Ignite Creation Date:
2024-05-05 @ 4:58 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00351520
Status:
COMPLETED
Last Update Posted:
2011-09-20
First Post:
2006-07-12
Brief Title:
Efficacy Trial on Oral Miltefosine in Comparison With Glucantime in the Treatment of ACL Caused by L Tropica
Sponsor:
Tehran University of Medical Sciences
Organization:
Tehran University of Medical Sciences
Study Overview
Official Title:
Phase 3 Clinical Trials of Drug Against Cutaneous Leishmaniasis
Status:
COMPLETED
Status Verified Date:
2011-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Cutaneous leishmaniasis is a parasitic skin lesion caused by different species of Leishmania and transmitted by the bite of infected sand flies Leishmaniasis is exist in 88 countries pentavalent antimonials sodium stibogluconate and meglumine antimoniate have been used as a standard treatment for this disease for last 80 years Pentavalent antimonials are only available as injectable which is painful toxic not affordable and moreover is not always effective even sometimes with several courses of treatment Many different modalities are used to treat the disease with little success Miltefosine is drug and has recently been shown to be effective in the treatment cutaneous leishmaniasis in Colombia The molecular mechanisms that contribute to this effectiveness are not clearly understood Only a well designed randomized clinical trial can precisely evaluate the efficacy of any therapeutic modalities in cutaneous leishmaniasis In this study the efficacy of oral treatment of miltefosine 25 mg per Kg body weight for 4 weeks will be compared with standard treatment of intramuscular injections of 60 mgkgday glucantime for 2 weeks in ACL parasitologically proven patients At 8 weeks after the initiation of the treatment any patient in the group who received miltefosine and has not responded to the treatment will be treated with the standard intramuscular injections of 60 mgkgday glucantime for 2 weeks The clinical trial will be carried out according to the International approved GCP Good Clinical Practice guide lines
Detailed Description:
Leishmaniasis caused by at least 20 different species of Leishmania and transmitted by the bite of infected sand flies Leishmaniasis is endemic in 88 countries mostly developing ones Leishmaniasis with an incidence rate of 15-2 million mostly cutaneous form and 350 million population at risk is a major health problem in some endemic countries such as Iran which is endemic to cutaneous leishmaniasis CL both anthroponotic CL ACL caused by L tropica and Zoonotic CL ZCL caused by L major 1 2 Pentavalent antimonials sodium stibogluconate and meglumine antimoniate have been used as standard treatment of leishmaniasis for about 80 years Pentavalent antimonials are only parentrally available which is painful toxic not affordable in most endemic areas and moreover is not always effective even sometimes with several courses of treatment recently resistance of Leishmania to antimonials is reported Other modalities such as physical immunological topical and systemic therapies are used with controversial results 34
Miltefosine is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis 5
Almost all strains of mice are resistant to L major and L mexicana infection in ressitant strain L major infection induces a transient self healing lesion similar to human CL accompanies with a Th1 response but susceptible BALBc mice infected with L major induces a Th2 type immune response and the infection develop to a systemic form of disease similar to human Kala azar and eventually every mouse is succumed to the disease Miltefosine has recently been shown to be effective in the treatment of visceral leishmaniasis VL caused by L donovani and New World CL caused by L vianna panamensis in Colombia 6-8 The results of an open-label multicenteric phase II trial of different doses of oral miltefosine 4 or 6 weeks on patients with VL caused by L donovani in India showed a cure rate of 95 all 120 patients showed an initial parasitologic cure and relapsed was seen in only 6 patients 6 In another randomized open trial in India VL patients received miltefosine orally approximately 25 mgkg daily for 28 days or amphotericin B 1 mgkg every other day for 30 days at the end of the treatment parasitological cure rate was 100 and only 6 of the patients received miltefosien showed relapse by 6 months 7 Phase I-II of an open dose escalating trial of miltefosine against American CL in Colombia showed that oral miltefosine is safe and the cure rate was 66 and 94 for different doses 8 In a placebo-controlled trial of miltefosine in Colombia and Guatemala American CL caused by L v panamensis was treated with miltfosine 25 mgkg per day orally for 28 days at the end of the teatment period the per-protocol cure rates for miltefosine group was 91 and for placebo group was 38 9
