Development of Topical Herbal Formulations for Treatment of Cutaneous Leishmaniasis

April 7, 2021 updated by: Muhammad Arif Asghar, Jinnah Sindh Medical University

Development of Topical Herbal Formulations for Treatment of Cutaneous Leishmaniasis: A Single Blind, Randomized, Placebo Controlled Preclinical and Clinical Trials

Infections due to protozoa of the genus Leishmania are a major worldwide skin problem, with high endemicity in developing countries including Pakistan. As far as concern for the treatment of cutaneous leishmaniasis (CL), there is no single therapeutic agent that has proved a satisfactory efficacy and safety. Therefore, the objective of this research study was to develop an alternative therapeutic approach for the treatment of CL. In the current research protocol, two herbal topical formulations (Gyburene and Thuscare) were prepared containing to contain 5% Casuarina equisetifolia L. and Thespesia populnea L. plant extract and evaluate their leishmanicidal potential in pre-clinical and randomized clinical trials studies. Preclinical studies were performed on BALB/c mice after the development of a lesion on the dermis caused by the Leishmania (L.) major parasite. Six weeks randomized, single single-blind placebo controlled study was also conducted on seventy eight L. major infected patients divided into three groups i.e. treated, reference and placebo with the 1:1 ratios.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

STUDY PROTOCOL

1.1. Introduction Leishmaniasis is a major neglected health problem frequently found in tropical and subtropical regions with the prevalence rate of 1.5 million per year globally. The disease is caused by protozoan parasite from genus Leishmania. Transmission occurred by sand fly of genus Phlebotomus in the (Old World) and Lutzomyia (New World). Cutaneous leishmaniasis is restricted to skin and around 185 million people at risk in 61 countries. Now it is endemic in Pakistan (different regions) and diffuses fastly, particularly in the refugee camps main causative agent found is L. major followed by L. tropica. Vigilant literature review revealed that besides the four provinces of Pakistan increased incidences of CL were found in Balochistan which is largest province (in area) followed by NWFP. In Sindh province (Dadu, Jacobabad, Larkana and Karachi) are commonly reported for cases while in Punjab (Multan and Dera Ghazi Khan) are mainly reported for the occurrence of disease. Diagnosis of this diseases is done by clinical picture usually dry lesions are caused by L. tropica while moist and early ulcerative lesions are caused by L. major, such lesions take months to years for healing eventually heal by own but satellite lesions and bacterial and fungal infections results in delayed and complicated healing process, but in non-endemic areas it is difficult to diagnose because of unclear form, along with this secondary infections, delay treatment as well as mistreatment sometimes can also cause changes in clinical picture. In such situations examination of smear from lesion is the diagnostic tool along with culture and histopathological examinations.

1.2. Clinical trials against CL Methanolic bark extract of Casuarina equisetifolia L. showed good antileishmanial potential against L.major using in vitro analysis which directed us towards an innovative therapeutic concept for development of new herbal formulations against leishmaniasis through accelerated wound closures in clinical trials on human contestants. Ulcerative CL is because of defective wound healing depending on this hypothesis current study is planned to explored clinical efficacy of new protocol Gyburene 5% cream as anti-parasitic agent followed by Thuscare 5% ointment for speed up wounds closure. The primary objective of this study is to evaluate anti leishmanial outcome of Gyburene 5% cream at wound closure and after six months while secondary objective is to evaluate that incessant wound care along with anti-parasitic agent can results in valuable enhancement in treatment.

1.3. Sample population and study design: This is a single-blind, randomized study. Seventy patients with confirmed with cutaneous leishmaniasis were recruited in the study. Participants were randomly allocated into two groups. Pilot group (did not receive any medication before) and resistant group (who already received medication either parental or topical). During trials 20 participants were dropped as a result of lack of follow up specially the affected people coming from rural areas.

1.3.1. Ethical consideration: The research protocol was approved by ethical committee of the Board of Advanced Studies and Research University of Karachi Vide Resol No. 16. Informed consents forms were taken from each patient.

1.3.2. Patient Assessment:

Medical history of each patient (age, sex, co-morbidities, wound condition, site and size of lesion with Giemsa smear test report) was taken prior to treatment protocol on clinical Performa specially designed for this study and consisted of two parts, first for personnel information and second for medical history. Lesion size was calculated using Vernier caliper in two dimensions and each participant advised for weekly follow up till end of therapy, portrait photograph were taken before, throughout and after therapy using digital camera for assessment of healing percentage. Cured patients follow up was done for further six months to ensure no set back has been happened. Presence or absence of parasite was confirmed by smear test while healed area was calculated by percentage of healing by following formula (Baie and Sheikh, 2000):

1.3.2.1. Inclusion criteria

  1. Patients who met the histological criteria for presence of parasite
  2. Age of older than 4 years and both gender.
  3. Lesions are less than 5 in number in each patient
  4. Size of lesion is less than 5cm2
  5. Participants who had stopped therapy greater than 4 weeks earlier and the lesions were not improving.
  6. Duration of disease for patients under trial was six months (acute) and more than one year (chronic).

