Introduction Leprosy, in other terms "Hansen's disease (HD)", is one among the oldest infectious and most little bothered stigmatized diseases. It is caused by bacteria "Mycobacterium leprae" that have higher predilections towards the skin and the nervous system, mainly peripheral.1 It is primarily seen in underdeveloped systems and has become a serious public health concern because to its social stigma and extensive geographic dispersion. People have always migrated within countries and around the world, influencing the epidemiological profile of HD.2 The long-term health results of persons affected by HD have improved significantly in recent decades as a result of the general effectiveness of the multidrug therapy (MDT) regimen and other anti-inflammatory drugs.3 In 2001, WHO announced that leprosy had been eradicated "at a global level," despite the fact that 719,330 new cases were reported in the preceding year. Six nations were responsible for 88% of new cases.4 In the data of 2011 from notifiable countries, more than 2 lakhs (219,075) new cases of leprosy were reported. This indicates the disease's silent transmission despite hidden in the society even though overall reduction in prevalence from previous surveys.5 Even after completing MDT, many patients continue to face illness-related problems, including a stigma that persists till death for contacted the disease, lepra responses, impairments, and the odd relapse or reinfection. All of these variables generate long-term issues for both patients and physicians.6 Globally, in many countries, complications or sequel of leprosy-related disabilities and deformities, as well as accompanying religious or social beliefs and physical changes, are the reasons to generate stigmatizing views against those affected by the disease.2 To far, no replicable, standardized, and clear-cut assessment scale has been developed to assess the significance of a leprosy cure.7 The study's small number of clinical trials can be attributed to the same cause. The editorial focuses on the characteristics of registered clinical trials on leprosy to better understand the types and methodology of these investigations. It is envisaged that such a thorough study would generate suggestions for future studies and highlight the importance of exploring various patient-friendly treatment options. Global Leprosy Databases All clinical trials on Leprosy and Lepra reactions registered with Clinicaltrials.gov and registries of countries such as India, Australia, Brazil, China, Korea, Cuba, EU, German, Iran, ISRCTN, Japan, Lebanese, Thailand, Netherlands, Pan African, Peru, and Sri Lanka were searched using keywords "Leprosy" and "Lepra reaction" in different permutations and combinations. The studies were analyzed using generic criteria such as registration month, blinding, comparator, disease severity, drug type, phase, sample size, sponsorship, study place, technique of generation and concealment, and duration. These data are represented as actual numbers. Studies and Distributions Using the aforementioned keywords, a total of 239 studies were obtained from the various registry sites, 83 of which were connected to leprosy. According to registration records, these research were done in 18 different nations. The geographical mapping of the research site revealed that India had the highest number of registered trials (n = 37), followed by Brazil (n = 21). Other studies were from Bangladesh, Nepal, Nigeria, Philippines, Taiwan, Belgium, USA, Colombia, Ethiopia, Germany, Japan, and Malawi. General Features of Registered Studies Systematic analysis revealed that there were 12 observational studies and 71 interventional studies. The class of drugs that were used as intervention comprised conventional MDT regimen, corticosteroids, minocycline, clofazimine, methotrexate, thalidomide, cyclosporine, metformin, amitriptyline, Montelukast, dapsone, zinc oxide, rifampicin, fuscidic acid, and indomethacin Figure 1.Figure 1: Drugs interventionThe various indications, for which these drugs were evaluated, were classified as leprosy treatment per se, lepra reaction, and leprosy sequelae. The class of drugs that were tried for treatment of various classes of leprosy included MDT. Clofazimine was tried for Paucibacillary leprosy. Fuscidic acid and indomethacin were investigated for the leprosy reactions and sequalae. The drugs that were tried in patients showing ENL reactions included corticosteroids, thalidomide, minocycline, metformin, and Montelukast. Amitriptyline was administered to patients who experienced neuropathic pain as a result of a leprosy sequelae ulcer, while zinc oxide was tried on individuals with chronic, long-standing ulcers Figure 2.Figure 2: IndicationsThe various vaccines used for intervention were BCG + Killed M. leprae in 3 trials, BCG alone, and Lepvax in one trial each.8–12 A large proportion of studies were funded by government agencies and institutions (n = 76). The placebo-controlled studies numbered 15. The most common way of creating the random sequence was computer-generated randomization (n = 19), and the most common method of concealment was sequentially numbered, sealed, opaque