The molecular mechanisms that contribute to the antileishmanial activity of miltefosine are not clearly understood but apparently the effect is not on immune response and macrophages since immunodefient mice such as SCID mice and other deficient mice are still susceptible to miltefosine action 10-12 It is shown that miltefosine induces nuclear DNA condensation and apoptosis-like death in L donovani 12-14
The controversy obsereved in the reports of the efficacy of different modalities for CL is mainly due to not considering the self healing nature of the disease in the design of the study Factors such as variations in the susceptibility of different Leishmania species to the various drugs and differences in the criteria used to evaluate the efficacy of the drugs are important Although no reliable report is available on the efficacy of glucantime in the treatment of ACL caused by L tropica but surely the efficacy is very poor and resistant of L tropica to glucantime exist manuscript submitted Only with well designed randomized clinical trial can precisely evaluate the efficacy of any therapeutic modalities in CL In this study the efficacy of oral treatment of miltefosine 25 mg per Kg body weight for 4 weeks will be compared with standard treatment of intramuscular injections of 60 mgkgday glucantime for 2 weeks in ACL parasitologically proven patients At 8 weeks after the initiation of the treatment any patient in the group who received miltefosine and has not responded to the treatment will be treated with the standard intramuscular injections of 60 mgkgday glucantime for 2 weeks The clinical trial will be carried out according to GCP Good Clinical Practice guide lines
Study areasetting Instructions describe the area or setting where the study will be conducted This description should cover the details relevant to the study topic Study site There are two sites of ACL with high incidence rate in Iran one is Mashad Khorasan and the second one is Bam Kerman the incidence rate of ACL in Bam is increasing after earthquake according to a recent survey which is currently underway The trial will be carried out in either site with enough number of ACL patients but also to complete the recruitment faster the trial could be carried out in both sites
62 Study subjects Instructions eligibility and exclusion criteria of the study subjects I Inclusion criteriaa Parasitologically proven cases of CL based on positive smear andor culture b Otherwise healthy subjects on the basis of medical history physical examination and results of blood tests complete blood count CBC liver function tests LFT and renal function tests RFT c Age 12-50 years d body weight more than 40 kilograms e willing to participate in the study and sign the informed consent by the patient or hisher parentguardian in case of younger than 18 years
II Exclusion criteria a Pregnant or lactating women b Duration of lesion more than 6 months c Number of lesions more than 5 d Lesions with bacterial supperinfection e History of full course of standard treatment antimonials f History of allergy to glucantime g Serious systemic illnesses as judged by the physician h Participation in any drug trials in the last 60 days
III Withdrawal criteriaa A serious adverse event occurs b Withdrawal of the consent
Withdrawn cases will be treated according to the investigators opinion and beneficial of the patients at no cost All withdrawn patients will be evaluated in final analysis intent-to-treat analysis
IV Treatment In this phase III randomized open trial subjects meeting inclusion criteria of the trial will be randomly allocated into two groups according to a randomization list One group will be treated with 25 mgkg body weight of oral miltefosine and the second group will be treated with intramuscular injections of 60 mgkgday glucantime for 2 weeks The oral miltefosine tablets will be delivered to each patient on days 0 7 14 and 21 A written instruction sheet will be given to each included patient and the patient will be instructed to contact the research team on appearance of symptoms suggesting severe side effects intractable diarrhea andor vomiting symtoms of liver kidney or hematopoietic system dysfunction A copy of the randomization list with the codes will be kept at WR office Eight weeks after the initiatin of the treatment any patient who received oral miltefosine and has active lesion will be treated with intramuscular glucantime injections 60mgkgday for 14 days
v Follow-up Every included patient will be visited at 1 2 3 4 8 and 24 weeks after the initiation of the treatment The flow chart is attached