1.3.2.2. Exclusion criteria

  1. Patients who had taken any immuosuppressive drugs or anti leishmanial drugs in last month.
  2. Pregnant women and lactating mothers.
  3. Contestants with complications of renal, hepatic and pulmonary disease, Immune-o- compromised patients such as (HIV).
  4. Patients suffering from conditions like malaria, tuberculosis and treatment regimen is going on for such infections.

1.3.3. Study treatment Prior to the initiate treatment protocol toxicological evaluation of herbal extracts was also done to ensure the safety of topical herbal pharmaceutical preparations. In case of more than one lesion any one targeted for biopsies although all received same treatment. Both groups of patient were treated with topical herbal formulations Gyburene 5% cream (for cure of CL) in morning and evening and Thuscare 5% ointment (for rapid wound healing and cure of super infections) only at night in two different directions at the angle of 90º to each other by leaving lesion uncovered.

Before application of second formulation all contestant were advised to wash the lesion with normal saline. Weekly follow up was done till completion of the therapy in order to ensure the entire cure such as for negative smear skin test amastigotes in Giemsa strain and complete healing with re-epithelialization of the lesion. Each formulation was dispensed in 10 g container (separately) enough for one week.

1.4. Statistical Analysis T-test used for comparison rate of healing between two groups while Kaplan Meier test between pilot and resistant group while Kaplan Meier test used to calculate healed area per week for both resistant and pilot group at P<0.05 using SPSS version 21.

Clinical evaluation Performa for Cutaneous Leishmaniasis (CL) Personal information Patient code: ------------------- Male/Female: ---------------------- Age: ---------- Address: --------------- Occupation: ------------------- Marital status: -------------

Contact No: -------------------------- CNIC No: ------------------------Family history:

Clinical information Morphology of lesion

  • Ulcerated
  • Crust
  • Plaque
  • Nodule Lesion condition
  • Dry
  • Wet Giemsa Smear test
  • Positive
  • Negative Duration of lesions
  • ≥ 6 month
  • Between 6-12 months
  • ≤ 6 month No of lesions
  • 1
  • 2
  • 3
  • 4
  • 5

Health condition

  • Arthritis
  • Allergy
  • Diabetes
  • Immune disorder
  • Blood pressure Differential diagnosis for CL
  • Bacterial and fungal skin infection
  • Eczema
  • Syphilis
  • Sarcoidosis
  • Blastomycosis
  • Others Area of lesion/visit Visit I: Area=……………cm2 Visit II: Area= …………..cm2 Visit III: Area=…………. cm2 Visit IV: Area=………… cm2 Visit V: Area=…………. cm2

Remarks of Dermatologist:

Signature of Dermatologist

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
78

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Pakistan
    • Sindh
      • Karachi, Sindh, Pakistan, 75850
        • Civil Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

4 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • The inclusion criteria for participants including;

    • • Patients who met the histological criteria for presence of parasite
    • Age of older than 4 years and both gender.
    • Lesions are less than 5 in number in each patient
    • Size of lesion is less than 5cm2
    • Participants who had stopped therapy greater than 4 weeks earlier and the lesions were not improving.
    • Duration of disease for patients under trial was six months (acute) and more than one year (chronic).

Exclusion Criteria:

  • The following patients were excluded:

    • Whose clinical data were incomplete
    • Participants who had received any anti anti-leishmanial or immunosuppressive drugs in the last 15 days
    • Patients with co-morbid conditions, immunocompromised patients,
    • Lactating mothers and pregnant women.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
No Intervention: Control
Experimental: Herbal topical formulation
Other: Herbal topical formulation

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
The lesion progression was followed microscopically and the strain presence present in biopsy material was also confirmed microscopically in both cultures and smears after six weeks treatment.
Time Frame: 6 weeks
The primary endpoint of leishmaniasis cure from topical herbal formulations was assessed microscopically in both cultures and smears.
6 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Measurement of lesions size between placebo, treated and reference groups after the six weeks treatment period
Time Frame: 6 weeks

For the monitoring of healing progressed, photographs were taken before, during and after completion of therapy using a digital camera while healed area was calculated by percentage of healing by following formula:

Healed area percent of wound contraction = ………………………………. ×100 Total area before treatment
6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Jinnah Sindh Medical University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Yousra Shafiq, Ph.D, Jinnah Sindh Medical University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2012

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 30, 2014

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 30, 2014

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 5, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 7, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 12, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 12, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 7, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
April 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • DISDSK-937/-22

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

All types of data after publication on request.

IPD Sharing Time Frame

After study will be published

IPD Sharing Access Criteria

On request

IPD Sharing Supporting Information Type

  • Study Protocol
  • Statistical Analysis Plan (SAP)
  • Informed Consent Form (ICF)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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