search
Back to results

Miltefosine/Paromomycin Phase III Trial for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa

Primary Purpose

Visceral Leishmaniasis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Miltefosine
Paromomycin
Sodium stibogluconate
Sponsored by
Drugs for Neglected Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Visceral Leishmaniasis

Eligibility Criteria

4 Years - 50 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis
  • Patients aged 4 to < 50 years who are able to comply with the study protocol.
  • 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 each country regulatory requirements

Exclusion Criteria:

  • Patients who are relapse cases
  • Patients with Para-Kala azar dermal leishmaniasis grade 3
  • Patients who have received any anti-leishmanial drugs in the last 6 months
  • Patients with severe malnutrition (for children aged <5 years: weight-for-height WHO reference curves by sex, z score <-3; for children patients 5-18 years: BMI-for-age WHO reference curves by sex, z score < -3; for adults >18 years: BMI < 16)*
  • Patients with positive HIV diagnosis
  • Patients with previous history of hypersensitivity reaction or known drug class allergy to any of the study treatments
  • Patients with previous history of cardiac arrhythmia or with a clinically significant abnormal ECG
  • Patients suffering from a concomitant severe infection such as TB, schistosomiasis or any other serious underlying disease (e.g. cardiac, renal, hepatic) or chronic condition which would preclude evaluation of the patient's response to study medication
  • Pregnant or lactating women
  • Female patients of child bearing age who do not accept to have a pregnancy test done at screening and/or who do not agree to use contraception from treatment period until 5 months after the end of treatment (see section 15.2)
  • Patients with haemoglobin < 5g/dl
  • Patients with signs of severe VL according to Investigator's judgement, requiring an indication for AmBisome therapy based on the clinical manifestations (such as jaundice, bleeding, edema) and clinically significant abnormalities in the following laboratory parameters: haemoglobin, WBC, platelets, liver enzymes (ALT and AST), total bilirubin and creatinine
  • Patients with pre-existing hearing loss based on audiometry at baseline

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

    • Note: for Ethiopia only: Patients with severe malnutrition (for patients 4-18 years: MUAC cut-off based on MUAC-for-height reference table; for patients > 18 years: MUAC < 170 mm)

Sites / Locations

  • Abdurafi MSF Health Center
  • University Hospital of Gondar
  • Kacheliba Hospital
  • El Hassan Centre for Tropical Medicine
  • Tabarak Allah MSF Hospital
  • Um El Kher Hospital
  • Amudat Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Arm 1 - MF/PM 14d

Arm 2 - MF 28d/PM 14d

Arm 3 - SSG/PM 17d

Arm Description

Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 14 days

Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 28 days

Sodium Stibogluconate 20 mg/kg/day IM/IV combined with Paromomycin 15 mg/kg/day IM for 17 days

Outcomes

Primary Outcome Measures

Definitive Cure
Cure at 6 months follow up defined as absence of clinical signs and symptoms of VL at D210 and no requirement for rescue treatment during the trial (e.g. no relapse or initial treatment failure).

Secondary Outcome Measures

Incidence of Treatment-Emergent Adverse Events
Frequency of SAEs and AEs requiring treatment discontinuation Frequency and severity of adverse events from the start of treatment through the last visit, at day 210.
Initial cure at day 28
Initial cure: cure at the end of treatment (Day 28), defined as recovery of clinical signs and symptoms; absence of parasites (microscopy) and no rescue treatment administered up to and including Day 28. Probable cure: absence of clinical signs and symptoms of VL at D56 and no prior requirement for rescue medication.
Pharmacokinetics of paromomycin and miltefosine
Total and partial blood plasma exposure to paromomycin and miltefosine defined as the area under the concentration-time curve
Pharmacodynamics
Blood parasite clearance over time (qualitative and quantitative), as measured by qPCR from blood samples
Compliance to miltefosine treatment in an outpatient setting
Compliance to MF treatment in an outpatient setting will be assessed through patients' hospital records history, drug accountability and PK measurements.

