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The Cure Rate after Placebo or No Therapy in American Cutaneous Leishmaniasis: A Systematic Review and Meta-Analysis
Gláucia Fernandes Cota1, Marcos Roberto de Sousa2, Tatiani Oliveira Fereguetti3
1Clinical Research and Public Policy in Infectious and Parasitic Diseases, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Fiocruz, Belo Horizonte, Minas Gerais, Brazil.
Introduction:
There are few drugs with proven efficacy in cutaneous leishmaniasis (CL), and pentavalent antimonial derivatives are still the main first-line therapeutic agents worldwide, despite their recognized high toxicities. Randomized controlled clinical trials assessing the efficacy and safety of new therapeutic modalities are of high priority, and the definition of the design of such trials raises debate about the use of placebo as a comparator. To support the use of placebo as a comparator, two main points need to be addressed: 1--the cure rate without any therapeutic intervention and 2--the damage caused by CL and its impact on patients.
Objective:
The aim of this study was to systematically assess the spontaneous cure rate for American CL and to broaden the discussion about placebo use in CL trials.
Methods:
The PRISMA guidelines for systematic reviews and the Cochrane manual were followed. The sources used were the PubMed and LILACS databases. Studies were included if they reported cure rates using placebo or no treatment in American CL.
Results:
Thirteen studies of a total of 352 patients were ultimately included in this review. The summarized global cure rates for all Leishmania species according to the intention-to-treat analyses performed at approximately three ("initial cure") and nine ("definitive cure") months after "no treatment" or placebo use were 26% (CI95%: 16 to 40%) and 26% (CI95%:16 to 38%), respectively. Notably, a significantly lower cure rate was observed for L. braziliensis infection (6.4%, CI95%:0.2 to 20%) than for L. mexicana infection (44%, CI95%:19 to 72%), p = 0.002. Of note, relapse occurred in 20% of patients with initial healing (CI95%:9.2 to 38.9%).
Conclusion:
These results clearly demonstrate a low spontaneous cure rate following no-treatment or placebo use, confirming that this strategy for the control group in CL studies expose patients to greater morbidity, especially for CL caused by L. braziliensis. Therefore, from this point, the crucial question to consider regarding placebo use is the seriousness of the suffering caused by this disease.
Insights
Cutaneous leishmaniasis (CL) has a low spontaneous cure rate, with only 26% of patients healing without treatment. This highlights the significant morbidity and suffering caused by CL, particularly L. braziliensis infections, questioning placebo use in clinical trials.
Area of Science:
- Tropical medicine
- Infectious diseases
- Clinical trial design
Background:
- Cutaneous leishmaniasis (CL) treatments are limited, with pentavalent antimonials being the primary option despite toxicity.
- High-priority randomized controlled trials (RCTs) for new CL therapies necessitate evaluating placebo use.
- Understanding spontaneous cure rates and disease impact is crucial for justifying placebo comparators in CL trials.
Purpose of the Study:
- To systematically evaluate the spontaneous cure rate of American cutaneous leishmaniasis.
- To inform the ongoing debate regarding the ethical use of placebo in CL clinical trials.
Main Methods:
- Systematic review adhering to PRISMA and Cochrane guidelines.
- Searched PubMed and LILACS databases for studies on American CL placebo or no-treatment cure rates.
- Included 13 studies involving 352 patients.
Main Results:
- Overall spontaneous cure rates were 26% at 3 months and 26% at 9 months.
- L. braziliensis infections showed significantly lower cure rates (6.4%) compared to L. mexicana (44%).
- Relapse occurred in 20% of patients who initially achieved healing.
Conclusions:
- The low spontaneous cure rate underscores the significant morbidity associated with untreated CL, especially L. braziliensis.
- Placebo use in CL trials exposes patients to prolonged suffering and increased disease burden.
- Ethical considerations regarding patient suffering are paramount when deciding on placebo use in CL research.
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