Leishmaniasis Clinical Trial
Official title:
Department of Defense Protocol for the Use of Sodium Stibogluconate (Pentostam) as a Treatment for Leishmaniasis
Leishmanias is a disease caused by the bite of sandflies and is found in many parts of the
world including the Europe, Southwest Asia, Africa and the Middle East. This disease is a
threat for military soldiers in areas where this disease is found. Sodium stibogluconate
(SSG) or Pentostam (Glaxo Smith Kline, United Kingdom) is an Investigational New Drug (IND)
product used by the Department of Defense for over 20 years to treat cutaneous, mucosal and
visceral leishmanias. This drug is not licensed for commercial use in the United States
because of very limited need for the product in the U.S.A. The primary objective of this
protocol is to collect safety data on the use of Pentostam for treatment of
laboratory-confirmed leishmaniasis with SSG 20mg/kg/d IV for 10 days or 20 days and visceral
and mucocutaneous leishmaniasis with SSG 20mg/kg/d IV for 28 days.
Due to low enrollment, the protocol was later amended in version 11 submitted 19May2010 in
serial no. 0096) to remove the efficacy objective and only collect safety data for enrolled
subjects. Prior to this amendment, data were entered on case report forms (CRFs). Per the
Sponsor's discretion, CRFs were no longer required and protocol-specified treatment details
and safety assessments were recorded in the patients' medical records (study file) only. No
data entry or statistical analyses of patient data was conducted.
Leishmaniasis is a protozoal disease transmitted by sandflies and is endemic in many parts of
the world including Central and South America, Europe, Southwest Asia, Africa, and the Middle
East. Infected humans may develop cutaneous (Old or New World), mucocutaneous (New World), or
visceral leishmaniasis. The disease is a medical threat for military soldiers assigned in
endemic areas and currently a major cause of morbidity in soldiers deployed to the Middle
East and a complication of military exercises in Panama, Honduras, and South America. Sodium
stibogluconate (SSG) is an Investigational New Drug (IND) product that has been in use by the
Department of Defense (DoD) for over 20 years for the treatment of cutaneous, mucosal and
visceral leishmaniasis. The primary objective of this protocol is to treat
laboratory-confirmed leishmaniasis with SSG 20mg/kg/d intravenously (IV) for 10 days or 20
days; visceral leishmaniasis will be treated with SSG 20mg/kg/d IV for 28 days as a second
line of therapy for those failing or intolerant of Ambisome; and mucosal leishmaniasis will
be treated with SSG 20mg/kg/d IV for 28 days. Subjects will be monitored daily and outcome
measured at the end of therapy by the degree of healing of cutaneous lesions or resolution of
laboratory abnormalities and symptoms in the case of mucosal and visceral leishmaniasis.
Pentavalent antimonials (Pentostam, Glaxo Smith Kline, United Kingdom) has been used to treat
leishmaniasis for more than 50 years. This drug has not been licensed for commercial use in
the United States, likely because of limited commercial marketability. Worldwide and within
the DoD, there is a great deal of experience and use of Pentostam for the treatment of
leishmaniasis. SSG is a pentavalent antimony (Sb) complexed to a carbohydrate whose exact
structure and mechanism of action are not known. It is provided as a 100 mg antimony/mL
solution that contains a preservative, m-chlorocresol. The kidneys excrete most of the dose
within 24 hours. In 1984, the World Health Organization recommended the daily dose of
antimony in the treatment of visceral leishmaniasis to be increased to 20 mg/kg/day. A
randomized controlled trial of 40 subjects with American, New World, cutaneous leishmaniasis
(ACL) found 100% cure rates with 20 mg/kg/day Sb for 20 days but only a 76% cure if 10
mg/kg/day for 10 days was used. A comparison of three treatment schedules in 36 subjects with
CL (single rapid infusion, continuous 24 hour infusion, or every eight hour doses) found no
advantage over using once daily dosing. A review of the controlled trials of SSG concludes
that a recommended course of therapy is 20 mg/kg/day with no upper limit to dose for 20 days
for CL and 20 mg/kg/day for 28 days for visceral or mucocutaneous leishmaniasis. The
Pentostam® package insert suggests that 10-20 mg/kg/day with a maximum dose of 850 mg for a
minimum of 20 days be used; however, based on the Centers for Disease Control and Prevention
(CDC) and Walter Reed Army Medical Center (WRAMC) experience and their practice guidelines,
20 mg/kg/day with no upper limit to dosage is used. In this protocol there will be no upper
limit to the dose. WRAMC recently published their CL treatment experience primarily in New
World leishmaniasis comparing SSG 20 mg/kg for 10 or 20 days and found 100% of volunteers in
the 10-day group were cured. In this study 15% were Leishmania major infections. Comparable
results are expected for Old World leishmaniasis based on clinical experience and current
literature.
Detailed toxicity data for the 20 mg/kg/day dose are provided by several studies. Percentages
from the WRAMC experience are included here. Subjective musculoskeletal complaints are common
(58%), as well as elevated hepatocellular (67%) and pancreatic enzyme levels (97%) and
nonspecific electrocardiogram (EKG) changes (T wave changes). These side effects are usually
reversible, and no deaths have been associated with SSG at WRAMC. Other SSG toxic effects
include headache (22%), rash (9%), thrombocytopenia, depression of various hematologic cell
lines (44%), phlebitis, anaphylaxis, inflammation around lesions, and transient coughing
after infusion. Other associated symptoms include anorexia, malaise, myalgia, abdominal pain,
headache, lethargy, sweating, vertigo, facial flushing, initial worsening of skin lesions,
epistaxis, jaundice and peripheral neuropathy. In our above-mentioned 10 versus 20 days
study, the adverse events (AE) were significantly decreased in the cohort receiving the 10
days versus 20 with myalgias in 42% (versus 68%), with less chemical pancreatitis and fewer
hematologic parameter disorders. Angioedema during SSG infusion has recently been described
in two subjects at WRAMC. Both subjects responded quickly to benadryl treatment without
complications. Both subjects were subsequently skin tested with SSG intradermally for
hypersensitivity and one reacted.
Alternative heat therapies have been used to successfully treat CL. Laboratory investigation
showed that Leishmania infection is sensitive to heat. Various forms of heat application in
human CL has shown variable efficacy. The TTI Thermomed™ device is currently U.S. Food and
Drug Administration (FDA), section 510-K cleared for use in the treatment of CL. This device
uses localized current field radio frequency. Other therapies that may be effective for
treating CL include topical paromomycin and oral fluconazole.
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