ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12621000831886

Ethics application status

Approved

Date submitted

7/07/2020

Date registered

29/06/2021

Date last updated

29/06/2021

Date data sharing statement initially provided

29/06/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

Study to compare thermotherapy and intralesional drug injection for the treatment of patients with cutaneous leishmaniasis lesions in Syria.

Scientific title

Randomised controlled trial to determine the efficacy of thermotherapy in comparison with intralesional meglumine antimoniate to treat cutaneous leishmaniasis in an operational setting in Syria.

Secondary ID [1]

PAR20002, Oxford University

Universal Trial Number (UTN)

U1111-1253-8297

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cutaneous Leishmaniasis

Condition category

Condition code

Skin

Other skin conditions

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

The study will compare two treatments for cutaneous leishmaniasis: intralesional meglumine antimoniate (IL MA) and thermotherapy. IL MA is the standard treatment for CL in Syria, making thermotherapy the interventional treatment.

The device used in this study – ThermoMed Model 1.8 (Thermosurgery Technologies, Inc., Inc, Phoenix, AZ) - has received both Food and Drug Administration (FDA) and WHO approval for use in treatment of CL and is already in use by MENTOR in Syria. The handheld ThermoMed 1.8 device delivers controlled localised radio frequencies to small areas of tissue, which generates heat that is tolerable to healthy cells but intolerable for abnormal cells as well as parasites. The operating frequency is 6.78 MHZ +/- 15 KHZ and the output power 7 watts (+/-1).

The application follows several steps, which are laid out in a Standard Operating Procedure document, which is present at every treatment location. The application is as follows:
(a) After the applicator is properly placed on patient, depress handset button.
(b) Temperature will ramp up to the selected temperature. The ThermoMed will automatically terminate treatment after 4 seconds of the applicator is not making contact with the tissue being treated. Treatment will also be terminated if ramp-up (time to reach selected temperature) exceeds 45 seconds. If no treatment is administered for 15 seconds, the ThermoMed will automatically shut down.
(c) During ramp up to the temperature selected (50 degrees Celsius) the ThermoMed will produce a steady tone of increasing pitch to indicate the temperature sensed by the applicator thermocouple. The red light on the handset will be on. After the selected temperature (50 degrees Celsius) is reached:
- The audio output will change from a steady tone to a tone that beeps every 2 seconds
- The red light on the handset will change from steady to blinking
(e) After 30 seconds at the selected temperature:
- The ThermoMed will emit a 1 second tone burst.
- The red light on the handset will be on for the same interval as the tone.
- The first (30) indicator light on the ThermoMed unit will be turned on (red).

Standard treatment for CL with thermotherapy consists of 1 treatment session with application of the ThermoMed device for a duration of 30 seconds at a selected heat of 50 degrees Celsius to each treated area. Larger lesions may require more than 1 application during the same session to cover the entire lesion area. For smaller lesions 1 application of the ThermoMed device will suffice. For patients with several CL lesions, all lesions may be treated during the same treatment session. No further treatment sessions are required. Lesions on or directly adjacent to lips, eyes/eyelids, nose, ears, fingers/toes, close to close to carotid and jugular vessels in neck, the antecubital fossa region or on volar aspect of wrist joint should not be treated using this device. Implantable cardiac devices such as pacemakers and metallic implants such as metal plates in skull also exclude a patient from receiving this treatment.

All treatments with the thermotherapy device will take place in either a health facility or a mobile leishmaniasis clinic and all staff that administer the treatment must at least have a nursing degree.

As with the MA injections, adherence to the treatment will be monitored through the patient registration book, which is present at each MENTOR-supported health facility as well as all mobile leishmaniasis clinics and via the case report form (CRF) designed for this trial.

Intervention code [1]

Treatment: Devices

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

The control treatment will be a course of intralesional Meglumine antimoniate (IL MA). MA is manufactured by Sanofi Aventis, France. It will be purchased and imported into Syria by MENTOR.

IL MA will be infiltrated around the CL lesions. The exact dose of MA will be determined at the clinician’s or nurse’s discretion, based on a thorough assessment of the lesion and depending on (a) the size of the lesion, (b) how elastic the skin is, and (c) how much of the drug leaks into the subcutaneous tissue layer. As a result, the volume of MA generally varies between 1 and 5mls. MENTOR will follow the WHO EMRO guidelines which state that each lesion should be injected twice per week for 3-4 weeks until complete cure is reached.

When injecting, the angle of the needle should be max 5-10 degrees to ensure injection into the dermal layer. 3-4 injection sites, 0.5 to 1cm outside the border of the lesion, should be chosen. These 3-4 injection sites should be at roughly equal distance from one another around the circumference of the lesion. Injection of the drug into the intradermal layer should cause blanching and slight swelling of the skin.

The drug will be injected by either a medical doctor or a qualified nurse at a MENTOR-supported health facility or a MENTOR mobile leishmaniasis clinic, which are visited by a Medical Officer at least once a week to provide on-the-job training, assess performance and assure that enough medical commodities are in stock.

Treatment adherence will be assessed via the patient registration book, which is present in all MENTOR-supported health facilities and mobile clinics, as well as the case report form (CRF) designed for this trial.

Control group

Active

Outcomes

Primary outcome [1]

The primary outcome is a composite outcome and falls under the first study objective "To compare the efficacy of thermotherapy treatment to an IL course of MA for the treatment of cutaneous leishmaniasis at three months post treatment in Syria."

The primary study outcome is: "Complete re-epithelization for ulcerated lesions, and obvious flattening for non-ulcerated lesions measured at 3 months post treatment completion."

Photographs of the lesions pre- and post-treatment will be taken and sent to two dermatologists, who are blinded to treatment arm and determine the outcome (treatment success or failure) independently from each other. In case the two dermatologists disagree on the outcome, a third dermatologist, equally blinded, will determine the outcome.

Timepoint [1]

3 months post treatment completion.

Secondary outcome [1]

The secondary outcome is a composite secondary outcome and falls under the second objective of the trial "Determine leishmania species, genotypes & molecular markers of antimonial resistance."

The secondary outcome is: "PCR of kinetoplast DNA (species), sequence internal transcriber spacer 2 and cytochrome b genes (genotype), gene expression of e.g. aquaglyceroporin 1, multidrug resistance protein A."

Timepoint [1]

Samples will be taken post-treatment completion to then determine the leishmania species, genotypes & molecular markers of antimonial resistance

Eligibility

Key inclusion criteria

All patients who present to the 5 selected static health facilities and mobile treatment clinics with Cutaneous Leishmaniasis lesions will be eligible for inclusion in this study if they meet all of the inclusion criteria and none of the exclusion criteria.

The inclusion criteria are as follows:
1. Participant with clinically diagnosed Old World Cutaneous Leishmaniasis < 4 cm in size
2. Participant is willing and able to give informed consent for participation in the study or
3. For children at least 5 years, a parent or guardian gives informed consent on their behalf
4. Participant agrees to follow the study processes and attend the follow-up appointment 3 months post treatment completion

Minimum age

5 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Pregnancy by history
2. Lactation
3. Lesions
*on or directly adjacent to lips, eyes/eyelids, nose
*nose
*ear
*fingers/toes
*close to carotid and jugular vessels in neck
*antecubital fossa region
*on volar aspect of wrist joint
4. Implantable cardiac devices such as pacemakers
5. Metallic implants such as metal plates in skull
6. Previous history of treatment to same lesion(s)

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

For treatment allocation, the sequentially numbered, opaque sealed envelopes (SNOSE) method to randomly allocate treatment will be used. The preparation will follow the instructions given by Doig & Simpson (2005) in their paper “Randomization and allocation concealment: a practical guide for researchers.”, whereby a stack of SNOSE treatment allocation envelopes will be prepared and then a certain number of envelopes will be allotted to each study clinic.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Random number tables will be used in every study clinic. Each patient that enters the clinic for CL treatment and fulfils the requirements of entering the study will be allotted a number from the table, starting at the beginning of a column. If the number is even, he/she will be included in the trial sample and vice versa.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people assessing the outcomes
The people analysing the results/data

Intervention assignment

Other design features

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

15/07/2021

Actual

Date of last participant enrolment

Anticipated

15/10/2021

Actual

Date of last data collection

Anticipated

15/02/2022

Actual

Sample size

Target

580

Accrual to date

Final

Recruitment outside Australia

Country [1]

Syrian Arab Republic

State/province [1]

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

The MENTOR Initiative

Address [1]

4th Floor (South Suite),
Burns House, Harland Road,
Haywards Heath, RH16 1PG

Country [1]

United Kingdom

Primary sponsor type

Charities/Societies/Foundations

Name

The MENTOR Initiative

Address

4th Floor (South Suite),
Burns House, Harland Road,
Haywards Heath, RH16 1PG

Country

United Kingdom

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Oxford Tropical Research Ethics Committee (OxTREC)

Ethics committee address [1]

University of Oxford
University Offices, Wellington Square
Oxford OX1 2JD

Ethics committee country [1]

United Kingdom

Date submitted for ethics approval [1]

05/06/2020

Approval date [1]

18/02/2021

Ethics approval number [1]

Summary

Brief summary

The aim of the study is to compare the efficacy of thermotherapy treatment to an intralesional course (IL) of Meglumine Antimoniate (MA) for the treatment of cutaneous leishmaniasis (CL) at three months post treatment in Syria. 

Cutaneous leishmaniasis is a skin disorder that is caused by a certain type of parasite which is spread by the bite of sand flies. If people become infected they develop one or more skin lesions, mostly open ulcers on exposed parts of the body, which, if not treated, can leave life-long scars, resulting in serious disability or stigma. If left untreated, the disease can also spread and develop into mucocutaneous leishmaniasis, which can lead to a partial or complete destruction of the nose and mouth parts. CL is widely endemic in Syria, with several thousand people getting infected every year as a result of poor living conditions and continuous displacement due to lasting conflicts. 

Up until now, a course of IL MA has been the standard treatment for CL lesions in Syria. MENTOR follows WHO EMRO guidelines which state that for intralesional antimoniate treatment, each lesion should be injected twice per week for 3-4 weeks until complete cure is reached. Each patient undergoing this treatment modality is treated twice per week. The treatment for CL with thermotherapy consists of 1 treatment session even for patients with several lesion, with an application of the ThermoMed device to each treated area. No further treatment sessions are required. 

The study will be conducted in a governorate in North-West Syria where MENTOR, an international non-governmental organisation (NGO), is currently operating leishmaniasis mobile clinics and supporting health facilities with supplies and technical support for treating patients with CL. 

Previous studies comparing thermotherapy with IL antimoniates have mostly been small and there are no data from Syria, where security is very volatile and CL incidence is high. Thermotherapy represents a very promising option because of its portability, good cost effectiveness, and ease of use. It also offers the opportunity to reduce reliance on international NGOs and foreign aid programmes and increase local capacity to sustainably manage CL. If shown to be effective in the Syrian context, the results would be widely generalisable, give greater clarity to health care workers on the clinical indications for thermotherapy vs. IL antimoniates and could change health policy.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Mr Hendrik Sauskojus

Address

The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom

Country

United Kingdom

Phone

+44 1444 412171

Fax

hendrik@mentor-initiative.net

Contact person for public queries

Name

Hendrik Sauskojus

Address

The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom

Country

United Kingdom

Phone

+44 1444 412171

Fax

hendrik@mentor-initiative.net

Contact person for scientific queries

Name

Hendrik Sauskojus

Address

The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom

Country

United Kingdom

Phone

+44 1444 412171

Fax

hendrik@mentor-initiative.net

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Due to the sensitive Syrian context, we will not be able to share IPD data.

What supporting documents are/will be available?

Current supporting documents:

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
8405	Informed consent form			hendrik@mentor-initiative.net		380037-(Uploaded-02-04-2021-02-19-22)-Study-related document.docx

Updated to:

Doc. No.	Type	Attachment
8405	Informed consent form	380037-(Uploaded-02-04-2021-02-19-22)-Study-related document.docx
23857	Statistical analysis plan	380037-(Uploaded-06-06-2024-20-36-58)-CL in Syria SAP Final 4-6-24.docx
23858	Study protocol	380037-(Uploaded-06-06-2024-20-39-49)-Syria CL Study Protocol.docx

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.

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