Randomised Clinical Trial in Treatment Modalities for Cutaneous Leishmaniasis Caused by Leishmania Tropica, in Pakistan

Randomised, Open Label, Multicentre, Non-inferiority Clinical Trial for New Treatment Modalities for Cutaneous Leishmaniasis Caused by Leishmania Tropica, in Pakistan

A four (4) -arm randomised control clinical trial to evaluate miltefosine, thermotherapy and the combination miltefosine-thermotherapy are effective, safe and tolerable alternative treatment options to treat cutaneous leishmaniasis caused by L. tropica, in Pakistan compared to the standard of care.

Until now, there is no well-established evidence based option to treat CL caused by the Leishmania tropica, besides antimonial injections. Alternative treatment options are not available in Pakistan, or there is limited evidence of the effectivity.

Effectiveness of thermotherapy in L. tropica is studied in only three studies in OWCL with a variable cure rate (54.1% - 98%). But it could be an attractive option, because only one treatment session is required and studies report less scarring tissue. Another promising treatment option is oral miltefosine. There is considerable evidence in the literature of the efficacy of miltefosine in treatment of CL caused by L. major, however no studies have been conducted to evaluate the efficacy in CL caused by L. tropica species. This oral treatment could have major benefits for CL patients as it can be provided in peripheral health facilities and to patients who have contraindications to antimony treatment (elderly, and patients with cardiac or renal disease, or diabetes). A combination of thermotherapy and miltefosine, the advantages offered by this combination are that a) the use of a topical plus a systemic treatment would hypothetically have an additive effect of two treatments with different modes of action. For the reason that systemic treatment could eliminate those circulating or remaining parasites located in the periphery of the lesion that topical treatment fails to remove, which might be the cause of a relapse, b) it may reduce the necessary length of treatment with miltefosine.

For these above reasons, in a prospective trial we aim to evaluate the effectiveness and safety of thermotherapy, miltefosine and the combination of thermotherapy and miltefosine in CL caused by L. tropica, with the objective to find a treatment with an efficacy which is non-inferior to the standard of care with antimony injections.

Update on trial adaptations:

As pre-specified in the trial design, a futility analysis was planned after recruitment of approximately 30% of participants. Following this analysis, the thermotherapy arm was discontinued due to futility as per November 2023 At a subsequent interim analysis, the Data and Safety Monitoring Board (DSMB) recommended also to discontinue the combination arm (thermotherapy plus miltefosine), as no added value of thermotherapy could be demonstrated (as per January 2025)

The trial continues with the only two (2) arms: oral miltefosine and the standard of care with antimonial injections.

Inclusion Criteria:

• Male and female patients with clinical and laboratory confirmed CL, and who can be treated with localised intralesional antimonial injections and/or thermotherapy:
• lesion size ≥0.5 cm and ≤4 cm
• not located on the ear, nose, near to the eye or mucosal membranes, on joints, or on a location that in the opinion of the principle investigator (PI) is difficult to apply thermotherapy (TT) or intralesional (IL) injections
• patient with ≤4 lesions
• duration of lesions less than five months by patient history
• Patients who have signed the informed consent form.

After adaptation : (end Dec 2024) one eligible criteria changed :

age from 10 to 6; all children from 6 years and older are eligible

Exclusion Criteria:

• Pregnant women and breast feeding women
• Non-pregnant women in reproductive age refusing effective (injectable) contraception for a period of five months
• Patients <6years old
• Patients who cannot be treated with localised IL antimonial injections or TT (patients with more than 4 lesions, lesions >4cm in diameter, or located on joints, lips, nose, ears or near eyes)
• History of clinically significant medical problems or treatment that might interact with the study treatment and interact with wound healing, such as diabetes, vascular diseases and any immunocompromising condition
• Within eight weeks of trial D1 received treatment for leishmaniasis with any medication
• History of known or suspected hypersensitivity of idiosyncratic reactions to trial medication or experiments
• Has laboratory values at screening: serum creatinine above normal level; ALT 3 times above normal range
• Patient who is not willing to attend the trial visits, or is not able to comply with follow-up visits up to three months.
• Known history of drug addiction and/or alcohol abuse

After adaption (end Dec 2024) one exclusion criteria changed:

age from 10 to 6 yrs, Children < 6 years are excluded

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