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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] 285614 0
None
Universal Trial Number (UTN)
U1111-1159-4330
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cutaneous leishmaniasis 293464 0
Condition category
Condition code
Skin 293742 293742 0 0
Dermatological conditions
Infection 293960 293960 0 0
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] 290568 0
Treatment: Devices
Intervention code [2] 290621 0
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] 293543 0
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] 293543 0
8 weeks , 10 weeks , 12 weeks and 16 weeks
Primary outcome [2] 293597 0
Recurrence
Timepoint [2] 293597 0
3 months after the last dose of treatment and 6 months after the last dose of treatment.
Secondary outcome [1] 311311 0
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] 311311 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6456 0
Sri Lanka
State/province [1] 6456 0
Anuradhapura

Funding & Sponsors
Funding source category [1] 290250 0
Self funded/Unfunded
Name [1] 290250 0
Address [1] 290250 0
Country [1] 290250 0
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] 288918 0
Hospital
Name [1] 288918 0
Anuradhapura Teaching Hospital
Address [1] 288918 0
Anuradhapura Teaching Hospital, A 13 road, 002500,Anuradhapura, North Central Province

Country [1] 288918 0
Sri Lanka

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291918 0
Ethical clearance was obtained from the Ethics review committee , Faculty of Medicine, Colombo
Ethics committee address [1] 291918 0
94,Cumaratunga Munidasa Mawatha,Colombo 00300,Western Province
Ethics committee country [1] 291918 0
Sri Lanka
Date submitted for ethics approval [1] 291918 0
Approval date [1] 291918 0
19/12/2013
Ethics approval number [1] 291918 0
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] 230 230 0 0
Attachments [2] 231 231 0 0
Attachments [3] 232 232 0 0

Contacts
Principal investigator
Name 52586 0
Dr Fathima Wardha Refai
Address 52586 0
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 52586 0
Sri Lanka
Phone 52586 0
+94 727800003 or +94 11 2580093 or +94 11 2699284
Fax 52586 0
+94 11 2699284
Email 52586 0
wardharefai@yahoo.com
Contact person for public queries
Name 52587 0
Dr Fathima Wardha Refai
Address 52587 0
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 52587 0
Sri Lanka
Phone 52587 0
+94 727800003 or +94 11 2580093 or +94 11 2699284
Fax 52587 0
94 11 2699284
Email 52587 0
wardharefai@yahoo.com
Contact person for scientific queries
Name 52588 0
Dr Fathima Wardha Refai
Address 52588 0
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.


7 MACLEOD ROAD
COLOMBO 4
Country 52588 0
Sri Lanka
Phone 52588 0
+94 727800003 or +94 11 2580093 or+94 11 2699284
Fax 52588 0
+94 11 2699284
Email 52588 0
wardharefai@yahoo.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary