Visceral LeishmaniasisPhase 3NCT02011958
Efficacy Trial of Ambisome Given Alone and Ambisome Given in Combination With Miltefosine for the Treatment of VL HIV Positive Ethiopian Patients.
A Phase 3 study testing Liposomal Amphotericin B and Miltefosine in people with Visceral Leishmaniasis, run by Drugs for Neglected Diseases at 2 sites in Ethiopia.
Trial summary
The overall objective of this trial is to identify a safe and effective treatment for visceral leishmaniasis (VL) in HIV co-infected Ethiopian patients. Patients will receive either Ambisome alone or Ambisome in combination with Miltefosine. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Visceral Leishmaniasis
- What is being tested?
- Liposomal Amphotericin B and Miltefosine
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 59 participants
- Where
- 2 sitesEthiopia
- Study dates
- Jul 2014to 15 Sep 2017
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Confirmed HIV positive test (2 rapid diagnostics tests (RDTs) followed by a confirmatory ELISA test).
- Diagnosis of VL (first episode or relapse) confirmed by bone marrow or spleen aspirate.
- Male and female age: 18-60 years.
- Written informed consent from the patient.
Who cannot join
- Women of child-bearing potential (defined as women who have achieved menarche) who are not using an assured method of contraception or are unwilling to use an assured method of contraception for the duration of treatment and four months after.
- Pregnant women or breast-feeding mothers.
- Patients with grade 2 or 3 post kala-azar dermal leishmaniasis (PKDL) lesions.
- Clinical or biological evidence of severe cardiac, renal or hepatic impairment.
- Known hypersensitivity to AmBisome® and/or miltefosine.
- Patients receiving allopurinol treatment
Trial locations and contacts
2 sites in 1 country.
Ethiopia2 sites
MSF
Abdurafi
Leishmaniasis Research Center, University Hospital of Gondar
Gonder
About this study
Official title: A Randomized Trial of Ambisome Monotherapy and Combination of Ambisome and Miltefosine for the Treatment of VL in HIV Positive Patients in Ethiopia Followed by Secondary VL Prophylactic Treatment With Pentamidine.
The overall objective of this trial is to identify a safe and effective treatment for visceral leishmaniasis (VL) in HIV co-infected Ethiopian patients.
Patients will receive either Ambisome alone or Ambisome in combination with Miltefosine.
Patients who do not undergo treatment failure will be given a VL prophylactic treatment with Pentamidine one month after the end of the study treatment.
Read the detailed description
Visceral Leishmaniasis (VL) is a neglected disease which is fatal if left untreated. Ethiopia is one of the countries where the majority of cases occur. With spread of HIV in VL endemic areas an increase in co-infected cases has been reported in Ethiopia.
HIV and VL mutually influence each other as they both affect cellular immunity. The most important features of co-infection include poor outcome, increased drug toxicity and relapse of treatment with the need for maintenance therapy.
There are few studies in co-infected patients. There are no specific recommendations for HIV-VL co-infected patients in Ethiopia.
This protocol will evaluate the efficacy and safety of the combination of Ambisome with Miltefosine and Ambisome monotherapy (high dose) in Ethiopia.
It is designed as a randomised, parallel arm, open-label trial. No comparator will be included.
The randomization will be stratified according to centre as well as wether VL is a primary case or a relapse. The study will be analysed according to group-sequential methods, specifically the triangular test. Data from each arm will be analysed after every 10 patients reach the primary endpoint of final cure at day 29. The data will be analysed as proportions according to an intention to treat and per protocol analysis for each arm.In order to address potential heterogeneity of the population, a test will be performed when a treatment is stopped. Depending on the outcome of this test for heterogeneity, recruitment may be continued into one stratum.
The treatment duration will be 28 days or 56 days in case of extended treatment.
- If at Day 29 assessment, tissue aspirate is parasite negative, the patient will be eligible for secondary prophylaxis (Pentamidine 4mg/kg IM (intramuscular) once a month up to a maximum of 18 months) and enter the 1 year follow up phase.
- If at day 29 assessment, tissue aspirate is positive but the patient is well, he/she will receive another complete course of treatment (but classified as treatment failure). The patient will be evaluated again on day 58. Those who still have a parasite positive tissue aspirate will be offered a rescue treatment. Those who are negative will be offered secondary prophylaxis if eligible (Pentamidine 4mg/kg IM once a month up to a maximum of 18 months).
