Evaluation of the Safety and Clinical Activity of Curaleish in the Topical Treatment of Cutaneous Leishmaniasis.

Study Overview
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Brief Summary
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Cutaneous Leishmaniasis (CL) is a parasitic disease caused by more than 15 different species of the protozoan parasite Leishmania. The CL usually begins with a papule at the site of the sandfly bite, increasing in size to form a nodule that ulcerates in a period of 1 to 3 months. The exact incidence of CL is not known. An estimated 1.2 million cases/year in approximately 102 countries worldwide suffer from different forms of CL. Among the different parasites that cause CL, L.tropica in the Old World and L.braziliensis in the New World are considered to be the most important due to the difficulty of healing, the public importance and the severity of the disease. Pentavalent antimony remains the first choice drug for the treatment of CL and the evidence to support its use is sometimes based on qualitative, retrospective and uncontrolled observations, with only some controlled clinical studies. Antimonials are widely used despite their toxicity, difficulty in the route of administration, and high cost. Miltefosine (hexadecylphosphocholine), an oral medication that has proven effective for some types of Leishmania, is potentially teratogenic, is contraindicated during pregnancy and requires appropriate counseling for female patients of childbearing age.

Detailed Description
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Curaleish is a topical formulation in lotion and cream that contains natural extracts (hydroalcoholic and glycolic for lotion and cream, respectively) of the branches (stems and leaves) of the Caesalpinia spinosa tree known as Tara or Davidivi , which was developed by Bionest SAS, Duitama, Colombia. The product is currently manufactured by Biohealthy SD S.A.S in accordance with Colombian Good Manufacturing Practices (BPM) and evaluated by PECET following the international standardized animal protocols and models of OECD. The development of a topical formulation of Curaleish is intended to offer a treatment to be applied locally in the lesion of the LC, with a high antiparasitic effect. The formulation of Curaleish lotion and Curaleish cream containing natural extracts, started from the activity demonstrated in In vitro for the hydroalcoholic extract of C. espinosa (EC50 = 18.4 ± 1.3 µg / mL) and a low cytotoxicity evidenced by an LC50 of 135.6 ± 0.7, 183.3 ± 1.1 and 136.6 ± 7.4 µg / mL in human liver cells HepG2, human macrophages U937 and peritoneal hamster macrophages, respectively, and a selectivity index of 9.41, 9.96 and 7.42, respectively. This activity was validated in in vivo studies in hamsters experimentally infected with L. braziliensis. Applying the cream alone twice a day for 28 days produced a cure in 83% and fails in 17%. On the other hand, the lotion applied once a day for 28 days showed cure in 67% and relapse in 33%. When the lotion was used in combination twice a day and the cream once a day for 28 days, 100% cure was achieved, which occurred early in most hamsters, this is at the end of the treatment. Accelerated stability tests for 3 months and natural stability (6 months) under Zone IV conditions of the ICH (conditions 25ºC / 60% RH, 30ºC / 65% RH, 30ºC / 75% RH and 40ºC / 75% RH) have shown that the product meets the criteria required for physical and microbiological analysis, established by the United States Pharmacopeia (USP). These parameters are for the cream: density 0.957 ± 0.000 g / mL for the cream and 0.958 ± 0.000 g / mL for the lotion; Extensibility area 123.24 ± 19.64 mm2 for the cream; pH of 6.69 ± 0.115 for the cream and 4.82 ± 0.017 for the lotion; <104 CFU of total aerobes and <103 CFU / mL for molds and yeasts. Weight, clinical appearance and behavior data, as well as histological studies obtained from preclinical acute dermal toxicity tests as well as cellular viability data obtained in skin irritation / corrosion tests for Curaleish lotion and cream, executed according With the OECD guidelines, it was concluded that skin contact with Curaleish products does not generate toxic effects at the local level (application site) or at the systemic level, so it can be considered as safe for use. An exploratory study to assess the safety, and to determine whether the Curaleish topical cream when the lotion is applied three times a day in combination with the cream, applied twice a day for 4 weeks showed that it is 83% effective for treatment of Colombian subjects with uncomplicated LC. 25 of 30 patients managed to cure between 1.5 and 3 months after the end of Curaleish treatment. The development of a topical formulation of Curaleish is intended to offer a treatment to be applied locally in the lesion of the CL, with a high antiparasitic effect. Skin irritation/corrosion tests for Curaleish lotion and cream, performed following the guidelines of the OECD, allowed to conclude that skin contact with Curaleish products does not generate toxic effects locally, or at a systemic level, therefore they can be considered safe for use. Main Objectives To assess the safety and tolerability of two Curaleish regimens administered topically in individuals with uncomplicated CL. The two regimes to evaluate are: Regimen 1: Curaleish lotion applied three times a day in combination with Curaleish cream applied two times a day for 4 weeks. Regimen 2: Curaleish lotion applied three times a day in combination with Curaleish cream applied two times a day for 6 weeks. Secondary Objectives Evaluate the safety of Curaleish (frequency and severity of adverse events (AEs)). Other secondary efficacy objectives include the assessment of the condition of the lesions over time up to 100% re-epithelialization of the ulcerated lesions and the proportion of individuals with 100% re-epithelization of not ulcerated lesions over time.

