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Clinical Trials

MainTitle

Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients With Pentamidine: a Cohort Study

This study has been completed
Sponsor
Institute of Tropical Medicine, Belgium

Collaborator
Addis Ababa University
University of Gondar
Tigray Regional Health Bureau, Tigray Region
Amhara Regional Health Bureau, Amhara Region
Medecins Sans Frontieres, Netherlands
Leishmania East Africa Platform (LEAP)
Drugs for Neglected Diseases

Information provided by (Responsible Party)
Institute of Tropical Medicine, Belgium
ClinicalTrials.gov Identifier
NCT01360762

First received: May 24, 2011
Last updated: February 4, 2016
Last Verified: February 2016
History of Changes
Purpose

Purpose

Visceral leishmaniosis (VL) is widely reported in Ethiopia, with about 30% of cases being associated with human immunodeficiency virus (HIV). In absence of antiretroviral treatment (ART), poor prognosis, high mortality and high relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. Conversely, co-infection can be successfully managed via a combination of effective treatment of the initial episode, timely ART and prevention of relapses.

Actually, until cellular immunity returns with ART, the patient is at risk of VL relapses, which can result in death, severe illness, reduced ART efficacy, drug-resistance and possibly transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are those with high levels of immunosuppression, with previous VL episodes, or with opportunistic infections (OIs). The most important factor to prevent relapses seems to be the clearance of visible parasites.

Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention with antimonials (part of mainstay treatment for VL in Ethiopia) and pentamidine (PM), not used for VL treatment in Africa. Such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a need of better care to patients at risk of relapse.

This prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population.

Condition Intervention Phase
Visceral Leishmaniosis
HIV-infection/Aids

Drug : Pentamidine
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Secondary Prophylaxis of Visceral Leishmaniasis Relapses in HIV Co-infected Patients Using Pentamidine as a Prophylactic Agent: a Prospective Cohort Study

Further study details as provided by Institute of Tropical Medicine, Belgium:

Primary Outcome Measures

  • Time to relapse or death [ Time Frame: 1 year ]
    Time to relapse or death (all causes)
  • Serious Adverse Events (SAEs) [ Time Frame: 1 year ]
    Proportion of patients with SAEs which are possibly, probably or definitely drug-related following clinician's assessment or that lead to permanent drug discontinuations during the first year of pentamidine administration
Secondary Outcome Measures:
  • Adverse events [ Time Frame: 1 year ]
    During the first year of pentamidine administration for prophylaxis: any drug-related non-serious adverse events (with drug-related defined as possibly, probably or definitely related to primary therapy following physicians assessment) as well as any serious adverse events (drug-related or not)
  • Number of treatment discontinuations and interruptions [ Time Frame: 30 months ]
    Number of treatment discontinuations and interruptions
  • Number of required additional interventions [ Time Frame: 30 months ]
    The number of required additional clinical interventions/therapeutic procedures

Enrollment: 72
Study Start Date: November 2011
Study Completion Date: November 2015
Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Pentamidine Secondary Prophylaxis (PSP)
Patients with co-infection of human immunodeficiency virus (HIV)and visceral leishmaniosis (VL), having being treated for VL, are allocated to pentamidine secondary prophylaxis, to prevent VL relapses. The treatment period is of 12 months, plus an "extended treatment period" of 0 to 6 months depending on the immunosuppression status, plus 12 months follow-up after the extended treatment period.
Drug: Pentamidine

Pentamidine isethionate 300 mg for one vial for intramuscular or intravenous route(1 mg of pentamidine isethionate is equivalent to 0.57 mg of pentamidine base)

Other Name: PENTACARINAT 300 mg, by Sanofi-Aventis

Detailed Description:

