Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure

Learn more about:
Related Clinical Trial
Incidence of Relapse and Post-Kala-Azar Dermal Leishmaniasis in South Sudan Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure Evaluation to Assess the Usability of rK28 for the Diagnosis of Visceral Leishmaniasis in Kenya Documentation of Patient Outcomes for SSG/Allopurinol Combination Treatment in Ethiopia A Clinical Study to Develop a Controlled Human Infection Model Using Leishmania Major-infected Sand Flies Safety, Tolerability and Pharmacokinetics (PK) Investigation of GSK3494245 in Healthy Participants Prevalence of HIV +ve Cases With AIDS Defining Opportunistic Infections Among ART Naive Patients Attending ART Centre Defining Skin Immunity of a Bite of Key Insect Vectors in Humans Clinical Investigation of Infections Due to Leishmanial Parasites Safety, False-Positive Reactions and Sensitizing Properties of Leishmania Tropica Skin Test Antigen Safety, Tolerability and Pharmacokinetics (PKs) Investigation of GSK3186899 in Healthy Subjects Frequency of Parasite Infection in Hyraxes and Sandflies During Outbreak of Leishmania Tropica Epidemic in The West Bank Single Oral Dose Escalation Study of DNDI-0690 in Healthy Male Subjects Phase 1 LEISH-F3 + SLA-SE Vaccine Trial in Healthy Adult Volunteers Phase 1 LEISH-F3 Vaccine Trial in Healthy Adult Volunteers Diagnosis and Treatment of Leishmanial Infections Study to Evaluate the Leish-111f + MPL-SE Vaccine in Healthy Adults Not Previously Exposed to Leishmania Parasite Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients. Open-Label Safety Study of Three-Antigen Leishmania Polyprotein With Adjuvant MPL-SE in Healthy Adults in India Mechanisms Relating to the Distinct in Vitro Susceptibility of Human Macrophages to L. Viannia Infection Th1/Th2 Polarization and Linkage to L. Viannia Infection Outcomes Open-Label, Sequential Step, Safety and Efficacy Study to Determine the Optimal Single Dose of Ambisome for Patients With VL LEISH-F3 + GLA-SE and the LEISH-F3 + MPL-SE Vaccine Steady State Global Bioequivalence Study of Amphotericin B Liposome for Injection 50 mg/ Vial in Fed Condition Miltefosine (Long Course) for Bolivian Mucosal Leishmaniasis Fractional CO2 Laser With Topical Pentostam Treatment for Cutaneous Leishmaniasis. Pharmacokinetics of Miltefosine in Children and Adults Trial to Determine Efficacy of Fexinidazole in Visceral Leihmaniasis Patients in Sudan Miltefosine/Paromomycin Phase III Trial for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa Safety Study to Evaluate the Leish-111f + MPL-SE Vaccine in the Prevention of Cutaneous Leishmaniasis in Healthy Subjects Previously Exposed to the Leishmania Parasite WR 279,396 Open Label Treatment Protocol in Tunisia Miltefosine for Mucosal Leishmaniasis Asymptomatic Leishmania Infection in HIV Patients Accuracy of a Rapid Diagnostic Test for Cutaneous Leishmaniasis in Morocco Phase 3 Study of Walter Reed (WR) 279,396 and Paromomycin Alone for the Treatment of Cutaneous Leishmaniasis in Panama Oral Miltefosine for the Treatment of Pediatric Cutaneous Leishmaniasis in Colombia Miltefosine for Brazilian Visceral Leishmaniasis Prospective Observational Study of Intralesional Treatment With Pentostam in Cutaneous Leishmaniasis Israeli Patients Efficacy/Safety of Sodium Stibogluconate (SSG) Versus Paromomycin (PM) and SSG/PM Combination to Treat V Leishmaniasis Intralesional Antimony for Bolivian Cutaneous Leishmaniasis Thermotherapy + a Short Course of Miltefosine for the Treatment of Uncomplicated Cutaneous Leishmaniasis in the New World¨ Efficacy of Radio-frequency Induced Heat (RFH)Therapy in Treatment of Cutaneous Leishmaniasis in India Cosmetic Outcome of Leishmaniasis Scar After WR279396 Application Safety and Immunogenicity of a Vaccine for Cutaneous Leishmaniasis Using Recombinant Human Interleukin-12 and Aluminum Hydroxide Gel as Adjuvants Pharmacokinetics/Safety of Miltefosine Allometric Dose for the Treatment of Visceral Leishmaniasis in Children in Eastern Africa LAMP Assay for the Diagnosis of Visceral Leishmaniasis Imiquimod Plus Antimony Immunochemotherapy for Cutaneous Leishmaniasis Topical Liposomal Amphotericin B Gel Treatment for Cutaneous Leishmaniasis A Community Trial for Visceral Leishmaniasis (VL) Fourth-generation Immucillin Derivative DI4G Associated Therapy in Cutaneous Leishmaniasis Pilot Study Using a Heat Pack to Treat Cutaneous Leishmaniasis Expand Access/Assess Safety and Efficacy of Paromomycin IM Injection for the Treatment of Visceral Leishmaniasis An Effectiveness Study of Paromomycin IM Injection (PMIM) for the Treatment of Visceral Leishmaniasis (VL) in Bangladesh Treatment of Leishmaniasis With Impavido® (Miltefosine): Higher-Weight Patient Registry Mediterranean Visceral Leishmaniasis With Leishmania Infantum Efficacy and Safety of Miltefosine or Thermotherapy for Cutaneous Leishmaniasis in Colombia. Allopurinol, Glucantime, or Allopurinol/Glucantime for Cutaneous Leishmaniasis in Brazil Controlled Nitric Oxide Releasing Patch Versus Meglumine Antimoniate in the Treatment of Cutaneous Leishmaniasis Safety and Efficacy of Low-Dose Pentavalent Antimony for Treatment of Cutaneous Leishmaniasis Amphotericin B to Treat Visceral Leishmaniasis in Brazilian Children Safety and Efficacy Study to Evaluate Different Combination Treatment Regimens for Visceral Leishmaniasis Reduced Doses of Antimony Plus Ranulocyte Monocyte Colony Stimulating Factor (GM-CSF) for Cutaneous Leishmaniasis Topical 3% Amphotericin B Cream for the Treatment of Cutaneous Leishmaniasis in Colombia Surveillance for Leishmaniasis Skin Lesions in Mali Oral Miltefosine Plus Topical Imiquimod to Treat Cutaneous Leishmaniasis Expression of Mif Alleles in Individuals With Leishmaniasis Miltefosine and GM-CSF in Cutaneous Leishmaniasis Immunogenetics of Visceral Leishmaniasis Efficacy and Safety Study of Drugs for Treatment of Visceral Leishmaniasis in Brazil Safety and Efficacy Study of Paromomycin to Treat Visceral Leishmaniasis Phase 3 Study to Evaluate WR 279,396 vs. Paromomycin Alone to Treat Cutaneous Leishmaniasis (in Tunisia) WR 279,396 for the Treatment of Cutaneous Leishmaniasis A Study to Assess Immune Response Status in Patients Before and After Treatment for Visceral Leishmaniasis Clinical Trial of Miltefosine to Treat Mucosal Leishmaniasis Amphotericin B Treatment in Visceral Leishmaniasis The Association of Miltefosine and Pentoxifylline to Treat Mucosal Leishmaniasis: A Clinical Trial in Brazil Miltefosine to Treat Mucocutaneous Leishmaniasis A Study of the Efficacy and Safety of the LEISH-F2 + MPL-SE Vaccine for Treatment of Cutaneous Leishmaniasis High Dose Fluconazole in Cutaneous Leishmaniasis in Bahia and Manaus Treatment of Cutaneous Leishmaniasis With a Combination of Miltefosine and Antimony Safety and Efficacy of Azithromycin to Treat Cutaneous Leishmaniasis Improved Case Detection and Vector Control for Visceral Leishmaniasis Local Heat Therapy Versus Sodium Stibogluconate for the Treatment of Cutaneous Leishmaniasis Short Course of Miltefosine and Liposomal Amphotericin B for Kala-azar SCH708980 With and Without AmBisome for Visceral Leishmaniasis Miltefosine to Treat Cutaneous Leishmaniasis in Bolivia Single Infusion of Liposomal Amphotericin B in Indian Visceral Leishmaniasis Combination Chemotherapy for the Treatment of Indian Kala-Azar Efficacy, Acceptability and Cost-effectiveness of Long Lasting Insecticide Nets (LLIN) in the Prevention of Kala Azar Immune Response of Visceral Leishmaniasis PatientsTreated With Antimonial Plus N-Acetylcysteine Comparison of Standard and Alternative Antimonial Dosage in Patients With American Cutaneous Leishmaniasis An Open Lable Randomised Study to Assess the Safety and Efficacy of Short Course Paromomycin in Visceral Leishmaniasis Antimony Plus Pentoxifylline in Cutaneous Leishmaniasis Topical Treatment of Cutaneous Leishmaniasis With WR 279,396: A Phase 2 Study in the Old World Add-on Study of Pentoxifylline in Cutaneous Leishmaniasis Sodium Stibogluconate Treatment of Leishmaniasis A Pilot Study for Capacity Building for a Multi-centre, Randomized Trial for Treatment of Kala Azar in Bangladesh Use of Sodium Stibogluconate as a Treatment for Leishmaniasis Visceral Leishmaniasis and Malnutrition in Amhara Regional State, Ethiopia A Phase II Study To Assess Safety and Efficacy Of Short-Course Regimens Of Amphotericin B Emulsion In Kala-Azar Single Dose Liposomal Amphotericin B for Visceral Leishmaniasis Topical Treatment of Recalcitrant Ulcerative Old World Leishmaniasis With WR 279,396