Official Title
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Evaluation of the Safety and Clinical Activity of Curaleish Lotion and Cream in the Topical Treatment of Cutaneous Leishmaniasis in Colombia

Conditions
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Leishmaniasis, Cutaneous

Intervention / Treatment
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* Drug: Experimental topical (Curaleish Topical)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between 18 - 60 years. Patient with confirmed parasitological diagnosis of CL in at least one lesion, performed at least through the following methods: 1) microscopic identification of amastigotes in tissue of the lesion; 2) Leishmania diagnose through PCR; 3) positive culture for promastigotes. Patient with a lesion that meets the following criteria: . Ulcer or nodule with a maximum size of 4 cm (the largest diameter). Not located in the ear, face, near mucous membranes, joints, or in places that, in the opinion of the PI, the study medication is difficult to apply topically. Patient with a maximum of four CL lesions. The duration of the lesion is less than three months according to the patient's history. The patient is able to give written informed consent. Patients whom the investigator believes are able to understand and are willing to comply with the requirements of the protocol. Exclusion Criteria: Patients who meet some of the following criteria must be excluded from the study: Women with positive pregnancy test during the screening process, or who are lactating; or women of childbearing age who do not agree to take contraceptives during treatment and until Day 45. The subject has a history of significant medical conditions or treatments that may interact negatively or positively with the topical treatment of Leishmaniasis, including any immune compromise condition. Within eight weeks (56 days) of beginning the study treatments, having received treatment for Leishmaniasis through any medication, including Glucantime that probably, in the opinion of the principal investigator (PI), might modify the course of the infection by Leishmania. Based on physical examinations performed, they have been diagnosed, or a diagnosis of Mucocutaneous Leishmaniasis is suspected. Known history or suspected hypersensitivity or idiosyncratic reactions to the study medication. Patients who do not wish to attend study appointments or who cannot keep up with follow-up visits for up to 6 months

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: An Open-label, Randomized, Non-comparative, Two-arm Exploratory study. After all the screening evaluations have been completed, the principal investigator or his designee will confirm the patient's eligibility on Day 1, and the randomization will be determined by IWRS where randomized identification of the patient will be provided. The treatment allocation will be performed according to a computer-generated random code.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Régimen 1<br>Regimen 1: Curaleish lotion applied three times a day in combination with Curaleish cream applied two times a day for 4 weeks. For both treatments, the patient applies Curaleish lotion in the morning, afternoon, and evening, that is to say, three times a day. And Curaleish cream in the morning and afternoon, that is, twice a day. | Drug: Experimental topical (Curaleish Topical)<br>* Curaleish is a formulation in lotion and cream. Curaleish lotion and Curaleish cream will be applied topically by each participant in all lesion until day 28 or 42, depending on the regimen to be evaluated. Study staff will be closely observing the safety assessment. The application until Day 28 or 42 will continue, even if the lesion has shown 100% re-epithelization before day 28 or day 42.<br>* Other names: Curaleish Topical;|
| Active Comparator: Régimen 2<br>Regimen 2: Curaleish lotion applied three times a day in combination with Curaleish cream applied two times a day for 6 weeks. For both treatments, the patient applies Curaleish lotion in the morning, afternoon, and evening, that is to say, three times a day. And Curaleish cream in the morning and afternoon, that is, twice a day. | Drug: Experimental topical (Curaleish Topical)<br>* Curaleish is a formulation in lotion and cream. Curaleish lotion and Curaleish cream will be applied topically by each participant in all lesion until day 28 or 42, depending on the regimen to be evaluated. Study staff will be closely observing the safety assessment. The application until Day 28 or 42 will continue, even if the lesion has shown 100% re-epithelization before day 28 or day 42.<br>* Other names: Curaleish Topical;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| post treatment (healing) | Healing: initial healing * without relapse and/or mucous commitment for the post-treatment evaluation of Day 180. *Initial healing: defined as 100% re-epithelialization of the lesion(s) following Day 90 post-treatment. | day 180 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2. Days 28 and 42, respectively, depending on the duration of each treatment group. (Adverse events) | Adverse events (AEs) will be evaluated according to the seriousness, temporal relationship, relationship with the study medication, and severity. The recording will be carried out through clinical examination, telephone calls, and through the completion of the subject's diary. The local AEs that will be evaluated are: Erythema Burning Pain Pruritus Irritation The following evaluations will be made: Frequency and severity (Mild, Moderate, Severe) of AEs by treatment group. Status (area of lesions, induration, erythema, etc.) in each measurement. Additionally, before starting treatment and at the end of it, renal (creatinine) and liver function (transaminases) tests will be performed on volunteers. | 28 days and 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leishmaniasis, Curaleish