Visceral leishmaniosis (VL) in Ethiopia has been reported in different parts of the country, with approximately 30% of cases being associated with human immunodeficiency virus (HIV). The ruralisation of HIV epidemic in VL endemic areas will hamper efforts to control VL. Clinical experience in Ethiopia has shown that anti-leishmanial treatment in the absence of anti-retroviral therapy (ART) does not result in favourable outcomes: poor prognosis, high mortality and relapse rates are characteristic of Ethiopian VL patients with HIV co-infection. The effective management of the initial VL episode, timely ART, and prevention of relapses should be the cornerstones of effective management of HIV/VL co-infection.
However, parasitological cure of VL in HIV co-infected patients cannot easily be established, and until cellular immunity returns with ART, the patient is at risk of relapses of VL, which can result in death, severe illness, negative effect on ART efficacy leading to other opportunistic infections (OIs), emergence of drug-resistant parasites, and possibly to transmission of drug-resistant Leishmania donovani. Patients most vulnerable to relapses are 1) those with high levels of immunosuppression, 2) patients with previous VL episodes, and 3) patients with OIs.
ART reduces the risk of VL relapse/recurrence by ~50%, while the type of anti-leishmanial primary treatment has little effect on relapses; the most important factor seems to be clearance of visible parasites (if residual parasites are seen at the end of treatment, the relapse rate is 100%).
Limited studies in Europe show that HIV co-infected patients may benefit from secondary prevention, by significantly prolonging the relapse-free period. The drugs studied for secondary prophylaxis in Europe have been meglumine antimoniate and AmBisome, which are part of mainstay treatment for VL in Ethiopia, and pentamidine (PM), which is not used for VL treatment in Africa. The effect of such maintenance treatment has not been studied in African VL, but the poor outcomes without secondary prevention highlight a clear need to offer better care to patients at high risk of relapse.
Indeed, secondary prophylaxis is generally recommended in Europe and the United States (see the 2009 Center for Disease Control guidelines). PM 4 mg/kg intravenous (IV) every 3-4 weeks has been proposed as secondary prophylaxis, and it is already used in countries like United Kingdom and Spain.
Consequently, this prospective cohort study aims at documenting the patient's outcomes of secondary prophylaxis with PM in VL-HIV co-infection, in terms of time to relapse or death, safety and feasibility, before it can be considered for more general use in Ethiopia. A placebo group is not included, due to the clear advantages of the intervention to the patient population targeted herewith. Furthermore as other available VL treatments are used as main line treatments, they cannot be considered as alternative comparators, given the potential risk of rapid emergence of drug resistance and subsequent spread in areas of anthroponotic VL.

Eligibility

Eligibility

Ages Eligible for Study: 18 Years and older  
Sexes Eligible for Study: All  
Accepts Healthy Volunteers: No  

Criteria

Inclusion Criteria:

  • Patients diagnosed with Visceral Leishmaniosis (VL) during the recruitment period that are EITHER treated for VL relapse and have a documented negative test of cure (TOC), OR are treated for primary VL and have a documented CD4 <200 or WHO stage 4 disease during the recruitment period and have a documented negative TOC
  • Patients treated for VL in the past with documented CD4 <200 or WHO stage 4 disease during the recruitment period AND documented negative TOC after the latest VL treatment and currently asymptomatic OR currently negative diagnostic test (microscopy)
  • Patients agreeing to start or continue antiretroviral treatment (first or second line)
  • Patients willing to provide written informed consent


Exclusion Criteria:
  • Patients with known hypersensitivity to pentamidine
  • Patients with known renal failure
  • Patients with diabetes mellitus (type I or II)
  • Patients unlikely to attend follow-up visits/comply with study requirements
  • Pregnant and lactating women
  • Any other condition that could increase the risk of toxicity of pentamidine to such an
extent outweighing the expected benefit (eg severe cardiac dysfunction).

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01360762

Locations

Ethiopia
Abdurafi Health Center/Médecins Sans Frontières
Abdurafi, Amhara, Ethiopia
Kahsay Abera Hospital
Humera, Tigray, Ethiopia
Leismania Research and Treatment Centre, University of Gondar Hospital
Gondar, Ethiopia

Sponsors and Collaborators

Institute of Tropical Medicine, Belgium
Addis Ababa University
University of Gondar
Tigray Regional Health Bureau, Tigray Region
Amhara Regional Health Bureau, Amhara Region
Medecins Sans Frontieres, Netherlands
Leishmania East Africa Platform (LEAP)
Drugs for Neglected Diseases

Investigators

Study Director: Ermias Diro, MD University of Gondar, Ethiopia
Study Director: Johan Van Griensven, MD, PhD ITM
More Information

More Information


Responsible Party: Institute of Tropical Medicine, Belgium  
ClinicalTrials.gov Identifier: NCT01360762   History of Changes  
Other Study ID Numbers: ITMC0109  
Study First Received: May 24, 2011  
Last Updated: February 4, 2016  

Keywords provided by Institute of Tropical Medicine, Belgium:

Secondary prophylaxis
Visceral leishmaniasis
Relapses
HIV co-infection
Pentamidine
Ethiopia

Additional relevant MeSH terms:
HIV Infections
Recurrence
Leishmaniasis
Leishmaniasis, Visceral
Pentamidine

ClinicalTrials.gov processed this data on October 16, 2017
This information is provided by ClinicalTrials.gov.