envelopes (n = 9). A large number of trials were open labelled (n = 29), followed by double blind studies (n = 13). Thirty-two trials had a sample size within the range of 7–50. Five trials had a sample size of more than 10,000. Most of the trials were in Phase 2 and Phase 3 (n = 13 each) Figure 3.Figure 3: Various phasesMost of the studies had a duration of 1–2 years (n = 23). The number of studies with more than 7-year duration was 4. Critical Analysis The present editorial analyzed the various registered clinical trials on leprosy and observed its characteristics and changing trends. Cure of leprosy involves much more than killing bacteria and the disappearance of skin lesions. Most of the treatments target only the pathological process of the disease which tend to be incomplete, leading to recurrence.13 Leprosy is most commonly found in developing countries, and its prevalence varies. We found that the maximum number of trials were conducted in India and Brazil, as these countries account for the maximum number of leprosy cases in accordance with the previous studies conducted.14 Although India was successful in implementation of MDT under the NLEP Programme, which helped in bringing down the national prevalence from "elimination as a national public health problem" to reduce to fewer than 1 per 10,000 by 2005 and further declined to 0.66 per 10,000 by 2016, India among other countries still contributes approximately 60% of the new leprosy cases loads reported worldwide each year.15 In Latin America, leprosy is recognized as a national public health concern only in Brazil; however, the continued detection of new cases in most countries highlights gaps in adequate medical care.16 Among the various interventional methods, trials on various drugs were the maximum (n = 34). Multidrug therapy regimen was the most used intervention for treatment of various classes of leprosy. In addition to being effective, the implementation of MDT regimen has been demonstrated to be safe and well accepted by both patients and program managers.17 Clofazimine was tried in patients with borderline lepromatous leprosy. Previous studies have shown that the addition of clofazimine can lead to a definite decrease the incidence of lepra reactions; however, the incidence of hyperpigmentation is to be looked for.18 Erythema Nodosum Leprosum Focus In managing ENL, the primary goals are to control inflammation, relieve pain, and prevent future episodes.19 In this study, we found that the various drugs used for management of ENL included corticosteroids, thalidomide, minocycline, metformin, and Montelukast. Prednisolone is most commonly used in the treatment of moderate and severe ENL reactions. Previous studies have shown that in steroid non-responder recurrent ENL patients, Steroid-based combination therapy with thalidomide and clofazimine was found to be effective.20 Due to its teratogenic potential, thalidomide is recommended to be used with utmost caution in individuals of reproductive age, regardless of sex.19 Neuropathy Focus A clear understanding of the management and treatment strategies for neuropathic complications in leprosy is crucial for alleviating disease burden and enhancing patients' quality of life.21 Trials including amitriptyline and zinc oxide as intervention were tried for the management of leprosy complications. Amitriptyline could be a newer search for future trials aimed at controlling neuropathic pain in leprosy.22 Zinc oxide has proven to be an effective, affordable, and well-tolerated alternative treatment for chronic trophic skin ulcers.23 Vaccine Focus There is an increasing need to step up leprosy elimination activities. Vaccines are provided along with MDT therapy as adjuvants in leprosy patients and for the contacts as prophylaxis, along with Single dose rifampicin, provide hope in this direction.24 In our study, we found that a combination of BCG + Killed M. leprae vaccine, BCG alone and Lepvax were evaluated for their therapeutic effects. Lepvax, which had completed phase Ia clinical trials successfully, is a hybrid recombinant protein composed of four M. leprae antigens – "ML2531, ML2380, ML2055, and ML2028" (collectively known as LEP-F1) – formulated in a stable emulsion with a synthetic TLR4 agonist adjuvant (GLA-SE).24 Apart from Lepvax other phase I trials that were registered included intervention with MLSA-LAM and MLCwA as new skin test antigens, evaluation of the impact of virgin coconut oil supplementation on oxidative stress levels and treatment outcomes in Hansen's disease patients undergoing MDT, along with a proposed intervention strategy focused on disability prevention among individuals affected by leprosy.25–29 Phase IV trials included interventions with corticosteroids in prevention of clinical sensory or motor function impairment, clofazimine in ENL reactions, role of anti-oxidants such as antioxidants like Vitamin C, Vitamin E, Manganese, Selenium, Zinc, Copper, Beta carotene in leprosy and effect topical autologous platelet-rich-fibrin-membrane with total-contact-cast in trophic ulcer developed as part of leprosy sequelae.30–33 Among the Phase 1 trials, safety and efficacy