Miltefosine for Children With PKDL
Condition: Post Kala Azar Dermal Leishmaniasis
MeSH terms: Leishmaniasis; Leishmaniasis, Visceral
Study type: Interventional
Phase: Phase 3

Summary: 
      Hypothesis:

      Primary hypothesis:

        1. Oral treatment with Miltefosine in children with PKDL at allometric daily dose (based on
           body weight and height) for 12 weeks is safe with a cure rate of ≥95%.

           Secondary hypothesis:

        2. Development of PKDL in children and adolescent is genetically predisposed and is
           associated with IL-10 & IFN-gamma gene polymorphism causing high and low serum level of
           IL-10 and IFN-gamma respectively.

        3. Nutritional & environmental factors such as low serum vitamin E, A, D, Zn & arsenic
           exposure are associated with PKDL.
    

Detailed description: 
      Background:

      Visceral leishmaniasis also known as kala-azar is a neglected tropical disease affecting the
      poorest of the poor living in the rural areas of Bangladesh, Nepal, India, South Sudan, Sudan
      and Brazil with an annual incidence of 500,000 new cases with 10% mortality. Since 2008, the
      first oral drug Miltefosine (MF) has been introduced for the treatment of VL in Bangladesh,
      India and Nepal as part of the National VL / Kala-azar (KA) Elimination Program (NKEP) in
      these three countries. The duration of treatment is 28 days at a dose of 100 mg / day or 50
      mg / day for adult with body weight ≥25 KG and< 25 Kg respectively. For children, it is ≤ 2
      mg/Kg/24h. The efficacy of MF for VL is 87%, but we have observed that 15% of those develop
      Post-kala-azar Dermal (PKDL) Leishmaniasis with an annual incidence of about 300 cases,
      mostly in the Mymensingh district of Bangladesh (the most VL endemic district in the
      country). The clinical manifestation of PKDL is macular/papular/nodular /mixed lesions.
      Children and adolescents with PKDL are otherwise clinically healthy, but these patients
      continue to carry the parasites for years and can transmit the parasites to others through
      sand fly bite. In this way these patients play a role as inter-epidemic reservoirs and can
      initiate new outbreaks of VL in the community. The only current treatment option is 120
      injections with SSG (one injection per day for 20 consecutive days in a month for 6 months).
      Injections are very painful and associated with risks including sudden heart failure from
      cardiac arrhythmias and death. Therefore, PKDL patients usually do not seek treatment and the
      compliance is very low, when they take treatment with SSG. Thus, a safe and effective
      treatment which can ensure better compliance is urgently needed. Recent studies in India
      showed that 12 weeks treatment with MF of adult PKDL patients is effective (94%) and safe.
      However, the study reported only 24 adult PKDL cases. Similar results have been observing
      with adult PKDL patients in Nepal. There is no information about the safety and efficacy of
      12 weeks MF treatment of children with PKDL and about pharmacokinetics of MF among these
      children. It is established that exposure to MF in VL children was less to oral MF at
      conventional dose of 2.5mg/Kg/day, thus allometric dosing of MF is now recommended by
      experts. A study is therefore urgently needed for efficacy and safety of allometric daily
      dose of MF for 12 weeks for treatment of PKDL in children.

      Risk factors for PKDL are poorly investigated. Younger age of VL patients and genetic
      susceptibility to PKDL are found to contribute to PKDL. Exposure to arsenic through drinking
      water and protein-energy malnutrition are public health problem in Bangladesh. Both arsenic
      and vitamin E and other nutrients deficiency may contribute to PKDL directly or in
      combination, because they inhibit innate and adaptive immunity to infections.

      Hypothesis(es) and Aims:

      1. Oral treatment with Miltefosine in children with PKDL at allometric daily dose for 12
      weeks is safe with a cure rate of ≥95%; 2. Development of PKDL in children and adolescent is
      genetically predisposed and is associated with IL-10 & IFN-gamma gene polymorphism causing
      high serum level of IL-10 and low serum level of IFN-gamma; 3. Nutritional & environmental
      factors such as low serum vitamin E & arsenic exposure are associated with PKDL .

      Study design:

      The study includes a cross sectional survey for suspected PKDL patients among children
      treated for VL in the past, followed by an open clinical trial with MF with 12 months follow
      up after treatment and a simultaneous case-control study for PKDL risk factors.
      Parasitologically confirmed (demonstration of parasite in skin specimens by microscopy and /
      qPCR) PKDL children will be subjects of the open clinical trial with oral Miltefosine (MF) at
      allometric daily dose. In the case-control component of the study, confirmed PKDL children
      will be cases. Children treated for VL in the past and currently without skin lesions will be
      the controls and will be matched with cases by geographic area, age, sex and time of VL
      treatment. Inclusion criteria are: a child treated for VL in the past, aged more than 2 years
      old and less than 18 years old, either sex, fulfill case definition as PKDL case / control,
      parents / guardian consent for participation of the child in the study. Exclusion criteria
      are: do not fulfill all inclusion criteria for a case/control, with skin fungal infection /
      leprosy, without clinical evidence for arsenic dermatosis, negative for rK39 rapid test,
      control child who will develop PKDL during follow up. Based on expected 95% cure rate, a
      sample size of 73 PKDL children would produce a two-sided 95% confidence interval with an
      estimated precision of 5%. Allowing for an attrition rate of 10%, the final sample size is 80
      children in each group and the total sample size is 160. Blood, urine and hair specimens will
      be collected from cases before treatment and at 12 months follow up, and from controls at
      baseline only. Primary outcome is safety and cure rate of 12 weeks treatment with MF. Cure
      will be defined by resolution of skin lesions by ≥90% and skin and blood specimens negative
      for LD bodies and leishmania DNA at 12 months after treatment. Safety will be measured by
      frequency of adverse events (AEs). We expect transient AEs like vomiting and diarrhea in less
      than 30% and serious adverse event in none.

      Potential Impact:

      If 12 weeks treatment with MF at allometric daily dose is found safe and effective for
      treatment in children with PKDL, then it will be scale up through the National VL Elimination
      Program. Through the case-control component, we may find nutritional / environmental risk
      factor for PKDL which will help to design preventative strategy against PKDL.
    

Intervention name(s): Miltefosine
Intervention type(s): Drug
Intervention MeSH terms: Miltefosine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Bangladesh, PKDL, Visceral Leishmaniasis, Children, Miltefosine