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- Patients and Methods
In India, post-kala-azar dermal leishmaniasis (PKDL) is a sequel to visceral leishmaniasis (VL) within a year or up to 32 years after VL has been cured (Ramesh et al. 1993). The disease begins with hypopigmented macules, papules or nodules on the face and then spreads to the other regions of the body (Ganguly et al. 2010). For the individual, cosmetic disfiguration is prolonged and is measured in years. For the community, the parasites within PKDL lesions are a reservoir of infection that perpetuates VL, which is anthroponotic in India (Ganguly et al. 2010).
Standard treatment of Indian PKDL is unsatisfactory because to achieve therapeutic effectiveness, heroic courses of parenteral/toxic agents have to be administered. Thakur et al. compared sodium stibogluconate (6–10 treatment courses of 20 mg antimony (Sb)/kg/day × 20 days, separated by a 20-day drug-free period) with amphotericin B (1 mg/kg/day on days 1–20, 20–40 and 61–80) (Thakur et al. 1997). 11 of 11 amphotericin B patients cured with 1-year follow-up, whereas 7 of 11 stibogluconate patients were cured. The currently recommended treatment includes these prolonged regimens of pentavalent antimonials or amphotericin B (Thakur et al. 1997), in spite of the toxicity experienced even for standard courses (Aronson et al. 1998; Fungizone product description 2012).
Miltefosine has been widely studied for its oral use as an antileishmanial drug at a dose of 2.5 mg/kg/day for 4 weeks. It was highly effective (>94% cure rates) for Indian VL in phase 3 and phase 4 studies (Sundar et al. 2002; Bhattacharya et al. 2007) and also reported effective in many (Soto et al. 2004; Machado et al. 2010; Chrusciak-Talhari et al. 2011), although not all (Vélez et al. 2010), published trials for cutaneous leishmaniasis.
If miltefosine, given for 100 days or less, were effective and well tolerated for Indian PKDL, this oral agent would offer an advantage over the currently recommended prolonged administration of parenteral stibogluconate or amphotericin B. Our objective was to compare miltefosine for 12 weeks, a period comparable to that used for the standard therapies, to miltefosine for 8 weeks.
Patients and Methods
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- Patients and Methods
The study was an open-label, randomised, parallel-group, multicentric trial at three Indian clinical trial sites.
Patients had to be ≥12 years of age, with nodules and papules consistent with post-kala-azar dermal leishmaniasis and with parasitological confirmation of Leishmania infection by visualising amastigotes in smears of slit-skin or skin snip specimens from one papule or nodule. Exclusion criteria were clinically meaningful abnormalities of laboratory tests (haematology, liver function tests, kidney function tests), any uncontrolled clinical condition including HIV or other major infectious diseases, lactation or pregnancy, or treatment with any antileishmanial drug within the previous 12 weeks. Patients were studied between July 2007 and October 2009.
Miltefosine was administered at a target dose of 2.5 mg/kg/day for 8 weeks (8 week group) or 12 weeks (12 week group) utilising 50-mg capsules: two capsules for patients ≥25 kg or one capsule for <25 kg. A separate randomisation scheme, generated and maintained by the product manufacturer, was used for each clinical site. For each site, patients were randomised between the two treatment groups in equal allocation.
Originally, a sample size of 20 patients per group was planned so that with an expected cure rate of 75%, the lower limit of the 95% confidence limit for cure would be >50%. Because of practical limitations, a sample size of 18 patients per group was ultimately chosen.
When the study was designed, we were faced with the difficulty of the most appropriate means of evaluating a disease with polymorphic presentation at multiple body sites. We concluded that papules or nodules rather than macules should be assessed, as papules and nodules are more reliably measured and are more likely to have demonstrable parasites, and that assessments should be made at three of the many possible cutaneous locations.
There were two efficacy parameters: the clinical score and the parasitological score. The clinical score was calculated from the ordinal scale below (Table 1). For example, the clinical score for a location was ‘5’ if there were either 9–10 papules in a location, or five nodules in that location, or 5–6 papules plus two nodules in that location. The parasitological score was also ordinal and conformed to the log scale.
Table 1. Calculation of clinical score and parasitological score
|Score||Clinical: papules and/or nodules||Parasitological|
|No. of papules||No. of nodules||No. of amastigotes|
The clinical score was determined prior to treatment, at the end of treatment (at 8 weeks or 12 weeks depending on the treatment group) and at 3, 6, 9 and 12 months after the end of treatment. The parasitological score was determined prior to treatment, at the end of treatment and subsequently for lesions that were positive at the end of treatment.
Final efficacy responses were determined at 12 months after the end of treatment. Cure was defined as a clinical score = 0 for all three locations and a parasitological score = 0 when last measured after treatment. For patients who cured by these criteria, the rest of the body was visually scanned to verify the absence of papules and nodules. An example of facial lesions pre-therapy and cure post-therapy is in Figure 1.
At each clinical visit during treatment, the investigator asked the patient about the occurrence, duration and severity of adverse events. Events were graded according to Common Toxicity Criteria (CTC) version 2.0. (Common Toxicity Criteria 2.0 1999). Entrance laboratory parameters were evaluated every 2 weeks during treatment.
The protocol was approved by the Ethics Committee of the following institutions: Institute of Medical Sciences, Banaras Hindu University; Rajendra Memorial Research Institute of Medical Sciences; Kalazar Research Centre; and WHO. Informed consent was obtained from each patient.
