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

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ClinicalTrials.gov Identifier: NCT03129646
Recruitment Status : Active, not recruiting
First Posted : April 26, 2017
Last Update Posted : July 21, 2020
Sponsor:
Collaborators:
The Netherlands Cancer Institute
The Institute of Endemic Diseases (IEND), University of Khartoum
Kenya Medical Research Institute
Makerere University
University of Gondar
Information provided by (Responsible Party):
Drugs for Neglected Diseases

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.

Condition or disease Intervention/treatment Phase
Visceral Leishmaniasis Drug: Miltefosine Drug: Paromomycin Drug: Sodium stibogluconate Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 439 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 24, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Leishmaniasis

Arm Intervention/treatment
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
Miltefosine 10mg and 50mg capsules
Other Name: Impavido

Drug: Paromomycin
Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp
Other Name: Paromomycin sulfate

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
Miltefosine 10mg and 50mg capsules
Other Name: Impavido

Drug: Paromomycin
Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp
Other Name: Paromomycin sulfate

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
Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp
Other Name: Paromomycin sulfate

Drug: Sodium stibogluconate
Sodium stibogluconate 33% 30 ml inj.
Other Name: SSG




Primary Outcome Measures :
  1. Definitive Cure [ Time Frame: 6 months follow-up (Day 210) ]
    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 :
  1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: From Screening to day 210 ]
    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.

  2. Initial cure at day 28 [ Time Frame: Initial cure: day 28; Probable cure: day 56 ]

    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.


  3. Pharmacokinetics of paromomycin and miltefosine [ Time Frame: During treatment, at 1 month (day 56) and 6 months (day 210) follow-up ]
    Total and partial blood plasma exposure to paromomycin and miltefosine defined as the area under the concentration-time curve

  4. Pharmacodynamics [ Time Frame: From baseline until day 210, and at any suspicion of relapse during the trial. ]
    Blood parasite clearance over time (qualitative and quantitative), as measured by qPCR from blood samples

  5. Compliance to miltefosine treatment in an outpatient setting [ Time Frame: Day 15 to day 28 miltefosine treatment ]
    Compliance to MF treatment in an outpatient setting will be assessed through patients' hospital records history, drug accountability and PK measurements.



Information from the National Library of Medicine

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Ages Eligible for Study:   4 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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 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 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 suffering from other conditions associated with splenomegaly such as schistosomiasis
  • 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 WBC < 1 x 10³/mm³
  • Patients with platelets < 40,000/mm³
  • Patients with abnormal liver function (ALT and AST) tests of more than three times the normal range
  • Patients with total bilirubin more than 1.5 times the upper normal range
  • Patients with serum creatinine above the ULN for age and sex
  • Patients with clinical signs of severe VL disease such as jaundice and bleeding
  • Patients with pre-existing clinical hearing loss based on audiometry at baseline
  • Patients who cannot comply with the planned scheduled visits and procedures of the study protocol

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03129646


Locations
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Ethiopia
Abdurafi MSF Health Center
Ābderafī, Amhara, Ethiopia
University Hospital of Gondar
Gondar, Ethiopia
Kenya
Kacheliba Hospital
Kapenguria, West Pokot, Kenya, 30601
Sudan
El Hassan Centre for Tropical Medicine
Doka, Gedaref, Sudan
Tabarak Allah MSF Hospital
Gadarif, Gedaref, Sudan
Um El Kher Hospital
Gedaref, Sudan
Uganda
Amudat Hospital
Amudat, Karamoja, Uganda
Sponsors and Collaborators
Drugs for Neglected Diseases
The Netherlands Cancer Institute
The Institute of Endemic Diseases (IEND), University of Khartoum
Kenya Medical Research Institute
Makerere University
University of Gondar
Investigators
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Principal Investigator: Jane Mbui, MD Kenya Medical Research Institute
Principal Investigator: Joseph Olobo, MD, Prof College of Health Sciences, Makerere University, Uganda
Principal Investigator: Ahmed M Musa, MD, Prof Institute of Endemic Diseases, Sudan
Principal Investigator: Rezika Mohammed, MD University Hospital of Gondar, Ethiopia
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Responsible Party: Drugs for Neglected Diseases
ClinicalTrials.gov Identifier: NCT03129646    
Other Study ID Numbers: DNDi-MILT/PM-01-VL
First Posted: April 26, 2017    Key Record Dates
Last Update Posted: July 21, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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
Additional relevant MeSH terms:
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Leishmaniasis
Leishmaniasis, Visceral
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Skin Diseases, Parasitic
Skin Diseases, Infectious
Skin Diseases
Paromomycin
Miltefosine
Antimony Sodium Gluconate
Anti-Bacterial Agents
Anti-Infective Agents
Antiprotozoal Agents
Antiparasitic Agents
Antifungal Agents
Antineoplastic Agents
Schistosomicides
Antiplatyhelmintic Agents
Anthelmintics