Brief Title

Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure

Official Title

Evaluation of Less Invasive Procedures for Visceral Leishmaniasis Treatment Efficacy Monitoring Test of Cure

Brief Summary

      Left untreated, visceral leishmaniasis (VL) is fatal. The highest burden of VL worldwide is
      in eastern Africa where field-adapted diagnostic and test-of-cure tools and treatment are
      lacking. The current laboratory tool to help assessing cure, treatment failure and relapse is
      microscopy, based on invasive sampling (e.g. splenic or bone marrow aspirate). Non-invasive,
      more sensitive tools will enable these assessments with minimum risk and discomfort to
      patients.

      This study aims to evaluate immunological and molecular tests to predict cure and relapse,
      and to replace with these the current invasive methods.

      The study will be conducted at the Leishmaniasis Research and Treatment Centre (LRTC), Gondar
      University Hospital, Ethiopia It will be a non-intervention study, the tools under evaluation
      will be considered as index tests; their results will not influence patient management during
      the duration of the study. Patient management will follow the national guidelines for VL
      diagnosis and management in Ethiopia.
    

Detailed Description

      CONTEXT Visceral leishmaniasis (VL), or kala-azar, is caused by parasitic protozoa of the
      Leishmania donovani species complex, which are transmitted by the bite of infected female
      phlebotomine sand flies. VL has a worldwide distribution throughout Asia, eastern Africa,
      South America and the Mediterranean basin. A proportion of infected individuals present with
      insidiously evolving symptoms, with splenomegaly, irregular fever, anaemia or pancytopaenia,
      weight loss and weakness, occurring progressively over a period of weeks or even months. And
      the disease can be fatal without treatment in up to 90% of cases.

      In 1990, the worldwide incidence of VL was estimated at 500,000 cases annually. Since then,
      it has significantly decreased. A WHO report on the 14 high-burden countries (> 100
      cases/year) reported 30,758 new cases of VL in 2014, with under-reporting between 1.2- and
      4-fold. This drastic reduction in the last decades is largely attributed to a sharp decline
      in incidence in Southeast Asia, from approximately 50,000 reported cases in 2006-2007, to
      10,311 in 2014. A successful elimination campaign, natural fluctuations in incidence and
      improvements in local living conditions have contributed to the decrease. Currently, the
      highest burden of VL worldwide is in eastern Africa, where there is a lack of appropriate
      diagnostic tools and treatment. Most of the cases are observed in Ethiopia, Kenya, Somalia,
      Sudan, South Sudan and Uganda. Of the six countries currently representing 91% of the overall
      VL burden worldwide, four are in eastern Africa - Ethiopia, South Sudan, Sudan and Somalia.

