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Trial registered on ANZCTR

Registration number

ACTRN12614001288617

Ethics application status

Approved

Date submitted

8/11/2014

Date registered

10/12/2014

Date last updated

10/12/2014

Type of registration

Retrospectively registered

Titles & IDs

Public title

A clinical trial to assess the safety and effect of heat therapy in comparison to standard intra-lesional sodium stibogluconate for cutaneous leishmaniasis

Scientific title

In patients with cutaneous leishmaniasis , thermotherapy was compared with standard intra-lesional therapy with regard to efficacy and safety.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1159-4330

Trial acronym

Linked study record

Health condition

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

cutaneous leishmaniasis

Condition category

Condition code

Skin

Dermatological conditions

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Arm 1-The device used was the ThermoMed 1.8, ThermoSurgery Technologies portable battery operated device. The generator has received clearance by the US Food and Drug Administration for the treatment of CL.
It delivers precisely controlled localized radio frequency waves to selectively destroy diseased tissue.Heat therapy was administered as a single session. The lesion and surrounding normal skin was cleaned with normal saline. Then the area was anasthetized with 2% lignocaine using a 1cc syringe .The device was used in according to manufacturers instructions (ThermoMed 1.8 ;Thermosurgery) .It generates a 6.78 mHz frequency applied with a hand set that is attached to two applicator electrodes which were placed on the diseased skin. A temperature of 50 degrees centigrade was applied for 30 seconds to cover an area about 49-73mm squared, according to the size of electrodes ( three sizes are provided). Then the applicator is moved to another area of the lesion until the entire area is treated. Once treatment begins the temperature is measured by a thermistor embedded in the applicator which ensures that the applied temperature remains constant. After treatment the lesions were covered with gauze to prevent secondary infections and patients were given an antibiotic cream( soframycin 1% per 30 grams depending on the size of lesion to cover the lesion) to be applied twice a day for 3 days.

Intervention code [1]

Treatment: Devices

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Arm 2-Intra-lesional sodium stibogluconate ( brand name Pentostam) .Intralesional SSG,( PentostaM) using a 1cc syringe with a fixed needle was administered after the lesion was cleaned with normal saline .SSG was administered intra-lesionally until complete blanching of the lesion and its margins.The injection was given at right angles to the lesion to infilterate in a “v”shaped pattern that ended with the needle being advanced to the base of the lesion.Depending on the size of the lesion the dose varied from about 1-3 ml given weekly until cured or up to 10 weeks .The same medical officer treated all the patients to minimize variations.

Control group

Active

Outcomes

Primary outcome [1]

Treatment efficacy was measured by the percentage of patients clinically cured by 8 weeks , 10 weeks , 12 weeks and 16 weeks after initiation of treatment in both groups.
Cure was defined as complete re-epithelialization of the CL lesion with no evidence of papules, active inflammation or induration .
Partially cured if healing was 50-100%
Non –responders or treatment failures were those who had lesions that were less than 50% healed at the end of three months or if new lesions occur while on treatment.

Timepoint [1]

8 weeks , 10 weeks , 12 weeks and 16 weeks

Primary outcome [2]

Recurrence

Timepoint [2]

3 months after the last dose of treatment and 6 months after the last dose of treatment.

Secondary outcome [1]

Any adverse events like secondary bacterial infections, allergy to treatment or hypersensitivity and worsening of the lesion clinically was recorded during or after treatment with either therapy .

Timepoint [1]

Every fortnightly up to 12 weeks and then monthly at 4th month.

Eligibility

Key inclusion criteria

Case definition - Patients with suggestive skin lesions (papules, nodules, plaques, ulcers and noduler-ulcers) who were clinically diagnosed by a consultant dermatologist and parasitologically confirmed as CL.

Minimum age

12 Years

Maximum age

90 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Non localized leishmaniasis ( VL, MCL, leishmanaisis recidivans, diffuse cutaneous lesihmaniasis and post kala-azar dermal leishmaniasis ).
2. Use of prior concomitant treatment for leishmaniasis including any traditional medicines.
3. Lesions close to nasal ,oral , urogenital , anal areas (mucosae) and the eyes
4. Multiple lesions
5. Any chronic or concomitant illnesses and people on pace makers and any metallic devices.
6. Pregnancy and breast feeding mothers
7. Children below 12 years of age
8. Immunocompromised states including HIV/AIDS and use of immunosuppressants like steroids
9. Alcohol abuse
10. Subjects not capable of understanding and complying with the study protocol
11. Known hypersensitivity or allergy to treatment