Full Information

First Posted
April 21, 2017
Last Updated
June 10, 2021
Sponsor
Drugs for Neglected Diseases
Collaborators
The Netherlands Cancer Institute, The Institute of Endemic Diseases (IEND), University of Khartoum, Kenya Medical Research Institute, Makerere University, University of Gondar
search

1. Study Identification

Unique Protocol Identification Number
NCT03129646
Brief Title
Miltefosine/Paromomycin Phase III Trial for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa
Official Title
An Open Label, Phase III, Randomized Controlled, Multicentre Non-Inferiority Trial to Compare Efficacy and Safety of Miltefosine and Paromomycin With SSG and PM Combination for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa
Study Type
Interventional

2. Study Status

Record Verification Date
July 2020
Overall Recruitment Status
Completed
Study Start Date
January 24, 2018 (Actual)
Primary Completion Date
December 11, 2020 (Actual)
Study Completion Date
December 11, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Drugs for Neglected Diseases
Collaborators
The Netherlands Cancer Institute, The Institute of Endemic Diseases (IEND), University of Khartoum, Kenya Medical Research Institute, Makerere University, University of Gondar

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is an open label, Phase III, randomized, controlled, parallel arm multicentre non-inferiority clinical trial to compare the efficacy and safety of two combination regimens of Miltefosine and Paromomycin with the standard SSG-PM for the treatment of primary adult and children VL patients in Eastern Africa.
Detailed Description
The 2 treatment regimens to be tested are: Arm 1: Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 14 days Arm 2: Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 28 days (recruitment in this arm was discontinued under protocol v4.0 dated 22 Jul 2019) The reference arm is the current standard treatment for VL: • Arm 3: Sodium Stibogluconate 20 mg/kg/day IM/IV combined with Paromomycin 15 mg/kg/day IM for 17 days The target population will be VL patients from 4 to 50 years old in order to cover both paediatric and adult population. Patients will be hospitalized for 14 days of PM and MF treatment for both arm 1 and arm 2. MF treatment will start at the same time as PM treatment and for arm 2 it will continue on an out-patient basis until completion of the 28 days treatment. SSG&PM combination therapy will be administered for 17 days according to routine VL treatment guidelines and patients will remain hospitalized for the entire duration of the treatment. All patients will be asked to return to the hospital for a full assessment on day 28, and for followup visits on day 56 and at six months. To respond to the objectives, study assessments will be carried out at screening and on days 1, 3, 7, 14, 21, 28, 56 (one-month post-treatment) and 210 (six-month post-treatment). These assessments will include clinical, parasitological, haematological, biochemistry, safety, pharmacokinetic and pharmacodynamics assessments.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Visceral Leishmaniasis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
439 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm 1 - MF/PM 14d
Arm Type
Experimental
Arm Description
Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 14 days
Arm Title
Arm 2 - MF 28d/PM 14d
Arm Type
Experimental
Arm Description
Paromomycin 20 mg/kg/d IM for 14 days combined with oral miltefosine allometric dosing for 28 days
Arm Title
Arm 3 - SSG/PM 17d
Arm Type
Active Comparator
Arm Description
Sodium Stibogluconate 20 mg/kg/day IM/IV combined with Paromomycin 15 mg/kg/day IM for 17 days
Intervention Type
Drug
Intervention Name(s)
Miltefosine
Other Intervention Name(s)
Impavido
Intervention Description
Miltefosine 10mg and 50mg capsules
Intervention Type
Drug
Intervention Name(s)
Paromomycin
Other Intervention Name(s)
Paromomycin sulfate
Intervention Description
Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp
Intervention Type
Drug
Intervention Name(s)
Sodium stibogluconate
Other Intervention Name(s)
SSG
Intervention Description
Sodium stibogluconate 33% 30 ml inj.
Primary Outcome Measure Information:
Title
Definitive Cure
Description
Cure at 6 months follow up defined as absence of clinical signs and symptoms of VL at D210 and no requirement for rescue treatment during the trial (e.g. no relapse or initial treatment failure).
Time Frame
6 months follow-up (Day 210)
Secondary Outcome Measure Information:
Title
Incidence of Treatment-Emergent Adverse Events
Description
Frequency of SAEs and AEs requiring treatment discontinuation Frequency and severity of adverse events from the start of treatment through the last visit, at day 210.
Time Frame
From Screening to day 210
Title
Initial cure at day 28
Description
Initial cure: cure at the end of treatment (Day 28), defined as recovery of clinical signs and symptoms; absence of parasites (microscopy) and no rescue treatment administered up to and including Day 28. Probable cure: absence of clinical signs and symptoms of VL at D56 and no prior requirement for rescue medication.