assessment of leprosy skin test antigens MLSA-LAM and MLCwA has been carried forward to Phase II. It was found that MLSA-LAM and MLCwA at both high and low doses were found to be safe for use in humans. These antigens were tested in individuals with known exposure to leprosy and in targeted populations. Although they demonstrated a specificity that was reasonably high, their sensitivity ranged between 20% and 25%, making them unsuitable for use as a skin test in detecting early-stage leprosy.34 There was also a complementary trial we looked for in this study, but detailed data were not available as the trial was withdrawn.27 We also found that studies with a large sample size > 10,000 were mainly conducted in African countries of Comoros, Madagascar, Senegal, etc., and were based on leprosy vaccines and single-dose rifampicin as postexposure prophylaxis. The information's on various clinical trials of leprosy drugs provided on the efficacy and safety of new treatment regimens may lead to changes in the standard treatment guidelines of countries. One such example is the change in standard MDT therapy by WHO in the year 2018. The new regimen that was proposed involved a shorter duration of treatment with rifampicin and dapsone in higher dose. It was found to be more effective and had fewer adverse events compared to the older regimen.35 Changes in the treatment guidelines may be also influenced by the emergence of various resistant strains for drugs of Leprae bacilli and also the new drugs availability. These changes may be implemented gradually, based on the infrastructure for the delivery of healthcare services.36 Apart from the conventional MDT regimen, various approved drugs as off label have been rationally tried in the management of leprosy such as rifapentin, clofazimine, clarithromycin, ofloxacin, minocycline bedaquiline, and fuscidic acid. These drugs usage will depend on the type and severity of the disease and drug resistance patterns. Rifapentin belongs to the class of anisomycins that act by inhibiting the bacterial RNA synthesis.37 Clofazimine acts by binding to bacterial DNA and inhibiting replication.38 Clarithromycin and minocycline inhibit protein synthesis, whereas bedaquiline inhibits the production of ATP by disrupting the proton gradient.39–41 In the present editorial focus, among 83 clinical trials, 76 were sponsored by Government Agencies and Institutions, while only 3 studies were sponsored by the pharmaceutical industries. This indicates a steady decrease in financial support from pharmaceutical companies for clinical trials and programs related to leprosy. Increasing interest and financing for research on leprosy-related clinical trials is an essential problem for the future.2 Future Perspectives Further, pharmacokinetic trials are highly mandated for the usage of safe and effective treatment regimens. The pharmacokinetics of anti-leprotic drugs can be affected by various unique features of leprosy, such as immunological reactions, bacillary load, and skin infiltration. They can help in identifying the potential interactions of drugs with other medications. This becomes important in determining the appropriate dosing regimens in the leprosy group with co-existing HIV.42 WHO Global Leprosy Strategy The WHO Global Leprosy Strategy 2021–203043 emphasizes a revolutionary strategy based on three key pillars: providing integrated, person-centered leprosy services, reducing disease transmission, and removing stigma while supporting human rights. These strategic objectives closely align with the gaps and opportunities revealed in our registry study. Notably, the increasing inclusion of vaccination and chemoprophylaxis trials – such as those testing single-dose rifampicin for contacts – reflects a proactive move toward transmission stoppage. Furthermore, research is increasingly focusing on socioeconomic determinants, relapse, and long-term effects, while monitoring tools are growing to monitor treatment resistance and recurrence. India's Roadmap for Zero Leprosy In keeping with this global framework, India's Roadmap for Zero Leprosy (2021) outlines an ambitious but attainable national target. It vows to increase efforts for early case detection by 2027 and eliminate leprosy by 2030, confirming India's commitment to WHO's elimination targets and its leadership in establishing regional public health priorities.44 Conclusion Registry-based research on conditions such as leprosy offers valuable insights into the real-world effectiveness of treatments across different therapeutic areas. A key benefit of these studies is access to extensive, diverse patient populations, potentially encompassing all diagnosed cases worldwide. In this study, drug-related trials constituted the maximum number of trials. Conducting clinical trials on a stigmatized disease is always associated with ethical concerns. However, with the changing attitude in destigmatizing the disease and improving ethical outlook, trials being registered and published can definitely support the global system in eradicating leprosy.
Thangaraju et al. (Fri,) studied this question.
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