A Study to Assess the Safety and Efficacy of 5-aminolevulinic Acid Hydrochloride (5-ALA HCl) and Sodium Ferrous Citrate (SFC) Added on Artemisinin-based Combination Therapy (ACT) in Adult Patients With Uncomplicated Malaria

February 28, 2020 updated by: Neopharma Japan Co., Ltd.

A Pilot, Double-blind, Randomized, Parallel-group, Placebo-controlled, Exploratory Study to Assess the Safety and Efficacy of 5-aminolevulinic Acid Hydrochloride (5-ALA HCl) and Sodium Ferrous Citrate (SFC) Added on Artemisinin-based Combination Therapy (ACT) in Adult Patients With Uncomplicated Malaria

This is a pilot, double-blind, randomized, parallel-group, placebo-control, exploratory study to evaluate the efficacy and safety of 5-aminolevulinic acid hydrochloride (5-ALA HCl) and sodium ferrous citrate (SFC) added on artemisinin-based combination therapy (ACT) compared with ACT alone in the treatment of malaria. Patients who are suffering from uncomplicated malaria, are eligible for randomization.The study will be conducted in a total of 75 patients with uncomplicated malaria.

Study Overview

Detailed Description

Approximately 75 patients will be randomized in a 1:2:2 ratio to 3 arms:

Arm 1: placebo+ACT group (15 patients)

Arm 2: 5 ALA/SFC+Placebo+ACT twice daily (BID) (30 patients)

Arm 3: 5-ALA/SFC+Placebo+ACT once daily (QD) (30 patients)

The study duration will be a maximum of 98 days with treatment period of 7 days and follow-up period of 91 days.

Study Type

Interventional

Phase

  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Male or female patients of 18 to 60 years inclusive.
  2. Weighing 35 to 90 kg.
  3. Women with child bearing potential willing to give consent for pregnancy test.
  4. Presence of symptomatic uncomplicated malaria of all species inclusive with a diagnosis confirmed by:

    A. Microscopically confirmed parasite infection, between 500 and 100,000 asexual parasite count/μL of blood.

    B. Fever, as defined by axillary/tympanic of ≥37.5°C within 24 hours before randomization (must be documented).

  5. Patients must be willing and able to give written informed consent and comply with all study visits and procedures. If a patient cannot read informed consent and/or write a signature, an impartial witness who speaks the language of the patient must be present during the entire informed consent process and discussion with the patient.

Exclusion Criteria:

  1. Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization (WHO) Criteria 2010.
  2. Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment.
  3. Known history of photo-hypersensitivity, porphyria, or hemochromatosis.
  4. Have taken any medication with antimalarial or antibiotic with antimalarial effect within 14 days before randomization.
  5. Received an investigational drug within the past 28 days.
  6. Patients whose Hemoglobin (Hb) level is lower than 8 g/dL.
  7. Liver function tests (aspartate aminotransferase/alanine aminotransferase [AST/ALT] levels) more than 2.5 times upper limit of normal values.
  8. Known human immunodeficiency virus (HIV) or Hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) positive, testing is not required.
  9. Known significant renal impairment as indicated by serum creatinine of ≥1.4 mg/dL or estimated glomerular filtration rate (eGFR) of <45 mL/min.
  10. Known history of hypersensitivity, allergic or adverse reactions to 5-aminolevulinic acid and sodium ferrous citrate.
  11. Presence or history of uncontrolled systemic disease.
  12. Female patients who are pregnant or breast-feeding.
  13. Any other condition in the opinion of the investigator makes the patient unsuitable for study
  14. Received any medication specified as contraindication for ACT or affecting blood concentration of ACT within 5 times the half-life of each medication before the first dose of study medication.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo + ACT
Patients will receive placebo for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3.
Tablets of ACT will be administered following Dosage and Administration in the package insert of ACT. ACT will be supplied as a combination tablet.
Other Names:
  • Artemether 20 mg and lumefantrine 120 mg
Matching placebo capsules to 5-ALA HCl and SFC will be administered to the patients
Experimental: 5 ALA/SFC+placebo+ACT BID

5-ALA HCl 300 mg and SFC 236 mg will be administered BID for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3.

Patients will receive 5-ALA HCl+Placebo and SFC+Placebo at odd number of study medication dosing (Dose 1, 3, 5, 7, 9, 11, 13) and only 5-ALA HCl and SFC at even numbers of study medication dosing (Dose 2, 4, 6, 8, 10,12, 14).

