Back to resultsA 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
Primary Purpose
Malaria
Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
5-aminolevulinic acid hydrochloride (5-ALA HCl) 600 mg QD
Sodium ferrous citrate (SFC) 472 mg QD
Artemisinin-based combination (ACT)
Placebo
5-aminolevulinic acid hydrochloride (5-ALA HCl) 300 mg BID
Sodium ferrous citrate (SFC) 236 mg BID
Sponsored by
About this trial
This is an interventional treatment trial for Malaria focused on measuring Uncomplicated malaria, sodium ferrous citrate (SFC), 5-aminolevulinic acid hydrochloride (5-ALA HCl), artemisinin-based combination therapy
Eligibility Criteria
Inclusion Criteria:
- 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.
Exclusion Criteria:
- Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization (WHO) Criteria 2010.
- Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment.
- 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.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Experimental
Experimental
Arm Label
Placebo + ACT
5 ALA/SFC+placebo+ACT BID
5-ALA/SFC+placebo+ACT QD
Arm Description
Patients will receive placebo for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3.
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).
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).
Outcomes
Primary Outcome Measures
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.
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.
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.
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
Gametocyte Clearance Time
Time from the first dose until first total and continued disappearance of gametocytes which remains at least a further 24 hours
Change in inflammatory parameter: C-reactive protein
Change from baseline in C-reactive protein to investigate change in inflammatory parameters
Change in inflammatory parameter: interleukin-6
Change from baseline in interleukin-6 to investigate change in inflammatory parameters
Change in inflammatory parameter: tumor necrosis factor (TNF)-alpha
Change from baseline in tumor necrosis factor (TNF)-alpha to investigate change in inflammatory parameters
Change in iron metabolism: Serum iron
Change from baseline in serum iron to investigate change in iron metabolism parameters
Change in iron metabolism: Hepcidin
Change from baseline in hepcidin to investigate change in iron metabolism parameters
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
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
Secondary Outcome Measures
Full Information
NCT ID
NCT04020653
First Posted
July 12, 2019
Last Updated
February 28, 2020
Sponsor
Neopharma Japan Co., Ltd.
Collaborators
Parexel
1. Study Identification
Unique Protocol Identification Number
NCT04020653
Brief Title
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
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Considering the Thai FDA requirement, changes of Malaria cases in Thailand and EC recommendation, the decision to withdrawal the study was made.
Study Start Date
September 6, 2019 (Anticipated)
Primary Completion Date
May 31, 2020 (Anticipated)
Study Completion Date
September 30, 2020 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Neopharma Japan Co., Ltd.
Collaborators
Parexel
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria
Keywords
Uncomplicated malaria, sodium ferrous citrate (SFC), 5-aminolevulinic acid hydrochloride (5-ALA HCl), artemisinin-based combination therapy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo + ACT
Arm Type
Placebo Comparator
Arm Description
Patients will receive placebo for Day 1 to Day 7 and ACT (as per package instruction) for Day 1 to Day 3.
Arm Title
5 ALA/SFC+placebo+ACT BID
Arm Type
Experimental
Arm Description
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).
Arm Title
5-ALA/SFC+placebo+ACT QD
Arm Type
Experimental
Arm Description
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).
Intervention Type
Drug
Intervention Name(s)
5-aminolevulinic acid hydrochloride (5-ALA HCl) 600 mg QD
Intervention Description
5-ALA HCl 150 mg capsules will be given to the patients as 600 mg QD
Intervention Type
Drug
Intervention Name(s)
Sodium ferrous citrate (SFC) 472 mg QD
Intervention Description
SFC 118 mg capsules will be given to the patients as 472 mg QD
Intervention Type
Drug
Intervention Name(s)
Artemisinin-based combination (ACT)
Other Intervention Name(s)
Artemether 20 mg and lumefantrine 120 mg
Intervention Description
Tablets of ACT will be administered following Dosage and Administration in the package insert of ACT. ACT will be supplied as a combination tablet.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo capsules to 5-ALA HCl and SFC will be administered to the patients
Intervention Type
Drug
Intervention Name(s)
5-aminolevulinic acid hydrochloride (5-ALA HCl) 300 mg BID
Intervention Description
5-ALA HCl 150 mg capsules will be given to the patients as 300 mg BID
Intervention Type
Drug
Intervention Name(s)
Sodium ferrous citrate (SFC) 236 mg BID
Intervention Description
SFC 118 mg capsules will be given to the patients as 236 mg BID
Primary Outcome Measure Information:
Title
Number of patients with adverse events
Description
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.
Time Frame
From screening visit (Day -1) untill the Follow-up Visit (Day 98)
Title
Cure rate on Day 28
Description
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.
Time Frame
Day 28
Title
Parasite Clearance Time
Description
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.
Time Frame
Every 4 hours for 72 hours from Day 1 to Day 7 until 4 consecutive negative readings
Title
Fever Reduction Time
Description
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
Time Frame
Every 4 hours for 72 hours from Day 1 to Day 7
Title
Gametocyte Clearance Time
Description
Time from the first dose until first total and continued disappearance of gametocytes which remains at least a further 24 hours
Time Frame
Day 1 to Day 7 + 24 hours
Title
Change in inflammatory parameter: C-reactive protein
Description
Change from baseline in C-reactive protein to investigate change in inflammatory parameters
Time Frame
Days 1, 3, 7, and 28
Title
Change in inflammatory parameter: interleukin-6
Description
Change from baseline in interleukin-6 to investigate change in inflammatory parameters
Time Frame
Days 1, 3, 7, and 28
Title
Change in inflammatory parameter: tumor necrosis factor (TNF)-alpha
Description
Change from baseline in tumor necrosis factor (TNF)-alpha to investigate change in inflammatory parameters
Time Frame
Days 1, 3, 7, and 28
Title
Change in iron metabolism: Serum iron
Description
Change from baseline in serum iron to investigate change in iron metabolism parameters
Time Frame
Days 1, 3, 7, 28, and 98
Title
Change in iron metabolism: Hepcidin
Description
Change from baseline in hepcidin to investigate change in iron metabolism parameters
Time Frame
Days 1, 3, 7, 28, and 98
Title
Change in iron metabolism: total iron binding capacity (TIBC)
Description
Change from baseline in total iron binding capacity (TIBC) to investigate change in iron metabolism parameters
Time Frame
Days 1, 3, 7, 28, and 98
Title
Change in iron metabolism: unsaturated iron binding capacity (UIBC)
Description
Change from baseline in unsaturated iron binding capacity (UIBC) to investigate change in iron metabolism parameters
Time Frame
Days 1, 3, 7, 28, and 98
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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.
Exclusion Criteria:
Patients with signs and symptoms of severe/complicated malaria requiring parenteral treatment according to the World Health Organization (WHO) Criteria 2010.
Severe vomiting, defined as more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment.
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.
12. IPD Sharing Statement
Plan to Share IPD
Undecided
Learn more about this trial
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
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