63 Study design Instructions mention the type of study design eg cross-sectional case-control intervention study etc This trial is an open randomized clinical trial under GCP guide lines The Center academic staffs are well qualified in training of GCP nationally and internationally several clinical trials both in therapeutic and vaccine development have been completed by this group
v Follow-up The patients will be visited at 1 2 3 4 8 and 24 weeks after the initiation of the treatment The flow chart is attached
63 Study design Instructions mention the type of study design eg cross-sectional case-control intervention study etc This study is a randomized open clinical trial under GCP guide lines The Center academic staff are well qualified in training of GCP nationally and internationally and have completed several clinical trials in both therapeutic and vaccine efficacy trials under GCP guide lines
Cutaneous leishmaniasis Skin lesions clinically suspicious and parasitologically proven by direct smear andor culture The study area is endemic for ACL but a portion of the Leishmania isolates will be used for charecterization and identification using monoclonal antibodies and PCR technique
Clinical cure The primary clinical efficacy parameter will be the complete re-epithelization of all lesions with disappearance of induration with or without scar No parasitological evaluation will be done on clinically cured lesions
Clinical improvement Reduction in the size of ulcer and induration Treatment failure No change or increase in the size of induration and ulcer Relapse Reappearance of the lesion at the site or periphery of the cured lesion will be considered as relapse
Parasitological cure Negative smear and culture at the end of the treatment and follow up period will be regarded as parasitological cure
1 Leishmaniasis Tropical Disease Research Progress 1995-96 Thirteenth Programme Report WHO Geneva 1997
2 Dowlati Y Cutaneous leishmaniasis clinical aspect Clin Dermatol 1996 14425-31
3 Dowlati Y Treatment of cutaneous leishmaniasis old world Clin Dermatol 1996 14513-7
4 Berman JD Human leishmaniasis clinical diagnostic and chemotherapeutic developments inthe last 10 years Clin Inf Dis 1997 24684-703
5 Schmidt-Ott R Klenner T Overath P Aebischer T Topical treatment with hexadecylphosphocholine Miltex efficiently reduces parasite burden in experimental cutaneous leishmaniasis Trans R Soc Trop Med Hyg 1999 93185-90
6 Jha TK Sundras S Thakur CP et al Miltefosine an oral agent for the treatment of indian viceral leishmaniasis N Engl J Med 1999 3411795-800
7 Sundar S Jha TK Thakur CP et al Oral miltefosine for Indian visceral leishmaniasis N Engl J Med 2002 347221739-46
8 Soto J Toledo J Gutierrez P Nicholls RS Padilla J Engel J Fischer C Voss A Berman J Treatment of American Cutaneous Leishmaniasis with Miltefosine an Oral Agent Clin Infec Dis 200133e57-e61
9 Soto J Arana BA Toledo J et al Miltefosine for new world cutaneous leishmaniasis Clin Infect Dis 2004 3891266-72
10 Leonard R Hardy J van Tienhoven G et al Randomized double-blind placebo-controlled multicenter trial of 6 miltefosine solution a topical chemotherapy in cutaneous metastases from breast cancer J Clin Oncol 2001 19214150-9
11 Escobar P Yardley V Croft SL Activities of Hexadecylphosphocholine Miltefosine AmBisome and Sodium Stibogluconate Pentostam against Leishmania donovani in Immunodeficient scid MiceAntimicrobAgents and Chemotherapy 2001 Vol 45 No61872-1875
12 Murray HW Delph-Etienne S Visceral Leishmanicidal Activity of Hexadecylphosphocholine Miltefosine in Mice Deficient in T Cells and Activated Macrophage Microbicidal Mechanisms J of Infec Dis 2000181795-799
13 Paris C Loiseau PM Bories C Breard J Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes Antimicrob Agents Chemother 2004 483852-9
14 Verma NK Dey CS Possible mechanism of miltefosine-mediated death of Leishmania donovani Antimicrob Agents Chemother 2004 4883010-5
Miltefosine is a phosphocholine analogue that affects cell-signaling pathways and membrane synthesis 5
Almost all strains of mice are resistant to L major and L mexicana infection in ressitant strain L major infection induces a transient self healing lesion similar to human CL accompanies with a Th1 response but susceptible BALBc mice infected with L major induces a Th2 type immune response and the infection develop to a systemic form of disease similar to human Kala azar and eventually every mouse is succumed to the disease Miltefosine has recently been shown to be effective in the treatment of visceral leishmaniasis VL caused by L donovani and New World CL caused by L vianna panamensis in Colombia 6-8 The results of an open-label multicenteric phase II trial of different doses of oral miltefosine 4 or 6 weeks on patients with VL caused by L donovani in India