Time Frame
Initial cure: day 28; Probable cure: day 56
Title
Pharmacokinetics of paromomycin and miltefosine
Description
Total and partial blood plasma exposure to paromomycin and miltefosine defined as the area under the concentration-time curve
Time Frame
During treatment, at 1 month (day 56) and 6 months (day 210) follow-up
Title
Pharmacodynamics
Description
Blood parasite clearance over time (qualitative and quantitative), as measured by qPCR from blood samples
Time Frame
From baseline until day 210, and at any suspicion of relapse during the trial.
Title
Compliance to miltefosine treatment in an outpatient setting
Description
Compliance to MF treatment in an outpatient setting will be assessed through patients' hospital records history, drug accountability and PK measurements.
Time Frame
Day 15 to day 28 miltefosine treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with clinical signs and symptoms of VL and confirmatory parasitological microscopic diagnosis Patients aged 4 to < 50 years who are able to comply with the study protocol. 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 each country regulatory requirements Exclusion Criteria: Patients who are relapse cases Patients with Para-Kala azar dermal leishmaniasis grade 3 Patients who have received any anti-leishmanial drugs in the last 6 months Patients with severe malnutrition (for children aged <5 years: weight-for-height WHO reference curves by sex, z score <-3; for children patients 5-18 years: BMI-for-age WHO reference curves by sex, z score < -3; for adults >18 years: BMI < 16)* Patients with positive HIV diagnosis Patients with previous history of hypersensitivity reaction or known drug class allergy to any of the study treatments Patients with previous history of cardiac arrhythmia or with a clinically significant abnormal ECG Patients suffering from a concomitant severe infection such as TB, schistosomiasis or any other serious underlying disease (e.g. cardiac, renal, hepatic) or chronic condition which would preclude evaluation of the patient's response to study medication Pregnant or lactating women Female patients of child bearing age who do not accept to have a pregnancy test done at screening and/or who do not agree to use contraception from treatment period until 5 months after the end of treatment (see section 15.2) Patients with haemoglobin < 5g/dl Patients with signs of severe VL according to Investigator's judgement, requiring an indication for AmBisome therapy based on the clinical manifestations (such as jaundice, bleeding, edema) and clinically significant abnormalities in the following laboratory parameters: haemoglobin, WBC, platelets, liver enzymes (ALT and AST), total bilirubin and creatinine Patients with pre-existing hearing loss based on audiometry at baseline Patients who cannot comply with the planned scheduled visits and procedures of the study protocol Note: for Ethiopia only: Patients with severe malnutrition (for patients 4-18 years: MUAC cut-off based on MUAC-for-height reference table; for patients > 18 years: MUAC < 170 mm)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jane Mbui, MD
Organizational Affiliation
Kenya Medical Research Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joseph Olobo, MD, Prof
Organizational Affiliation
College of Health Sciences, Makerere University, Uganda
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ahmed M Musa, MD, Prof
Organizational Affiliation
Institute of Endemic Diseases, Sudan
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Rezika Mohammed, MD
Organizational Affiliation
University Hospital of Gondar, Ethiopia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Abdurafi MSF Health Center
City
Ābderafī
State/Province
Amhara
Country
Ethiopia
Facility Name
University Hospital of Gondar
City
Gondar
Country
Ethiopia
Facility Name
Kacheliba Hospital
City
Kapenguria
State/Province
West Pokot
ZIP/Postal Code
30601
Country
Kenya
Facility Name
El Hassan Centre for Tropical Medicine
City
Doka
State/Province
Gedaref
Country
Sudan
Facility Name
Tabarak Allah MSF Hospital
City
Gadarif
State/Province
Gedaref
Country
Sudan
Facility Name
Um El Kher Hospital
City
Gedaref
Country
Sudan
Facility Name
Amudat Hospital
City
Amudat
State/Province
Karamoja
Country
Uganda

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
36164254
Citation
Musa AM, Mbui J, Mohammed R, Olobo J, Ritmeijer K, Alcoba G, Muthoni Ouattara G, Egondi T, Nakanwagi P, Omollo T, Wasunna M, Verrest L, Dorlo TPC, Musa Younis B, Nour A, Taha Ahmed Elmukashfi E, Ismail Omer Haroun A, Khalil EAG, Njenga S, Fikre H, Mekonnen T, Mersha D, Sisay K, Sagaki P, Alvar J, Solomos A, Alves F. Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial. Clin Infect Dis. 2023 Feb 8;76(3):e1177-e1185. doi: 10.1093/cid/ciac643.
Results Reference
derived

Learn more about this trial

Miltefosine/Paromomycin Phase III Trial for Treatment of Primary Visceral Leishmaniasis (VL) Patients in Eastern Africa

We'll reach out to this number within 24 hrs