Leishmaniasis
Conditions
Keywords
Leishmaniasis, Sodium stibogluconate, Pentostam, sand fly
Brief summary
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 viseral 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 objective of this protocol is to provide sodium stibogluconate for the treatment of cutaneous leishmaniasis and mucosal leishmaniasis (pentavalent antimonials curently considered the drug of choice for these infections) Provide sodium stibogluconate as a second line treatment for viscerotropic and visceral leishmaniasis (liposomal amphotericin is the drug of choice for these types as it is FDA approved for vusceral leishmaniasis).
Detailed description
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. Pentavalent antimonials (Pentostam, GSK, UK, and Glucantime, Rhone-Poulenc, France) have been used to treat leishmaniasis for more that 50 years. Neither of these drugs are licensed for commercial use in the United States, likely because of limited use. Worldwide, there is a great deal of experience and use of these products. Pentostam or sodium stibogluconate is a pentavalent antimony drug complexed to carbohydrate the exact structure and mechanism of action of which are not known. It is provided as a 100 mg antimony/ml solution that contains a preservative, m-chlorocresol. Most of the dose is excreted by the kidneys within 24 hours. Pentostam is presently 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. In August, 1997, the FDA approved Ambisome (liposomal amphotericin) for the treatment of visceral leishmaniasis. As a result, in the treatment of visceral and viscerotropic leishmaniasis, the use of antimonials will now be considered a second-line therapy In 1984, the World Health Organization recommended that the daily dose of antimony in the treatment of visceral leishmaniasis 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. 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 has been cleared as a 510-k device by the U.S. Food and Drug Administration (FDA) 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.
Interventions
100 mg/ml/vial. Treatment for laboratory-confirmed leishmaniasis with SSG 20mg/kg/d intravenously (IV) for 10 days or 20 days for less responsive; 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.
Sponsors
Walter Reed Army Medical Center
U.S. Army Medical Research and Development Command
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* DoD healthcare beneficiary of any age and gender. * Clinicoepidemiologic or parasitologic diagnosis (microscopy, PCR or culture) of Leishmania infection. * Able to provide informed consent or assent (children). * All participants (both male and female) must agree to take precautions not to become pregnant or father a child for at least 2 months after receiving SSG.
Exclusion criteria
* Pregnancy. Females of childbearing potential must have negative urine human chorionic gonadotropin hormone (HCG) within 96 hours start of infusion period. * History of hypersensitivity to pentavalent antimonials. * Any of the following on screening examination: 1. QTc interval greater or equal to 0.5 sec 2. Severe cardiac disease (disabling valvular heart disease, myopathy, or arrhythmias) 3. History of recurrent pancreatitis 4. Liver failure or active hepatitis with transaminases \> 3x upper limit of normal 5. Renal failure or creatinine \> 2.5 mg/dL 6. Thrombocytopenia (platelets \<100,000/mm3) 7. White blood cell count \< 2000 / mm3 8. Hematocrit \< 30 %
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Safety Endpoint - Frequency of Complications of Therapy | 5 years | The primary safety endpoint is the frequency of complications of therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement of Lesions, Resolution of Fever and Lab Abnormalities for Visceral Leishmaniasis and Regression of Mucosal Lesions . | 5 years | Improvement of lesions for cutaneous leishmanias, resolution of fever and lab abnormalities for visceral leishmaniasis and regression of mucosal lesions for mucocutaneous disease. |
Countries
United States
Participant flow
Recruitment details
Recruitment commenced on 11May2002 with follow-up periods ranging from 12 to 24 months after completion of treatment. Treatment was received at Walter Reed Army Medical Center, Washington, DC, USA.
Participants by arm
| Arm | Count |
|---|---|
| SSG 20 mg/kg All consented subjects who meet all inclusion and no exclusion criteria will enter this open label protocol and be treated with 20 mg/kg once daily intravenously with SSG.
Sodium Stibogluconate (SSG): 100 mg/ml/vial. Treatment for laboratory-confirmed leishmaniasis with SSG 20mg/kg/d intravenously (IV) for 10 days or 20 days for less responsive; 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. | 414 |
| Total | 414 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 85 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | SSG 20 mg/kg |
|---|---|
| Age, Continuous | 28.1 years STANDARD_DEVIATION 7.96 |
| Lesion data - Duration since onset | 111.6 Days STANDARD_DEVIATION 47.62 |
| Lesion data - Number of lesions | 5.0 Lesions STANDARD_DEVIATION 5.04 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 62 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 50 Participants |
| Race (NIH/OMB) White | 295 Participants |
| Region of Enrollment United States | 414 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 405 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 414 / 414 |
| serious Total, serious adverse events | 17 / 414 |
Outcome results
Primary
The Primary Safety Endpoint - Frequency of Complications of Therapy
The primary safety endpoint is the frequency of complications of therapy
Time frame: 5 years
Population: Analysis was per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SSG 20 mg/kg | The Primary Safety Endpoint - Frequency of Complications of Therapy | 414 participants |
Secondary
Improvement of Lesions, Resolution of Fever and Lab Abnormalities for Visceral Leishmaniasis and Regression of Mucosal Lesions .
Improvement of lesions for cutaneous leishmanias, resolution of fever and lab abnormalities for visceral leishmaniasis and regression of mucosal lesions for mucocutaneous disease.
Time frame: 5 years
Population: Analysis per protocol
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SSG 20 mg/kg | Improvement of Lesions, Resolution of Fever and Lab Abnormalities for Visceral Leishmaniasis and Regression of Mucosal Lesions . | 414 participants |