showed a cure rate of 95 all 120 patients showed an initial parasitologic cure and relapsed was seen in only 6 patients 6 In another randomized open trial in India VL patients received miltefosine orally approximately 25 mgkg daily for 28 days or amphotericin B 1 mgkg every other day for 30 days at the end of the treatment parasitological cure rate was 100 and only 6 of the patients received miltefosien showed relapse by 6 months 7 Phase I-II of an open dose escalating trial of miltefosine against American CL in Colombia showed that oral miltefosine is safe and the cure rate was 66 and 94 for different doses 8 In a placebo-controlled trial of miltefosine in Colombia and Guatemala American CL caused by L v panamensis was treated with miltfosine 25 mgkg per day orally for 28 days at the end of the teatment period the per-protocol cure rates for miltefosine group was 91 and for placebo group was 38 9
The molecular mechanisms that contribute to the antileishmanial activity of miltefosine are not clearly understood but apparently the effect is not on immune response and macrophages since immunodefient mice such as SCID mice and other deficient mice are still susceptible to miltefosine action 10-12 It is shown that miltefosine induces nuclear DNA condensation and apoptosis-like death in L donovani 12-14
The controversy obsereved in the reports of the efficacy of different modalities for CL is mainly due to not considering the self healing nature of the disease in the design of the study Factors such as variations in the susceptibility of different Leishmania species to the various drugs and differences in the criteria used to evaluate the efficacy of the drugs are important Although no reliable report is available on the efficacy of glucantime in the treatment of ACL caused by L tropica but surely the efficacy is very poor and resistant of L tropica to glucantime exist manuscript submitted Only with well designed randomized clinical trial can precisely evaluate the efficacy of any therapeutic modalities in CL In this study the efficacy of oral treatment of miltefosine 25 mg per Kg body weight for 4 weeks will be compared with standard treatment of intramuscular injections of 60 mgkgday glucantime for 2 weeks in ACL parasitologically proven patients At 8 weeks after the initiation of the treatment any patient in the group who received miltefosine and has not responded to the treatment will be treated with the standard intramuscular injections of 60 mgkgday glucantime for 2 weeks The clinical trial will be carried out according to GCP Good Clinical Practice guide lines
Study areasetting Instructions describe the area or setting where the study will be conducted This description should cover the details relevant to the study topic Study site There are two sites of ACL with high incidence rate in Iran one is Mashad Khorasan and the second one is Bam Kerman the incidence rate of ACL in Bam is increasing after earthquake according to a recent survey which is currently underway The trial will be carried out in either site with enough number of ACL patients but also to complete the recruitment faster the trial could be carried out in both sites
62 Study subjects Instructions eligibility and exclusion criteria of the study subjects I Inclusion criteriaa Parasitologically proven cases of CL based on positive smear andor culture b Otherwise healthy subjects on the basis of medical history physical examination and results of blood tests complete blood count CBC liver function tests LFT and renal function tests RFT c Age 12-50 years d body weight more than 40 kilograms e willing to participate in the study and sign the informed consent by the patient or hisher parentguardian in case of younger than 18 years
II Exclusion criteria a Pregnant or lactating women b Duration of lesion more than 6 months c Number of lesions more than 5 d Lesions with bacterial supperinfection e History of full course of standard treatment antimonials f History of allergy to glucantime g Serious systemic illnesses as judged by the physician h Participation in any drug trials in the last 60 days
III Withdrawal criteriaa A serious adverse event occurs b Withdrawal of the consent
Withdrawn cases will be treated according to the investigators opinion and beneficial of the patients at no cost All withdrawn patients will be evaluated in final analysis intent-to-treat analysis