- If at day 29 assessment, tissue aspirate is positive and the patient is unwell, he/she will be treated with rescue treatment (and considered as treatment failure)
- All patients, independently of their outcome at day 29 and/or day 58 will enter the follow-up assessments at day 210 and day 390.
Rescue treatment will also be given in case of relapse during the follow-up period and in case of occurence of severe grade 2 or grade 3 PKDL or PKDL with mucosal and/or eye involvement after treatment period.
All patients who are not yet on antiretroviral treatment (ART) at inclusion will commence ART once they have completed routine voluntary counselling and testing procedures. Patients who are already on ART at diagnosis of VL will continue ART throughout the study.
- Conditions
- Visceral Leishmaniasis
- Being tested
- Liposomal Amphotericin B, Miltefosine
- Keywords
- Visceral Leishmaniasis, HIV positive patients, Phase III trial, Randomised, Liposomal amphotericin B, Ambisome, Miltefosine, Pentamidine, Efficacy, Safety
- Medical subject headings
- Leishmaniasis, Visceral
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Liposomal Amphotericin BDrug
Also called Ambisome
40 mg/kg total dose: IV infusion of 5mg/kg per day on day 1 to 5, 10,17,24 (when administered as a monotherapy)
30 mg/kg total dose: IV infusion 5 mg/kg per day on day 1, 3, 5, 7, 9, 11 (when administered in combination with Miltefosine)
MiltefosineDrug
Also called Impavido
Orally taken every day during 28 days
- 1 x 50 mg capsule per day if the patient weights less or equal to 25 kg
- 2 x 50 mg capsules per day if the patient weights more than 25 kg (1 capsule in the morning / 1 capsule in the evening)
| Study group | Role | What they receive |
|---|---|---|
| Liposomal Amphotericin B / Miltefosine | Experimental | Liposomal Amphotericin B : 30mg/kg total dose: IV infusion 5mg/kg per day on day 1, 3, 5, 7, 9, 11
Miltefosine: orally taken every day during 28 days
* 1 x 50 mg capsule per day if patient weights less or equal to 25 kg
* 2 x 50 mg capsules per day if the patient weights more than 25 kg Receives: Drug: Liposomal Amphotericin B; Drug: Miltefosine |
| Liposomal Amphotericin B | Experimental | Liposomal Amphotericin B: 40 mg/kg total dose : IV infusion of 5mg/kg per day on day 1 to 5, 10, 17, 24 Receives: Drug: Liposomal Amphotericin B |
What is being measured
The primary outcome is the main question the study is designed to answer.
Initial parasitological cure at day 29
Absence of parasites in tissue aspirate at day 29; hence no rescue medication provided up to this time-point.
Measured: Day 29
Secondary outcomes (1)
Relapse-free survival at day 390
The patient being alive and disease free from day 29 (if initially cured) or day 58 in case of extended treatment (absence of signs and symptoms of visceral leishmaniasis or if symptomatic, a negative parasitological assessment by tissue aspirate)
Measured: Day 390
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2013 (estimated)
- Study startJul 2014
- Primary completionAug 2016
- Study completion15 Sep 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Visceral LeishmaniasisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 59 participants (actual)
Sponsor and investigators
- Lead sponsor
- Drugs for Neglected Diseases
- Sponsor type
- University, hospital or other
- Collaborators
- Medecins Sans Frontieres, Netherlands, London School of Hygiene and Tropical Medicine, Addis Ababa University, Institute of Tropical Medicine, Belgium, Slotervaart Hospital, University of Gondar
- Responsible party
- Sponsor
- Investigators
- Ermias Diro, Dr. MD, Principal investigator, University of Gondar
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02011958
- Sponsor's protocol ID
- HIV/VL 0511
- Status last verified
- Apr 2019
- First submitted
- 18 Nov 2013
- Last updated
- 8 Apr 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Diro E, Blesson S, Edwards T, Ritmeijer K, Fikre H, Admassu H, Kibret A, Ellis SJ, Bardonneau C, Zijlstra EE, Soipei P, Mutinda B, Omollo R, Kimutai R, Omwalo G, Wasunna M, Tadesse F, Alves F, Strub-Wourgaft N, Hailu A, Alexander N, Alvar J. A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia. PLoS Negl Trop Dis. 2019 Jan 17;13(1):e0006988. doi: 10.1371/journal.pntd.0006988. eCollection 2019 Jan.