      With targets for VL elimination being reached in Southeast Asia, the WHO has recently
      encouraged partners to improve the tools for better control and eventual elimination of VL in
      specific foci in eastern Africa. Important challenges for disease control include:
      inconsistent performance of RDTs in different regions; suboptimal efficacy of treatment with
      potentially toxic injectable medicines; lack of drug resistance monitoring; insufficient
      access to early diagnosis and treatment; and lack of a test-of-cure and prediction of
      relapses. All this has a significant impact on morbidity, mortality, loss of quality of life
      and economic development. We believe that improving access to diagnostic and treatment
      monitoring tools for VL is the cornerstone of successful VL control/elimination approaches.

      New drugs and drug combinations for VL are being evaluated by DNDi and LEAP partners at
      several study sites, who showed that in Eastern Africa, sodium stibogluconate (SSG) and
      paromomycine (PM) in combination offer an advantage compared to the previous SSG monotherapy.
      Close patient monitoring during treatment and follow-up, provides a unique opportunity for
      evaluating new tools and markers of cure and relapses, as we propose in this study.

      STUDY RATIONALE In VL clinical trials, patients fulfilling pre-defined inclusion criteria are
      enrolled based on diagnosis by Leishmania positive tissue aspirate (spleen, bone marrow or
      lymph node) and microscopy, which is also the method used as the parasitological test-of-cure
      at the end of treatment. Although sensitive (variable depending on the tissue sample), this
      traditional method bears limitations, warranting new improved non-invasive tools. Spleen
      aspiration and microscopy also have limitations, including difficulty in harmonizing
      microscopy results, as tissue aspirates are not homogeneous, reflecting inaccurate
      assessments of parasite load. In many patients, the spleen shrinks with treatment, making
      monitoring by splenic aspiration at the end of treatment difficult. In these cases, bone
      marrow aspirates are often analysed for test-of-cure, which makes quantitative comparisons of
      parasite loads before and after treatment even more difficult. Finally, splenic aspiration is
      invasive with risk of severe complications.

      Diagnosing VL using a sensitive diagnostic test based on peripheral blood is much more
      favourable. Nucleic acid amplification tests (NAAT) have proven sensitive for detection of
      Leishmania parasites in blood and have a potential role in the diagnostic algorithm of
      primary VL. However, in VL endemic settings, most NAAT are restricted to well-equipped
      laboratories. Recently, FIND, in collaboration with other partners, developed a robust NAAT,
      loop-mediated isothermal amplification (LAMP) that can be used at the basic laboratory level
      (e.g. microscopy laboratory). An additional advantage of LAMP is that by using a fluorimeter
      or turbidimeter, it could reproducibly semi-quantify parasite load, avoiding parasite grading
      based on microscopy of tissues obtained invasively. The WHO has recently recommended LAMP for
      the diagnosis of pulmonary tuberculosis.

