Post Kala Azar Dermal Leishmaniasis Clinical Trial
Official title:
A Study for Safety and Efficacy of Miltefosine for Treatment of Children and Adolescents With Post-Kala-azar Dermal Leishmaniasis (PKDL) in Bangladesh and Association of Serum Vitamin E and Exposure to Arsenic With PKDL
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.
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.
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00982774 -
Safety and Immunogenicity of the LEISH-F2 + MPL-SE Vaccine With SSG for Patients With PKDL
|
Phase 1 |