PubMed 30653490Diro E, Edwards T, Ritmeijer K, Fikre H, Abongomera C, Kibret A, Bardonneau C, Soipei P, Mutinda B, Omollo R, van Griensven J, Zijlstra EE, Wasunna M, Alves F, Alvar J, Hailu A, Alexander N, Blesson S. Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007132. doi: 10.1371/journal.pntd.0007132. eCollection 2019 Feb.
PubMed 30789910
Study at a glance
From the registry record, last updated by the sponsor on 8 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized Trial of Ambisome Monotherapy and Combination of Ambisome and Miltefosine for the Treatment of VL in HIV Positive Patients in Ethiopia Followed by Secondary VL Prophylactic Treatment With Pentamidine.
- ClinicalTrials.gov ID
- NCT02011958
- Acronym / sponsor ID
- HIV/VL 0511
- Conditions
- Visceral Leishmaniasis
- Keywords
- Visceral Leishmaniasis, HIV positive patients, Phase III trial, Randomised, Liposomal amphotericin B, Ambisome, Miltefosine, Pentamidine
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 59 participants (actual)
- Lead sponsor
- Drugs for Neglected DiseasesUniversity, hospital or other
- Collaborators
- Medecins Sans Frontieres, Netherlands, London School of Hygiene and Tropical Medicine, Addis Ababa University, Institute of Tropical Medicine, Belgium, Slotervaart Hospital, University of Gondar
- Study start
- Jul 2014 (actual)
- Primary completion
- Aug 2016 (actual)
- Study completion
- 15 Sep 2017 (actual)
- First posted
- 16 Dec 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The overall objective of this trial is to identify a safe and effective treatment for visceral leishmaniasis (VL) in HIV co-infected Ethiopian patients.
Patients will receive either Ambisome alone or Ambisome in combination with Miltefosine.
Patients who do not undergo treatment failure will be given a VL prophylactic treatment with Pentamidine one month after the end of the study treatment.
Detailed description
Visceral Leishmaniasis (VL) is a neglected disease which is fatal if left untreated. Ethiopia is one of the countries where the majority of cases occur. With spread of HIV in VL endemic areas an increase in co-infected cases has been reported in Ethiopia.
HIV and VL mutually influence each other as they both affect cellular immunity. The most important features of co-infection include poor outcome, increased drug toxicity and relapse of treatment with the need for maintenance therapy.
There are few studies in co-infected patients. There are no specific recommendations for HIV-VL co-infected patients in Ethiopia.
This protocol will evaluate the efficacy and safety of the combination of Ambisome with Miltefosine and Ambisome monotherapy (high dose) in Ethiopia.
It is designed as a randomised, parallel arm, open-label trial. No comparator will be included.
The randomization will be stratified according to centre as well as wether VL is a primary case or a relapse. The study will be analysed according to group-sequential methods, specifically the triangular test. Data from each arm will be analysed after every 10 patients reach the primary endpoint of final cure at day 29. The data will be analysed as proportions according to an intention to treat and per protocol analysis for each arm.In order to address potential heterogeneity of the population, a test will be performed when a treatment is stopped. Depending on the outcome of this test for heterogeneity, recruitment may be continued into one stratum.
The treatment duration will be 28 days or 56 days in case of extended treatment.
- If at Day 29 assessment, tissue aspirate is parasite negative, the patient will be eligible for secondary prophylaxis (Pentamidine 4mg/kg IM (intramuscular) once a month up to a maximum of 18 months) and enter the 1 year follow up phase.
- If at day 29 assessment, tissue aspirate is positive but the patient is well, he/she will receive another complete course of treatment (but classified as treatment failure). The patient will be evaluated again on day 58. Those who still have a parasite positive tissue aspirate will be offered a rescue treatment. Those who are negative will be offered secondary prophylaxis if eligible (Pentamidine 4mg/kg IM once a month up to a maximum of 18 months).
- If at day 29 assessment, tissue aspirate is positive and the patient is unwell, he/she will be treated with rescue treatment (and considered as treatment failure)
- All patients, independently of their outcome at day 29 and/or day 58 will enter the follow-up assessments at day 210 and day 390.
Rescue treatment will also be given in case of relapse during the follow-up period and in case of occurence of severe grade 2 or grade 3 PKDL or PKDL with mucosal and/or eye involvement after treatment period.