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- Patients and Methods
Of the 36 randomised patients (Table 2), one patient in the 8-week group was lost after taking drug for 2 weeks and was not analysed. There were 18 analysable patients in the 12-week group and 17 analysable patients in the 8-week group. As the mean weight was 52 kg, all patients except one received 100 mg miltefosine per day, which equates to approximately 2 mg/kg/day.
Table 2. Study data
| ||12-week group||8-week group||All patients|
|Number of patients|
|Age in years: mean (SD)||29 (12)||24 (9)||27 (10)|
|Gender: % male||83||53||63|
|Weight in kg: mean (SD)||55 (11)||51 (18)||52 (14)|
|Pre-treatment clinical score: mean (SD) [range]||11 (5) [1–18]||11 (6) [1–18]||11 (5) [1–18]|
|Pre-treatment parasitology score: no. of locations positive/no. of locations tested||2.0/2.4||2.0/2.3||2.0/2.3|
|End of therapy|| || || |
|Post-treatment clinical score (% pre-treatment score)||2.3 (22%)||2.4 (27%)||2.4 (24%)|
|Post-treatment parasitology score: no. locations positive/no. pts||0/18||1/17||1/35|
|End of 12 months of follow-up|
|Cure: no. of pts||14||13||27|
|Fail: no. of pts||1||3||4|
|Lost: no. of pts||3||1||4|
|ITT cure rate: no. of pts/no. of pts total (%) [95% CI]||14/18 (78%) [61–88%]||13/17 (76%) [53–90%]||27/35 (77%) [61–88%]|
|PP cure: no. of pts/no. of pts total (%) [95% CI]||14/15 (93%) [71–95%]||13/16 (81%) [57–93%]||27/31 (87%) [71–95%]|
|Vomiting: no. of patients||4||4|| |
|Day of onset (duration in days) [CTC grade]||48 (1) , 52 (1) , 69 (1) , 76 (5) ||38 (1) , 32 (1) , 39 (1) , 33 (5) || |
|Diarrhoea: no. of patients||1||0|| |
|Day of onset [duration in days] (CTC grade)||76 (4) ||na|| |
|Elevated bilirubin: no. of patients||0||1|| |
|Day of onset [duration in days] (CTC grade)||na||16 (12) || |
The mean clinical score pre-treatment was 11 of a maximum of 18 (maximum score of ‘6’ for each of three bodily locations). Lesions in a mean of 2.3 of the maximum of three locations were evaluated for parasites and were positive in 2.0 instances. For each parasitologically positive lesion, the parasitological score was 1 to 3 in all cases except for one score of ‘4’ [data not shown]. Entrance characteristics were similar for the two treatment groups.
At the end of treatment, the clinical score had dropped to 22–27% of its pre-treatment value in both groups. Parasites were no longer recoverable except for one lesion in the 8-week group.
After 12 months of follow-up for the 12-week group, 14 patients were cured, one patient failed and three patients were lost at the 3-month follow-up (two patients) or at the 9-month follow-up (one patient). In the 8-week group, 13 patients were cured, three patients failed and one patient was lost at the 6-month follow-up. The difference in cure rates was not significantly different: P = 0.60–0.99 (Fisher's exact test) for the per-protocol and ITT cure rates, respectively.
Clinical abnormalities consisted of vomiting reported by four patients in each group and one case of diarrhoea. The duration of vomiting was 1 day for all but two patients. The severity of vomiting was CTC grade 1 for six patients and CTC grade 2 for two patients. There was one laboratory abnormality: one case of elevated bilirubin.
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For Indian PKDL in this study, the ITT cure rate for patients administered oral miltefosine continuously for 12 weeks was 78% (95% CI = 61–88%) by ITT analysis and 93% (95% CI = 71–95%) by per-protocol analysis after 12 months of follow-up.
A total of 12 weeks of therapy were well tolerated. The primary side effects when miltefosine is used to treat cutaneous disease are gastrointestinal (Soto et al. 2004), but gastrointestinal events occurred in only nine of 35 patients (26%) and were not of greater frequency, duration or severity in the 12-week group than in the 8-week group.
Recently, miltefosine was reported to cure 23 of 26 Indian PKDL patients with one treatment failure (Ramesh et al. 2011). In that study, miltefosine was initially administered at a relatively high dose (150 mg/day) for a relatively short time for this disease (60 days = 8.5 weeks). Gastrointestinal intolerance caused one patient to leave the study, and seven further patients stayed in the study but the dose was reduced to 100 mg/day. In addition, because cure was not apparent in three patients after the initial 60 days of 150-mg/day therapy, this dose was extended for a further 15–30 days [2–4 weeks] to effect cure. Although it is reasonable to attempt to shorten therapy by initial administration of >2.5 mg/kg/day for 8 weeks, we favour the lower miltefosine dose and the predetermined time period of 12 weeks as per the present report to lower gastrointestinal events while maintaining a therapeutic effect.
In India, PKDL is a problem for the individual patient and important for VL control. For a disease for which chemotherapy needs to be administered for approximately 100 days, an oral agent is inherently superior to parenteral agents, and miltefosine is the only oral agent that is generally effective for the leishmaniases. This report and the recent report of Ramesh et al. (2011) both have the limitations of modest number of patients and emphasis on patients with papules and nodules that are the most easily evaluated lesions. Nevertheless, the efficacy data of these reports are strongly positive and, given the unattractive alternatives, indicate that 2–3 months of treatment with miltefosine can be considered a treatment of choice for Indian PKDL.