      A top research priority highlighted by the WHO Expert Committee on the Control of
      Leishmaniasis is identification of a biomarker of treatment failure and relapses, as opposed
      to cure after chemotherapy [1]. New tools and biomarkers to monitor the immune response of VL
      patients during therapy, such as immunoglobulin isotypes or cytokines, and that can be used
      to predict relapses, are important in eastern Africa, given the high relapse rate and that
      VL/HIV co-infection is a major determinant of relapses [1,3]. New T-cell-based interferon-γ
      release assays have shown that IFN-γ in Leishmania-stimulated whole blood increases gradually
      and significantly after successful treatment of patients infected with L. donovani or L.
      infantum . Whole blood stimulation and cytokine release assay (CRA) and cell proliferation
      assay (CPA) have demonstrated their usefulness to predict relapses in immunodepressed
      patients. CRA and IFN-γ analysis helped to confirm cure and risk of relapses in solid organ
      transplant individuals, while CPA was a good predictive marker of non-appearance of relapses
      in HIV patients co-infected with Leishmania. On the other hand, with the use of simple
      serological tests (ELISA), a strong evidence has been presented for the use of
      anti-Leishmania IgG1 in monitoring treatment outcomes in VL [10]. We propose a collaboration
      between European and Ethiopian research institutions, with sound expertise on VL, which will
      capitalize on LEAP's working infrastructure to evaluate the usefulness of an ELISA test
      detecting anti-Leishmania IgG1 antibodies, Leishmania-specific lymphocyte proliferation,
      cytokine release assays and LAMP to predict treatment failure and relapse in VL patients.

      With targets for VL elimination being reached in Southeast Asia, the WHO has recently
      encouraged partners to improve the tools for better control and eventual elimination of VL in
      specific foci in eastern Africa. Important challenges for disease control include:
      inconsistent performance of RDTs in different regions; suboptimal efficacy of treatment with
      potentially toxic injectable medicines; lack of drug resistance monitoring; insufficient
      access to early diagnosis and treatment; and lack of a test-of-cure and prediction of
      relapses. All this has a significant impact on morbidity, mortality, loss of quality of life
      and economic development. Improving access to diagnosis and treatment monitoring tools for VL
      is the cornerstone of successful VL control/elimination approaches.

      OBJECTIVES The objective of the proposed study is to evaluate immunological (whole blood
      cytokine release assay, cell proliferation assay, IgG1 anti-Leishmania) and molecular
      (loop-mediated isothermal amplification) tests to predict cure and relapse, and to replace
      with these the current invasive methods.
    


Study Type

Observational


Primary Outcome

To assess the diagnostic performance of the immunological tests under evaluation for predicting cure and treatment failure at end-of-treatment assessment

Secondary Outcome

 To assess the diagnostic performance of the immunological tests under evaluation for predicting cure, treatment failure and relapse during follow-up

Condition

Visceral Leishmaniasis

Intervention

ELISA, LAMP, Cytokine Release Assay


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

60

Start Date

September 1, 2021

Completion Date

December 2022

Primary Completion Date

December 2022

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with clinical signs and symptoms of VL and confirmatory parasitological
             microscopic diagnosis.

          -  Patients for whom written informed consent has been obtained (if aged 18 years and
             over) or signed by parents(s) or legal guardian for patients under 18 years of age (in
             the case of minors, assent from the children also needs to be obtained as per country
             regulatory requirements).

        Exclusion Criteria:

        VL cases will not be enrolled in the study if any of the following exclusion criteria
        apply:

          -  Patients who are cases of VL relapse, post- or para-kala-azar dermal leishmaniasis or
             who have received any anti-leishmanial drugs within the last six months.

          -  Patients not eligible for treatment with SSG+PM:

               -  Patients with severe malnutrition.

               -  Patients with positive HIV diagnosis.

               -  Patients with previous history of hypersensitivity reaction or known drug class
                  allergy to any of the study treatments (SSG or PM).

               -  Patients with previous history of cardiac arrhythmia or with a clinically
                  significant abnormal ECG.

               -  Patients suffering from a concomitant severe infection such as TB or any other
                  serious underlying disease (cardiac, renal, hepatic), or chronic condition which
                  would preclude evaluation of the patient's response to study medication.

          -  Patients who cannot comply with the planned procedures and scheduled visits of the
             study protocol.
      

Gender

All

Ages

N/A - N/A


Contacts

, , 

Location Countries

Ethiopia

Location Countries

Ethiopia

Administrative Informations


NCT ID

NCT05426577

Organization ID

VL-ToC-AfriKADIA


Responsible Party

Sponsor

Study Sponsor

Foundation for Innovative New Diagnostics, Switzerland

Collaborators

 Leishmaniasis Research and Treatment Cener University of Gondar, Ethiopia

Study Sponsor

, , 


Verification Date

June 2022