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CompletedNCT03129646Updated Feb 29, 2024

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

A Phase 3 interventional study of Miltefosine and Paromomycin in Visceral Leishmaniasis, sponsored by Drugs for Neglected Diseases. Completed at 7 sites in 4 countries. Open to participants aged 4 Years to 50 Years. Per ClinicalTrials.gov, last updated 2024-02-29.

Sponsored by Drugs for Neglected Diseases · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
439
Allocation
Randomized
Ages
4 Years to 50 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • Visceral Leishmaniasis
03

Who can participate

Ages eligible
4 Years to 50 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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)
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
439 participants (actual)

Study arms

  • Experimental
    Arm 1 - MF/PM 14d

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

    Drug: Miltefosine · Drug: Paromomycin

  • Experimental
    Arm 2 - MF 28d/PM 14d

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

    Drug: Miltefosine · Drug: Paromomycin

  • Active comparator
    Arm 3 - SSG/PM 17d

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

    Drug: Paromomycin · Drug: Sodium stibogluconate

Interventions

  • DrugMiltefosine

    Miltefosine 10mg and 50mg capsules

    Also known as: Impavido

  • DrugParomomycin

    Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

    Also known as: Paromomycin sulfate

  • DrugSodium stibogluconate

    Sodium stibogluconate 33% 30 ml inj.

    Also known as: SSG

05

What researchers measure

Primary outcomes

  1. 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).

    Time frame: 6 months follow-up (Day 210)

Secondary outcomes

  1. Incidence of Treatment-Emergent Adverse Events

    1. Frequency of SAEs and AEs requiring treatment discontinuation 2. 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

  2. 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.

    Time frame: Initial cure: day 28; Probable cure: day 56

  3. Pharmacokinetics of paromomycin and miltefosine

    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

  4. Pharmacodynamics

    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.

  5. 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.

    Time frame: Day 15 to day 28 miltefosine treatment

06

Study locations

7 sites
  • Abdurafi MSF Health Center
    Ābderafī, Amhara, Ethiopia
  • University Hospital of Gondar
    Gondar, Ethiopia
  • Kacheliba Hospital
    Kapenguria, West Pokot 30601, Kenya
  • El Hassan Centre for Tropical Medicine
    Doka, Gedaref, Sudan
  • Tabarak Allah MSF Hospital
    Gadarif, Gedaref, Sudan
  • Um El Kher Hospital
    Gedaref, Sudan
  • Amudat Hospital
    Amudat, Karamoja, Uganda
07

References and documents

Publications

  • 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. PubMed 36164254 ↗

Study documents

  • Protocol, analysis plan and consent form · Mar 13, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided

08

Registry details

Key details

Study ID
NCT03129646
Lead 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
Responsible party
Sponsor
First posted
Apr 26, 2017
Start date
Jan 24, 2018
Primary completion
Dec 11, 2020
Completion
Dec 11, 2020
Last update
Feb 29, 2024

Study contacts

Jane Mbui, MD
principal investigator · Kenya Medical Research Institute
Joseph Olobo, MD, Prof
principal investigator · College of Health Sciences, Makerere University, Uganda
Ahmed M Musa, MD, Prof
principal investigator · Institute of Endemic Diseases, Sudan
Rezika Mohammed, MD
principal investigator · University Hospital of Gondar, Ethiopia

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Jul 2020. You cannot join it, but the record below documents what was studied.

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