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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.
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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.
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Secondary ID [1]
301576
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PAR20002, Oxford University
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Universal Trial Number (UTN)
U1111-1253-8297
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Cutaneous Leishmaniasis
317943
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Condition category
Condition code
Skin
315977
315977
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0
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Other skin conditions
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Infection
320201
320201
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0
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Other infectious diseases
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
317869
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Treatment: Devices
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Intervention code [2]
320163
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Treatment: Drugs
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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.
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Control group
Active
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Outcomes
Primary outcome [1]
324340
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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.
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Assessment method [1]
324340
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Timepoint [1]
324340
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3 months post treatment completion.
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Secondary outcome [1]
384380
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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."
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Assessment method [1]
384380
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Timepoint [1]
384380
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Samples will be taken post-treatment completion to then determine the leishmania species, genotypes & molecular markers of antimonial resistance
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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
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Minimum age
5
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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)
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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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.
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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.
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
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Other design features
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Phase
Phase 4
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Type of endpoint/s
Efficacy
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
15/07/2021
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Actual
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Date of last participant enrolment
Anticipated
15/10/2021
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Actual
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Date of last data collection
Anticipated
15/02/2022
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Actual
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Sample size
Target
580
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Accrual to date
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Final
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Recruitment outside Australia
Country [1]
22713
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Syrian Arab Republic
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State/province [1]
22713
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Funding & Sponsors
Funding source category [1]
306002
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Charities/Societies/Foundations
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Name [1]
306002
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The MENTOR Initiative
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Address [1]
306002
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4th Floor (South Suite),
Burns House, Harland Road,
Haywards Heath, RH16 1PG
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Country [1]
306002
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United Kingdom
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Primary sponsor type
Charities/Societies/Foundations
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Name
The MENTOR Initiative
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Address
4th Floor (South Suite),
Burns House, Harland Road,
Haywards Heath, RH16 1PG
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Country
United Kingdom
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Secondary sponsor category [1]
309043
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None
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Name [1]
309043
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Address [1]
309043
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Country [1]
309043
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
306237
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Oxford Tropical Research Ethics Committee (OxTREC)
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Ethics committee address [1]
306237
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University of Oxford
University Offices, Wellington Square
Oxford OX1 2JD
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Ethics committee country [1]
306237
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United Kingdom
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Date submitted for ethics approval [1]
306237
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05/06/2020
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Approval date [1]
306237
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18/02/2021
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Ethics approval number [1]
306237
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
103206
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Mr Hendrik Sauskojus
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Address
103206
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The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom
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Country
103206
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United Kingdom
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Phone
103206
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+44 1444 412171
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Fax
103206
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Email
103206
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[email protected]
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Contact person for public queries
Name
103207
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Mr Hendrik Sauskojus
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Address
103207
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The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom
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Country
103207
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United Kingdom
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Phone
103207
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+44 1444 412171
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Fax
103207
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Email
103207
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[email protected]
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Contact person for scientific queries
Name
103208
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Mr Hendrik Sauskojus
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Address
103208
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The MENTOR Initiative
Burns House, Harlands Road,
Haywards Heath, RH16 1PG
England, United Kingdom
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Country
103208
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United Kingdom
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Phone
103208
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+44 1444 412171
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Fax
103208
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Email
103208
0
[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Due to the sensitive Syrian context, we will not be able to share IPD data.
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What supporting documents are/will be available?
No Supporting Document Provided
Current supporting documents:
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
8405
Informed consent form
[email protected]
380037-(Uploaded-02-04-2021-02-19-22)-Study-related document.docx
Updated to:
Doc. No.
Type
Citation
Link
Email
Other Details
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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