Efficacy of Transdermal Microneedle Patch for Topical Anesthesia Enhancement in Paediatric Thalassemia Patients

Thalassemia in Children Clinical Trial

Official title:

Transdermal Microneedle Patch To Enhance Topical Anaesthesia Before Intravenous Line Insertion for Blood Transfusion In Paediatric Thalassemia Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05078463
• Other study ID #: UKM PPI/111/8/JEP-2021-578
• Secondary ID: PRGS/2/2020/TK05
• Status: Completed
• Phase: Phase 2
• Start date: September 15, 2021
• Est. completion date: August 11, 2022

Study information

• Verified date: August 2022
• Source: Universiti Kebangsaan Malaysia Medical Centre
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Microneedle (MN) is the 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 minutes. So far, maltose MN efficacy in enhancing the transdermal drug delivery (TDD) of topical anaesthetic agent such as Eutectic Mixture of Local Anesthetics (EMLA) and thus reducing the pain experienced by paediatric thalassemic patients requiring intravenous cannulation for regular blood transfusion has not been extensively studied. Therefore, the goals of this research are: 1) To compare the VAS score between thalassemic paediatric patients receiving EMLA before IV cannulation for blood transfusion and those receiving EMLA without microneedle application; 2) To compare the skin conductance algesimeter index between those receiving EMLA and microneedle and those receiving EMLA without microneedle application prior to intravenous (IV) cannulation for blood transfusion; 3) To evaluate the agreement between VAS score and the skin conductance algesimeter index obtained via PainMonitor™ machine.

Description:

This is a prospective, phase II, randomized, double-blind (participants and care providers), cross-over, negative controlled trial.

Prior to the administration of intervention / control, relevant clinic-demographic profiles (age, gender, ethnicity, anthropometric measurements, presence of comorbidities, thalassemia types etc) will be recorded and entered in the case report forms (CRFs) that are specifically designed for this study.

This research study uses Eutectic Mixture of Local Anesthetics (EMLA) Cream (lidocaine 2.5% and prilocaine 2.5%) as the topical anaesthetic agent. EMLA Cream 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 is the participant's VAS score measured after applying EMLA Cream (with and without MN application) for 15 and 30 minutes.

The window period given to EMLA Cream for its effect to work will be based on the usual clinical practice observation where it is usually applied for 30 minutes prior to IV catheterization. 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 slight anaesthetic effect. Thus, the study investigators postulate that, with the aid of microneedle, the time to onset of action for EMLA Cream could be greatly reduced, thus requiring less time for EMLA cream to achieve its maximal effects.

According to the routine hospital protocol, all study participants received their blood transfusion based on the Good Clinical Practice (GCP) guidelines. For each participant, the individual will be randomized to one of the 24 treatment sequences and there will be a minimum of 3-weeks washout period before administering the next intervention.

The investigator identified and drew a grid of 1cm × 1cm on the dorsum hand, which served as an ideal site for cannulation. The administrator of intervention (procedurist) will apply either 1 Finger Tip Units (FTUs) of EMLA Cream (approximately 0.68g/cm2) or 0.5 Finger Tip Unit (FTU) (approximately 0.369 g/cm2) over the preparation area. If the patient is subjected to MN patching at his/her visit, the MN patch will be applied by thumb force with the pillar handler pressed firmly against the dorsal hand surface for 5 seconds, mimicking a stamping action, to patch MN to the skin entirely before applying EMLA cream. Otherwise, an empty (i.e without MN) PVA-containing PET sham patch will be applied instead. Besides, the height-to-base ratio (4:1) used for MN will also optimally minimise its adverse effects (pain, redness), thus preserving the masking (blinding) of study participants from knowing the types of interventions received. The preparation area will be covered with an adhesive dressing ( 3M™Tegaderm™, Maplewood, Minnesota, USA) after EMLA cream application. After the allocated application time (15 or 30 minutes), the attending medical officer will set up the transfusion line with a 22-gauge hypodermic needle inserted into the dorsum hand. Throughout the process, the parents/guardians will be allowed to stay by the patient's side at all times.

After the intervention is given to the patients, the participants will be guided on the operating manual for a 10-points, 100mm VAS pain score. 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.

After each procedure, the children then will be asked to move and place the slider in the slot that accurately describes his/her pain at the following time points: 1) right after application of MN/ sham patch or before EMLA Cream application (baseline VAS score); 2) one minute after IV cannulation. The investigator will record the location of the slot where the slider is placed in (millimetres (mm), clearly printed on the ruler's backside) and this will be the participant's VAS score. Throughout the process, there will be a trained nurse standing by at the day-care to assist the verification of the pain scale and to aid the participants who require additional assistance.

Besides, 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 blood transfusion. The skin conductance peaks (in microSiemens (μS) and the average rise time (in microSiemens per second (μS/s)) will be recorded. Those parameters indicate the skin's sympathetic nerve block induced by the applied EMLA cream.

For skin conductance algesimeter index, the readings right after MN / sham patch application (baseline skin conductance algesimeter index score) and one minute IV cannulation will be obtained from the PainMonitor™ machine.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: August 11, 2022
• Est. primary completion date: August 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 17 Years

Eligibility

Inclusion Criteria:

1. Patients aged at least 6 to 17 years old

2. Patients requiring venous cannulation for blood transfusion

Exclusion Criteria:

1. Patients with a previous history of sensitization or allergy to EMLA cream

2. Patients with a previous history of allergy to materials used in the study (e.g. Polyvinyl Alcohol (PVA), Polyethylene Terephthalate (PET), Maltose, Electrodes and Plaster constituents)

3. Patients receiving other forms of analgesic agents within 24 hours prior to the cannulation procedures

4. Patients with generalized skin disorders / rash

5. Patients who are agitated or aggressive

Related Conditions & MeSH terms

• Thalassemia
• Thalassemia in Children

Intervention

Device:
• Microneedle
Maltose Microneedle Patch (Patch Size: 1 cm x 1 cm, 36 microneedles per patch, microneedle's height, base width and tip radius are 400 µm, 100 µm and 3 µm, respectively) will be firmly applied for 5 seconds on the 1 cm x 1 cm site for IV cannulation on the dorsal surface of the hand for blood transfusion, prior to EMLA cream application.

Drug:
• 1 Finger Tip Unit (FTU) EMLA Cream (30-minute application time)
1 Finger Tip Units (FTU) EMLA applied for 30 minutes on the dorsal surface of the IV cannulated hand for blood transfusion
• 1 Finger Tip Unit (FTU) EMLA (15-minute application time)
1 Finger Tip Unit (FTU) EMLA applied for 15 minutes on the dorsal surface of the IV cannulated hand
• 0.5 Finger Tip Unit (FTU) EMLA (30-minute application time)
0.5 Finger Tip Unit (FTU) EMLA applied for 30 minutes on the dorsal surface of the IV cannulated hand for blood transfusion

Device:
• Sham Patch
A Polyvinyl Alcohol (PVA)-containing Polyethylene Terephthalate (PET) Sham Patch of a size of 1cm x 1cm will be applied for 5 seconds against the pre-specified 1 cm x 1 cm grid on the dorsal surface of the IV cannulated hand for blood transfusion.

Locations

Country	Name	City	State
Malaysia	Hospital Canselor Tuanku Muhriz, Universiti Kebangsaan Malaysia (Ukm Medical Centre)	Kuala Lumpur	Wilayah Persekutuan Kuala Lumpur

Sponsors (3)

Lead Sponsor	Collaborator
Universiti Kebangsaan Malaysia Medical Centre	Institue of Microengineering and Nanoelectronics (IMEN), Universiti Kebangsaan Malaysia, Universiti Kebangsaan Malaysia Medical Molecular Biology Institute (UMBI)

Country where clinical trial is conducted

Malaysia, 

References & Publications (18)

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Loizidou EZ, Inoue NT, Ashton-Barnett J, Barrow DA, Allender CJ. Evaluation of geometrical effects of microneedles on skin penetration by CT scan and finite element analysis. Eur J Pharm Biopharm. 2016 Oct;107:1-6. doi: 10.1016/j.ejpb.2016.06.023. Epub 2016 Jun 30. — View Citation

Mooney K, McElnay JC, Donnelly RF. Children's views on microneedle use as an alternative to blood sampling for patient monitoring. Int J Pharm Pract. 2014 Oct;22(5):335-44. doi: 10.1111/ijpp.12081. Epub 2013 Dec 6. — View Citation

Nayak A, Das DB, Vladisavljevic GT. Microneedle-assisted permeation of lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel. Pharm Res. 2014 May;31(5):1170-84. doi: 10.1007/s11095-013-1240-z. Epub 2013 Nov 8. — View Citation

Pires LR, Vinayakumar KB, Turos M, Miguel V, Gaspar J. A Perspective on Microneedle-Based Drug Delivery and Diagnostics in Paediatrics. J Pers Med. 2019 Nov 15;9(4). pii: E49. doi: 10.3390/jpm9040049. — View Citation

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* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Visual Analogue Score (VAS)	VAS score is measured in a continuous scale (range 0-100). It is obtained using a Med-05-100 VAS Pain Scale ruler (Schlenker Enterprises Ltd, Lombard, USA) with 0-100 mm slider. It is measured based on the pain experienced on the IV cannulated hand for blood transfusion. Higher VAS score indicates greater intensity or degree of pain whilst lower VAS score indicates lesser pain intensity.	The measurements will be made at 1 minute after IV cannulation which will be inserted following EMLA (with or without microneedle) application
Primary	Skin Conductance Algesimeter Index	The skin conductance peaks per second, measured in microSiemens per second (µS/s), is obtained using PainMonitor™ (Med-Storm Innovation AS, Oslo, Norway) device on the hypothenar eminence of the opposite hand not receiving blood transfusion. Higher skin conductance algesimeter index indicates greater pain intensity and lower values indicate lesser pain intensity.	The measurements will be made at 1 minute after IV cannulation which will be inserted following EMLA (with our without microneedle) application