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

NCT03129646 | Completed Phase 3

• 1 other identifier: DNDi-MILT/PM-01-VL
• Study Type: interventional
• Target: 439
• Locations: 4 countries
• Sites: 7

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.

Conditions

Visceral Leishmaniasis

Outcome Measures

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).

  6 months follow-up (Day 210)

Secondary Outcomes (5)

• Incidence of Treatment-Emergent Adverse Events

  From Screening to day 210

• Initial cure at day 28

  Initial cure: day 28; Probable cure: day 56

• Pharmacokinetics of paromomycin and miltefosine

  During treatment, at 1 month (day 56) and 6 months (day 210) follow-up

• Pharmacodynamics

  From baseline until day 210, and at any suspicion of relapse during the trial.

• Compliance to miltefosine treatment in an outpatient setting

  Day 15 to day 28 miltefosine treatment

Study Arms (3)

Arm 1 - MF/PM 14d

EXPERIMENTAL

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

Drug: Miltefosine; Drug: Paromomycin

Arm 2 - MF 28d/PM 14d

EXPERIMENTAL

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

Drug: Miltefosine; Drug: Paromomycin

Arm 3 - SSG/PM 17d

ACTIVE COMPARATOR

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

Miltefosine DRUG

Miltefosine 10mg and 50mg capsules

Also known as: Impavido

Arm 1 - MF/PM 14d; Arm 2 - MF 28d/PM 14d

Paromomycin DRUG

Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

Also known as: Paromomycin sulfate

Arm 1 - MF/PM 14d; Arm 2 - MF 28d/PM 14d; Arm 3 - SSG/PM 17d

Sodium stibogluconate DRUG

Sodium stibogluconate 33% 30 ml inj.

Also known as: SSG

Arm 3 - SSG/PM 17d

Eligibility Criteria

• Age: 4 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Drugs for Neglected Diseases: lead
• The Netherlands Cancer Institute: collaborator
• The Institute of Endemic Diseases (IEND), University of Khartoum: collaborator
• Kenya Medical Research Institute: collaborator
• Makerere University: collaborator
• University of Gondar: collaborator

Study Sites (7)

Abdurafi MSF Health Center

Ābderafī, Amhara, Ethiopia

Location

University Hospital of Gondar

Gonder, Ethiopia

Location

Kacheliba Hospital

Kapenguria, West Pokot County, 30601, Kenya

Location

El Hassan Centre for Tropical Medicine

Doka, Al Qaḑārif, Sudan

Location

Tabarak Allah MSF Hospital

Gedaref, Al Qaḑārif, Sudan

Location

Um El Kher Hospital

Gedaref, Sudan

Location

Amudat Hospital

Amudat, Karamoja, Uganda

Location

Related Publications (1)

• 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.

  PMID: 36164254 DERIVED

MeSH Terms

Conditions

Leishmaniasis, Visceral

Interventions

miltefosine; Paromomycin; Antimony Sodium Gluconate

Condition Hierarchy (Ancestors)

Leishmaniasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Aminoglycosides; Glycosides; Carbohydrates; Organic Chemicals; Gluconates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 21, 2017
• First Posted: April 26, 2017
• Study Start: January 24, 2018
• Primary Completion: December 11, 2020
• Study Completion: December 11, 2020
• Last Updated: February 29, 2024

Record last verified: 2020-07

Locations

ET (2); KE (1); UG (1); SU (3)