IV Treatment In this phase III randomized open trial subjects meeting inclusion criteria of the trial will be randomly allocated into two groups according to a randomization list One group will be treated with 25 mgkg body weight of oral miltefosine and the second group will be treated with intramuscular injections of 60 mgkgday glucantime for 2 weeks The oral miltefosine tablets will be delivered to each patient on days 0 7 14 and 21 A written instruction sheet will be given to each included patient and the patient will be instructed to contact the research team on appearance of symptoms suggesting severe side effects intractable diarrhea andor vomiting symtoms of liver kidney or hematopoietic system dysfunction A copy of the randomization list with the codes will be kept at WR office Eight weeks after the initiatin of the treatment any patient who received oral miltefosine and has active lesion will be treated with intramuscular glucantime injections 60mgkgday for 14 days
v Follow-up Every included patient will be visited at 1 2 3 4 8 and 24 weeks after the initiation of the treatment The flow chart is attached
63 Study design Instructions mention the type of study design eg cross-sectional case-control intervention study etc This trial is an open randomized clinical trial under GCP guide lines The Center academic staffs are well qualified in training of GCP nationally and internationally several clinical trials both in therapeutic and vaccine development have been completed by this group
v Follow-up The patients will be visited at 1 2 3 4 8 and 24 weeks after the initiation of the treatment The flow chart is attached
63 Study design Instructions mention the type of study design eg cross-sectional case-control intervention study etc This study is a randomized open clinical trial under GCP guide lines The Center academic staff are well qualified in training of GCP nationally and internationally and have completed several clinical trials in both therapeutic and vaccine efficacy trials under GCP guide lines
Cutaneous leishmaniasis Skin lesions clinically suspicious and parasitologically proven by direct smear andor culture The study area is endemic for ACL but a portion of the Leishmania isolates will be used for charecterization and identification using monoclonal antibodies and PCR technique
Clinical cure The primary clinical efficacy parameter will be the complete re-epithelization of all lesions with disappearance of induration with or without scar No parasitological evaluation will be done on clinically cured lesions
Clinical improvement Reduction in the size of ulcer and induration Treatment failure No change or increase in the size of induration and ulcer Relapse Reappearance of the lesion at the site or periphery of the cured lesion will be considered as relapse
Parasitological cure Negative smear and culture at the end of the treatment and follow up period will be regarded as parasitological cure
1 Leishmaniasis Tropical Disease Research Progress 1995-96 Thirteenth Programme Report WHO Geneva 1997
2 Dowlati Y Cutaneous leishmaniasis clinical aspect Clin Dermatol 1996 14425-31
3 Dowlati Y Treatment of cutaneous leishmaniasis old world Clin Dermatol 1996 14513-7
4 Berman JD Human leishmaniasis clinical diagnostic and chemotherapeutic developments inthe last 10 years Clin Inf Dis 1997 24684-703
5 Schmidt-Ott R Klenner T Overath P Aebischer T Topical treatment with hexadecylphosphocholine Miltex efficiently reduces parasite burden in experimental cutaneous leishmaniasis Trans R Soc Trop Med Hyg 1999 93185-90
6 Jha TK Sundras S Thakur CP et al Miltefosine an oral agent for the treatment of indian viceral leishmaniasis N Engl J Med 1999 3411795-800
7 Sundar S Jha TK Thakur CP et al Oral miltefosine for Indian visceral leishmaniasis N Engl J Med 2002 347221739-46
8 Soto J Toledo J Gutierrez P Nicholls RS Padilla J Engel J Fischer C Voss A Berman J Treatment of American Cutaneous Leishmaniasis with Miltefosine an Oral Agent Clin Infec Dis 200133e57-e61
9 Soto J Arana BA Toledo J et al Miltefosine for new world cutaneous leishmaniasis Clin Infect Dis 2004 3891266-72
10 Leonard R Hardy J van Tienhoven G et al Randomized double-blind placebo-controlled multicenter trial of 6 miltefosine solution a topical chemotherapy in cutaneous metastases from breast cancer J Clin Oncol 2001 19214150-9
11 Escobar P Yardley V Croft SL Activities of Hexadecylphosphocholine Miltefosine AmBisome and Sodium Stibogluconate Pentostam against Leishmania donovani in Immunodeficient scid MiceAntimicrobAgents and Chemotherapy 2001 Vol 45 No61872-1875
12 Murray HW Delph-Etienne S Visceral Leishmanicidal Activity of Hexadecylphosphocholine Miltefosine in Mice Deficient in T Cells and Activated Macrophage Microbicidal Mechanisms J of Infec Dis 2000181795-799
13 Paris C Loiseau PM Bories C Breard J Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes Antimicrob Agents Chemother 2004 483852-9
14 Verma NK Dey CS Possible mechanism of miltefosine-mediated death of Leishmania donovani Antimicrob Agents Chemother 2004 4883010-5
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| WHOEMRO | None | None | None |