For the participants allotted to the standard 5% EMLA dermal patch, 1 FTU of 5% EMLA
cream will be applied and covered with a piece of adhesive to form a dermal patch. This
will be applied for 30 minutes on the dorsum of the hand which will be cleaned and dried
first. This application is equivalent to 12.5mg lignocaine and 12.5mg prilocaine. The
EMLA patch will be firmly applied to the designated area (dorsal aspect of the hand).
During the trial day, the participants will not be allowed to take any analgesic
medications (NSAID, Opioids, Paracetamol) since they will modulate the level of pain
experienced by the participants due to the received interventions. Other medications and
concomitant care will be permitted during the trial.
3. Pain Assessment
The study participants will first be guided on the operating manual for a 10-points, 100mm
VAS pain score by an outcome assessor. The participants will be presented with a ruler that
contains 100-mm slots with "No Pain" written on the left side and "Worst Pain" on the
opposite right side. The study participants will then be asked to move and place the slider
in the slot that accurately describes his/her pain at the following time points: 1) within 5
minutes after application of lignocaine-impregnated MN patch and before venepuncture/IV
cannulation (baseline VAS score); 2) within 5 minutes after venepuncture/IV cannulation. The
investigator/outcome assessor, who is blinded to the subject intervention arm will record the
location of the slot where the slider is placed in millimetres (mm), clearly printed on the
ruler's reverse side and this will be the participant's VAS score. Throughout the process,
there will be a trained investigator standing by to assist the verification of the pain scale
and to aid the participants who require additional assistance.
For a subset of randomly selected patients, before applying MN patch and EMLA Cream, the
patients will be attached with the PainMonitor™ (Med-Storm Innovation AS, Oslo, Norway)
device whereby the electrodes will be attached to the hypothenar eminence of the opposite
hand not receiving the vein cannulation. The procedurist will set up this machine and
application before the interventions are commenced. The skin conductance peaks (in
microSiemens (μS) and the skin algesimeter index (in microSiemens per second (μS/s)) will be
recorded by the outcome assessor who will be blinded to the subject intervention arm. Those
parameters indicate the skin's sympathetic nerve block induced by the topical anaesthetic.
The measurement time points start from the point of intervention and the recordings continued
for at least 15 seconds.