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

NCT04020653 | Withdrawn Phase 2

• 1 other identifier: NPJ005-MAL-0122
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Malaria

Keywords

Uncomplicated malaria; sodium ferrous citrate (SFC); 5-aminolevulinic acid hydrochloride (5-ALA HCl); artemisinin-based combination therapy

Outcome Measures

Primary Outcomes (12)

• Number of patients with adverse events

  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

  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 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 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 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

  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

  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

  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

  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

  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)

  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)

  Change from baseline in unsaturated iron binding capacity (UIBC) to investigate change in iron metabolism parameters

  Days 1, 3, 7, 28, and 98

Study Arms (3)

Placebo + ACT

PLACEBO COMPARATOR

Patients will receive placebo for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3.

Drug: Artemisinin-based combination (ACT); Drug: Placebo

5 ALA/SFC+placebo+ACT BID

EXPERIMENTAL

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).

Drug: Artemisinin-based combination (ACT); Drug: Placebo; Drug: 5-aminolevulinic acid hydrochloride (5-ALA HCl) 300 mg BID; Drug: Sodium ferrous citrate (SFC) 236 mg BID

5-ALA/SFC+placebo+ACT QD

EXPERIMENTAL

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).

Drug: 5-aminolevulinic acid hydrochloride (5-ALA HCl) 600 mg QD; Drug: Sodium ferrous citrate (SFC) 472 mg QD; Drug: Artemisinin-based combination (ACT); Drug: Placebo

Interventions

5-aminolevulinic acid hydrochloride (5-ALA HCl) 600 mg QD DRUG

5-ALA HCl 150 mg capsules will be given to the patients as 600 mg QD

5-ALA/SFC+placebo+ACT QD

Sodium ferrous citrate (SFC) 472 mg QD DRUG

SFC 118 mg capsules will be given to the patients as 472 mg QD

5-ALA/SFC+placebo+ACT QD

Artemisinin-based combination (ACT) DRUG

Tablets of ACT will be administered following Dosage and Administration in the package insert of ACT. ACT will be supplied as a combination tablet.

Also known as: Artemether 20 mg and lumefantrine 120 mg

5 ALA/SFC+placebo+ACT BID; 5-ALA/SFC+placebo+ACT QD; Placebo + ACT

Placebo DRUG

Matching placebo capsules to 5-ALA HCl and SFC will be administered to the patients

5 ALA/SFC+placebo+ACT BID; 5-ALA/SFC+placebo+ACT QD; Placebo + ACT

5-aminolevulinic acid hydrochloride (5-ALA HCl) 300 mg BID DRUG

5-ALA HCl 150 mg capsules will be given to the patients as 300 mg BID

5 ALA/SFC+placebo+ACT BID

Sodium ferrous citrate (SFC) 236 mg BID DRUG

SFC 118 mg capsules will be given to the patients as 236 mg BID

5 ALA/SFC+placebo+ACT BID

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female patients of 18 to 60 years inclusive.
• Weighing 35 to 90 kg.
• Women with child bearing potential willing to give consent for pregnancy test.
• 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).
• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Neopharma Japan Co., Ltd.: lead
• Parexel: collaborator

MeSH Terms

Conditions

Malaria

Interventions

Aminolevulinic Acid; ferrous citrate; Sodium Glutamate; Artemether; Lumefantrine; BID protein, human

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Levulinic Acids; Keto Acids; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Glutamic Acid; Glutamates; Amino Acids, Acidic; Amino Acids, Dicarboxylic; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Sesquiterpenes; Terpenes; Hydrocarbons; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 12, 2019
• First Posted: July 16, 2019
• Study Start: September 6, 2019
• Primary Completion: May 31, 2020
• Study Completion: September 30, 2020
• Last Updated: March 3, 2020

Record last verified: 2020-02