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)

Informed consent was obtained to participate in the study.Samples of lesion aspirate and scrapings from the active edge of the lesions were taken for laboratory investigation for the confirmation of presence of Leishmania parasites by microscopy and culture
Once the patients were eligible to participate in the trial, they were briefed about the study, its aims and protocol by the investigator. Informed written consent was obtained from the patients by a trained research assistant to avoid any bias ( the investigator refrained from taking consent). The clinical trial data form was completed and photographs of the baseline lesions were taken. The clinical trial data form was filled to obtain demographic and clinical details with regard to baseline size and type of lesion. Patients then proceeded to the nursing officer to be randomized into one of the arms of the trial.

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

An independent senior nursing officer at the skin clinic was trained to assign patients to either treatment group by making them pick one of two identical cardboard pieces out of a box (the cardboard pieces had been labelled with different treatment codes on one of its sides) .After patients were assigned by the nurse to each treatment group the card board pieces were returned to the box.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

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

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Efficacy

Statistical methods / analysis

The software used was SPSS version 20 to enter data and analyze. The demographic details and lesion characteristics were provided using descriptive statistics with chi squared test to check for any significant difference among the two groups in each treatment arm.
The association between cure rate at (8,10,12,16 weeks) and sex, age, site of lesion and lesion characteristics were assessed using a stratified analysis with chi-squared test. A p value of greater than 0.05 was taken to be significant.
Sample size calculation:
The sample size was calculated using the non-inferiority design, to show that the new intervention thermotherapy is no worse than the standard therapy intra-lesional SSG by a margin of delta . Delta is defined as a clinically acceptable margin of difference between the treatments being compared.
The formula below designed for hypothesis testing of non-inferiority trials when the outcome measure is a dichotomous variable is used in the sample size calculation.
N= sample size per group
delta= the clinically acceptable margin of difference from the treatments being compared.
The literature review done for clinical trials comparing the two modes of treatment show that there is a clinically acceptable margin of difference of about 10% .

The null hypothesis -Thermotherapy is inferior to intra-lesional SSG by a clinically acceptable marginal difference of 10%.
P= the response to standard treatment –intralesional SSG is 92% effective.
N=2( Z(1-apha)+Z(1-beta )divided by delta x P(1-P)
Z(1-alpha)=1.645
Z(1-beta)=0.845
alpha -is the probability of type 1 error that occurs in rejecting the null hypothesis when it is actually true and its value is taken as 0.05.
beta- the probability of rejecting the null hypothesis when its false. This is given by the power of the research (1- type II error/beta): the probability of rejecting the null hypothesis when it is false. Conventionally, the power is set at 0.80.
The sample size calculated when p=92% is 92 patients per arm of treatment, considering loss to follow up we can add on another 5% and the total number of patients per arm was calculated as 97.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

8/01/2014

Date of last participant enrolment

Anticipated

Actual

18/06/2014

Date of last data collection

Anticipated

Actual

Sample size

Target

194

Accrual to date

Final

Recruitment outside Australia

Country [1]

Sri Lanka

State/province [1]

Anuradhapura

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Address [1]

Country [1]

Primary sponsor type

University

Name

University of Colombo

Address

No. 25, Kynsey Road, Colombo 8, 00800,Western Province
Colombo 8

Country

Sri Lanka

Secondary sponsor category [1]

Hospital

Name [1]

Anuradhapura Teaching Hospital

Address [1]

Anuradhapura Teaching Hospital, A 13 road, 002500,Anuradhapura, North Central Province

Country [1]

Sri Lanka

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Ethical clearance was obtained from the Ethics review committee , Faculty of Medicine, Colombo

Ethics committee address [1]

94,Cumaratunga Munidasa Mawatha,Colombo 00300,Western Province

Ethics committee country [1]

Sri Lanka

Date submitted for ethics approval [1]

Approval date [1]

19/12/2013

Ethics approval number [1]