All patients who are not yet on antiretroviral treatment (ART) at inclusion will commence ART once they have completed routine voluntary counselling and testing procedures. Patients who are already on ART at diagnosis of VL will continue ART throughout the study.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Liposomal Amphotericin B / Miltefosine | Experimental | Drug: Liposomal Amphotericin B, Drug: MiltefosineLiposomal Amphotericin B : 30mg/kg total dose: IV infusion 5mg/kg per day on day 1, 3, 5, 7, 9, 11 Miltefosine: orally taken every day during 28 days * 1 x 50 mg capsule per day if patient weights less or equal to 25 kg * 2 x 50 mg capsules per day if the patient weights more than 25 kg |
| Liposomal Amphotericin B | Experimental | Drug: Liposomal Amphotericin BLiposomal Amphotericin B: 40 mg/kg total dose : IV infusion of 5mg/kg per day on day 1 to 5, 10, 17, 24 |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Confirmed HIV positive test (2 rapid diagnostics tests (RDTs) followed by a confirmatory ELISA test).
- Diagnosis of VL (first episode or relapse) confirmed by bone marrow or spleen aspirate.
- Male and female age: 18-60 years.
- Written informed consent from the patient.
Key exclusion criteria (6 listed)
- Women of child-bearing potential (defined as women who have achieved menarche) who are not using an assured method of contraception or are unwilling to use an assured method of contraception for the duration of treatment and four months after.
- Pregnant women or breast-feeding mothers.
- Patients with grade 2 or 3 post kala-azar dermal leishmaniasis (PKDL) lesions.
- Clinical or biological evidence of severe cardiac, renal or hepatic impairment.
- Known hypersensitivity to AmBisome® and/or miltefosine.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Liposomal Amphotericin BAlso: Ambisome40 mg/kg total dose: IV infusion of 5mg/kg per day on day 1 to 5, 10,17,24 (when administered as a monotherapy) 30 mg/kg total dose: IV infusion 5 mg/kg per day on day 1, 3, 5, 7, 9, 11 (when administered in combination with Miltefosine) | Drug | Liposomal Amphotericin B, Liposomal Amphotericin B / Miltefosine |
| MiltefosineAlso: ImpavidoOrally taken every day during 28 days * 1 x 50 mg capsule per day if the patient weights less or equal to 25 kg * 2 x 50 mg capsules per day if the patient weights more than 25 kg (1 capsule in the morning / 1 capsule in the evening) | Drug | Liposomal Amphotericin B / Miltefosine |
Primary outcome
Initial parasitological cure at day 29
Time frame: Day 29
Absence of parasites in tissue aspirate at day 29; hence no rescue medication provided up to this time-point.
1 secondary outcome
Relapse-free survival at day 390
Time frame: Day 390
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Apr 2019.
- Results publication: PubMed 30653490Diro E, Blesson S, Edwards T, Ritmeijer K, Fikre H, Admassu H, Kibret A, Ellis SJ, Bardonneau C, Zijlstra EE, Soipei P, Mutinda B, Omollo R, Kimutai R, Omwalo G, Wasunna M, Tadesse F, Alves F, Strub-Wourgaft N, Hailu A, Alexander N, Alvar J. A randomized trial of AmBisome monotherapy and AmBisome and miltefosine combination to treat visceral leishmaniasis in HIV co-infected patients in Ethiopia. PLoS Negl Trop Dis. 2019 Jan 17;13(1):e0006988. doi: 10.1371/journal.pntd.0006988. eCollection 2019 Jan.
- Results publication: PubMed 30789910Diro E, Edwards T, Ritmeijer K, Fikre H, Abongomera C, Kibret A, Bardonneau C, Soipei P, Mutinda B, Omollo R, van Griensven J, Zijlstra EE, Wasunna M, Alves F, Alvar J, Hailu A, Alexander N, Blesson S. Long term outcomes and prognostics of visceral leishmaniasis in HIV infected patients with use of pentamidine as secondary prophylaxis based on CD4 level: a prospective cohort study in Ethiopia. PLoS Negl Trop Dis. 2019 Feb 21;13(2):e0007132. doi: 10.1371/journal.pntd.0007132. eCollection 2019 Feb.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ermias Diro, Dr. MD principal investigator
University of Gondar
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Liposomal Amphotericin B and Miltefosine in people with Visceral Leishmaniasis, run by Drugs for Neglected Diseases at 2 sites in Ethiopia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Apr 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Ethiopia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Initial parasitological cure at day 29 (time frame: Day 29). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02011958, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Apr 2019.