Tablets of ACT will be administered following Dosage and Administration in the package insert of ACT. ACT will be supplied as a combination tablet.
Other Names:
  • Artemether 20 mg and lumefantrine 120 mg
Matching placebo capsules to 5-ALA HCl and SFC will be administered to the patients
5-ALA HCl 150 mg capsules will be given to the patients as 300 mg BID
SFC 118 mg capsules will be given to the patients as 236 mg BID
Experimental: 5-ALA/SFC+placebo+ACT QD
5-ALA HCl 600 mg and SFC 472 mg will be administered QD in the morning or evening for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3. Patients will receive 5-ALA HCl and SFC at odd number of study medication dosing (Dose 1, 3, 5, 7) and placebo at even numbers of study medication dosing (Dose 2, 4, 6).
Tablets of ACT will be administered following Dosage and Administration in the package insert of ACT. ACT will be supplied as a combination tablet.
Other Names:
  • Artemether 20 mg and lumefantrine 120 mg
Matching placebo capsules to 5-ALA HCl and SFC will be administered to the patients
5-ALA HCl 150 mg capsules will be given to the patients as 600 mg QD
SFC 118 mg capsules will be given to the patients as 472 mg QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with adverse events
Time Frame: From screening visit (Day -1) untill the Follow-up Visit (Day 98)
Number of patients with any adverse events or clinically significant abnormal laboratory parameters to investigate safety and tolerability of 5-ALA HCl and SFC in simultaneous administration with ACT.
From screening visit (Day -1) untill the Follow-up Visit (Day 98)
Cure rate on Day 28
Time Frame: Day 28
Cure rate is defined as the proportion of patients with polymerase chain reaction (PCR)-corrected Adequate Clinical and Parasitological Response (ACPR). PCR-corrected ACPR is defined as patients with clearance of asexual parasites within 28 days of initiation of study medication and without recrudescence within 28 days. Cure rate to investigate the preliminary efficacy of 5-ALA HCl and SFC in simultaneous administration with ACT.
Day 28
Parasite Clearance Time
Time Frame: Every 4 hours for 72 hours from Day 1 to Day 7 until 4 consecutive negative readings
Time from first dosing to time of first of 4 consecutive readings with zero parasite count in blood. Calculated based on parasite count in blood every 4 hours after the start of study medication for 72 hours until there are 4 consecutive negative readings.
Every 4 hours for 72 hours from Day 1 to Day 7 until 4 consecutive negative readings
Fever Reduction Time
Time Frame: Every 4 hours for 72 hours from Day 1 to Day 7
Time to Fever Reduction is defined as the time from first dosing to first normal reading of temperature (<37.5 °C) for two consecutive normal temperature reading plus confirmed normal temperature every 4 hours after the start of study medication for 72 hours
Every 4 hours for 72 hours from Day 1 to Day 7
Gametocyte Clearance Time
Time Frame: Day 1 to Day 7 + 24 hours
Time from the first dose until first total and continued disappearance of gametocytes which remains at least a further 24 hours
Day 1 to Day 7 + 24 hours
Change in inflammatory parameter: C-reactive protein
Time Frame: Days 1, 3, 7, and 28
Change from baseline in C-reactive protein to investigate change in inflammatory parameters
Days 1, 3, 7, and 28
Change in inflammatory parameter: interleukin-6
Time Frame: Days 1, 3, 7, and 28
Change from baseline in interleukin-6 to investigate change in inflammatory parameters
Days 1, 3, 7, and 28
Change in inflammatory parameter: tumor necrosis factor (TNF)-alpha
Time Frame: Days 1, 3, 7, and 28
Change from baseline in tumor necrosis factor (TNF)-alpha to investigate change in inflammatory parameters
Days 1, 3, 7, and 28
Change in iron metabolism: Serum iron
Time Frame: Days 1, 3, 7, 28, and 98
Change from baseline in serum iron to investigate change in iron metabolism parameters
Days 1, 3, 7, 28, and 98
Change in iron metabolism: Hepcidin
Time Frame: Days 1, 3, 7, 28, and 98
Change from baseline in hepcidin to investigate change in iron metabolism parameters
Days 1, 3, 7, 28, and 98
Change in iron metabolism: total iron binding capacity (TIBC)
Time Frame: Days 1, 3, 7, 28, and 98
Change from baseline in total iron binding capacity (TIBC) to investigate change in iron metabolism parameters
Days 1, 3, 7, 28, and 98
Change in iron metabolism: unsaturated iron binding capacity (UIBC)
Time Frame: Days 1, 3, 7, 28, and 98
Change from baseline in unsaturated iron binding capacity (UIBC) to investigate change in iron metabolism parameters
Days 1, 3, 7, 28, and 98

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 6, 2019

Primary Completion (Anticipated)

May 31, 2020

Study Completion (Anticipated)

September 30, 2020

Study Registration Dates

First Submitted

July 12, 2019

First Submitted That Met QC Criteria

July 12, 2019

First Posted (Actual)

July 16, 2019

Study Record Updates

Last Update Posted (Actual)

March 3, 2020

Last Update Submitted That Met QC Criteria

February 28, 2020

Last Verified

February 1, 2020

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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