EC-13-129

Summary

Brief summary

Once the patients were eligible to participate in the trial, they were briefed about the study, its aims and protocol by the investigator. Informed written consent was obtained from the patients by a trained research assistant to avoid any bias ( the investigator refrained from taking consent). The clinical trial data form was completed and photographs of the baseline lesions were taken. The clinical trial data form was filled to obtain demographic and clinical details with regard to baseline size and type of lesion. Patients then proceeded to the nursing officer to be randomized into one of the arms of the trial. The assigned treatments are as follows:-
Thermotherapy ( Test group)
Heat therapy was administered as a single session. The lesion and surrounding normal skin was cleaned with normal saline. Then the area was anasthetized with 2% lignocaine using a 1cc syringe .The device was used in according to manufacturers instructions (ThermoMed 1.8 ;Thermosurgery) . It generates a 6.78 mHz frequency applied with a hand set that is attached to two applicator electrodes which were placed on the diseased skin. A temperature of 50 degrees centigrade was applied for 30 seconds to cover an area about 49-73 mm2 according to the size of electrodes ( three sizes are provided). Then the applicator is moved to another area of the lesion until the entire area is treated. Once treatment begins the temperature is measured by a thermistor embedded in the applicator which ensures that the applied temperature remains constant. After treatment the lesions were covered with gauze to prevent secondary infections and patients were given an antibiotic cream( soframycin( 1% in 30 grams) as much as required to cover the lesion) to be applied twice a day for 3 days.

SSG (control group)
One of the trained medical officers administered branded SSG, Pentostam using a 1cc syringe with a fixed needle after the lesion was cleaned with normal saline .SSG was administered intra-lesionally until complete blanching of the lesion and its margins.The injection was given at right angles to the lesion to infilterate in a “v”shaped pattern that ended with the needle being advanced to the base of the lesion.Depending on the size of the lesion the dose varied from about 1-3 ml given weekly until cured or up to 10 weeks .The same medical officer treated all the patients to minimize variations. Patients were followed up fortnightly up to 12 weeks and then monthly up to the 4th month to assess response to treatment and then after 3 months of complete cure to assess for any relapse or recurrence.The clinical trial data form was completed at every follow up visit with regard to size of lesion, degree of re-epithilialization , whether cured or not , whether further treatment was required and remarks were documented. Photographs were taken at each visit and were saved in folders for each patient. The occurrence of adverse effects were evaluated by asking patients and examining lesions and were documented in the remarks section of the data form.

Trial website

Trial related presentations / publications

Efficacy and safety of thermotherapy versus intra-lesional sodium stibogluconate in L donovani-induced cutaneous leishmaniasis: A randomized controlled clinical trial
Abstract for American Society of tropical medicine and hygiene (ASTMH) 2014 November.
F.W Refai, N.P Madarasingha, S.Weerasingha, U.Senarath, R.Fernandopulle, A. Satoskar, N.D Karunaweera

Public notes

Attachments [1]

/AnzctrAttachments/367382-Data sheet clinical trial_0001.pdf

Attachments [2]

/AnzctrAttachments/367382-Abstract for ASTMH-full.docx

Attachments [3]

/AnzctrAttachments/367382-ERC-Approval for Trial.pdf

Contacts

Principal investigator

Name

Dr Fathima Wardha Refai

Address

MD Parasitology trainee attached to the Post Graduate Institute of
Medicine (PGIM) and currently training at the Department of Parasitology, Faculty of Medicine , University of Colombo.
1.PGIM address:No.160,Professor Nandadasa Kodagoda Mawatha (Norris Canal Road), 00700, Colombo 7.
2.Department of Parasitology, Faculty of Medicine Colombo University of Colombo address: No 25, Kynsey Road, Colombo 8
0080, Sri Lanka.

Country

Sri Lanka

Phone

+94 727800003 or +94 11 2580093 or +94 11 2699284

Fax

+94 11 2699284

[email protected]

Contact person for public queries

Name

Dr Fathima Wardha Refai

Address

1.PGIM address:No.160,Professor Nandadasa Kodagoda Mawatha (Norris Canal Road), 00700, Colombo 7.
2.Department of Parasitology, Faculty of Medicine Colombo University of Colombo address: No 25, Kynsey Road, Colombo 8
0080, Sri Lanka.

Country

Sri Lanka

Phone

+94 727800003 or +94 11 2580093 or +94 11 2699284

Fax

94 11 2699284

[email protected]

Contact person for scientific queries

Name

Dr Fathima Wardha Refai

Address

Country

Sri Lanka

Phone

+94 727800003 or +94 11 2580093 or+94 11 2699284

Fax

+94 11 2699284

[email protected]

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Embase	Interventions for Old World cutaneous leishmaniasis.	2017	https://dx.doi.org/10.1002/14651858.CD005067.pub4
Embase	Efficacy, safety and cost-effectiveness of thermotherapy in the treatment of leishmania donovani-induced cutaneous leishmaniasis: A randomized controlled clinical trial.	2017	https://dx.doi.org/10.4269/ajtmh.16-0879

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically