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

NCT ID: NCT03129646

Last Updated: 2024-02-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 439 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-24
• Study Completion Date: 2020-12-11

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.

Conditions

Visceral Leishmaniasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm 1 - MF/PM 14d

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

Group Type: EXPERIMENTAL

Miltefosine

Intervention Type: DRUG

Miltefosine 10mg and 50mg capsules

Paromomycin

Intervention Type: DRUG

Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

Arm 2 - MF 28d/PM 14d

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

Group Type: EXPERIMENTAL

Miltefosine

Intervention Type: DRUG

Miltefosine 10mg and 50mg capsules

Paromomycin

Intervention Type: DRUG

Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

Arm 3 - SSG/PM 17d

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

Group Type: ACTIVE_COMPARATOR

Paromomycin

Intervention Type: DRUG

Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

Sodium stibogluconate

Intervention Type: DRUG

Sodium stibogluconate 33% 30 ml inj.

Interventions

Miltefosine

Miltefosine 10mg and 50mg capsules

Intervention Type: DRUG

Paromomycin

Paromomycin sulfate equiv to 750mg paromomycin / 2ml amp

Intervention Type: DRUG

Sodium stibogluconate

Sodium stibogluconate 33% 30 ml inj.

Intervention Type: DRUG

Other Intervention Names

Impavido; Paromomycin sulfate; SSG

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)

• Minimum Eligible Age: 4 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Netherlands Cancer Institute

OTHER

Sponsor Role: collaborator

The Institute of Endemic Diseases (IEND), University of Khartoum

UNKNOWN

Sponsor Role: collaborator

Kenya Medical Research Institute

OTHER

Sponsor Role: collaborator

Makerere University

OTHER

Sponsor Role: collaborator

University of Gondar

OTHER

Sponsor Role: collaborator

Drugs for Neglected Diseases

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Jane Mbui, MD

Role: PRINCIPAL_INVESTIGATOR

Kenya Medical Research Institute

Joseph Olobo, MD, Prof

Role: PRINCIPAL_INVESTIGATOR

College of Health Sciences, Makerere University, Uganda

Ahmed M Musa, MD, Prof

Role: PRINCIPAL_INVESTIGATOR

Institute of Endemic Diseases, Sudan

Rezika Mohammed, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital of Gondar, Ethiopia

Locations

Abdurafi MSF Health Center

Ābderafī, Amhara, Ethiopia

University Hospital of Gondar

Gonder, , Ethiopia

Kacheliba Hospital

Kapenguria, West Pokot County, Kenya

El Hassan Centre for Tropical Medicine

Doka, Al Qaḑārif, Sudan

Tabarak Allah MSF Hospital

Gedaref, Al Qaḑārif, Sudan

Um El Kher Hospital

Gedaref, , Sudan

Amudat Hospital

Amudat, Karamoja, Uganda

Countries

Ethiopia; Kenya; Sudan; Uganda

References

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.

Reference Type: DERIVED

PMID: 36164254 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

DNDi-MILT/PM-01-VL

Identifier Type: -

Identifier Source: org_study_id