Pyramax in Asymptomatic Carriers of P. Falciparum Monoinfections

A Randomized, Open-Label Exploratory Study To Determine The Efficacy Of Different Treatment Regimens Of Pyramax® (Pyronaridine-Artesunate) In Asymptomatic Carriers Of Plasmodium Falciparum Monoinfections

This study will assess the efficacy of Pyramax administered for three-day, two-day or one day, in clearing a P. falciparum infection in asymptomatic carriers.

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Study Overview

• Status: Unknown
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Drug: Pyronaridine tetraphosphate 180mg:artesunate 60mg

Detailed Description

This is a randomized, open-label, three-arm, out-patient study in asymptomatic individuals with P. falciparum monoinfection confirmed at baseline, who are >5 years of age and >20kg body weight. A total of 300 participants will be randomised into the study; 100 participants in each of three treatment arms.

Patients who fulfil the entry criteria (all inclusion and none of the exclusion criteria) will be recruited and randomized to receive Pyramax orally for three days, two days or one day in a randomization ratio of 1:1:1.

All participants will be followed until Day 63 (counted from day 0) and blood samples will be taken on Days 0, 1, 2, 3, 7, 14, 21, 28, 35, 42 and 63 for malaria diagnostics, parasite density and qPCR. In addition, blood samples reverse-transcriptase (RT)-PCR will be taken on Days 0, 1, 2, 3, 7 and 14.

Participants will be administered local SOC treatment if they meet any of the protocol-specific criteria of treatment failure: Early treatment failure, Late clinical failure, or Late parasitological failure up to and including Day 63, or if the participant withdraws at any time before Day 63, and is parasite positive.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 2

Contacts and Locations

Study Locations

• Gambia
  • Banjul,
    • Fajara,, Banjul,, Gambia
      • MRC Unit The Gambia at the London School of Hygiene and Tropical Medicine,
• Zambia
  • Ndola, Zambia
    • Tropical Diseases Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Evidence of asymptomatic infection with Plasmodium falciparum monoinfection on thin and thick blood smears with parasite density between 20/µL and 50,000/µL
2. Absence of any clinical symptoms of malaria at the time of enrolment and within 72 hours before enrolment
3. Age >5 years old and >20 kg body weight
4. Ability to swallow oral medication
5. Evidence of a personally signed and dated Informed Consent document indicating that the participant (or a legally acceptable representative if a participant is <18 years of age) has been informed of all pertinent aspects of the study and that all questions by the participant have been sufficiently answered. Assent will be obtained from participants <18 years of age as required by national regulations.
6. Participants who are willing to and are able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria:

1. Haemoglobin <7 g/dL (measured at screening)

2. History of having received any antimalarial treatment (alone or in combination) during the following periods before screening:

   1. Piperaquine, mefloquine, naphthoquine or sulfadoxine-pyrimethamine within 6 weeks prior to screening
   2. Amodiaquine, chloroquine within 4 weeks prior to screening
   3. Any artemisinin derivative (artesunate, artemether or dihydroartemisinin), quinine, lumefantrine or any other anti-malarial treatment or antibiotic with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones and azithromycin) within 14 days prior to screening
3. Any herbal products or traditional medicines during the 7 days prior to screening (if spontaneously reported by the patient)
4. Known allergy to the study drugs (pyronaridine and/or any artemisinin derivatives)
5. Positive urinary pregnancy test for women of reproductive age
6. Lactating women
7. Evidence of severe malnutrition
8. Participation in other studies within 30 days before the current study begins and/or during study participation
9. Inability to comprehend and/or unwillingness to follow the study protocol
10. Previously randomized in this study

11. Severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study. Examples would include but not limited to:

    1. Immunological disorders (including known seropositive HIV antibody),
    2. Severe psychiatric disorders (active depression, recent history of depression, generalised anxiety, psychosis, schizophrenia or other major psychiatric disorders) and major medical disorders related to cardiovascular, respiratory (including active tuberculosis), renal, gastrointestinal, endocrine, infectious, malignancy, neurological (including auditory) and history of convulsions or other abnormality (including recent head trauma),
    3. Clinical signs or symptoms of hepatic injury (such as nausea, abdominal pain associated with jaundice) or known severe liver disease (i.e. decompensated cirrhosis, Child-Pugh stage 3 or 4)
12. Participant the Investigator considers at particular risk of receiving an anti-malarial or of participating in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm Pyramax 3 days; Pyramax (pyronaridine tetraphosphate 180mg:artesunate 60mg) will be administered, once per day according to body weight for three days (Arm A)	Drug: Pyronaridine tetraphosphate 180mg:artesunate 60mg; ACT; Other Names: Pyramax
EXPERIMENTAL: Arm Pyramax 2 days; Pyramax (pyronaridine tetraphosphate 180mg:artesunate 60mg) will be administered, once per day according to body weight for two days (Arm B)	Drug: Pyronaridine tetraphosphate 180mg:artesunate 60mg; ACT; Other Names: Pyramax
EXPERIMENTAL: Arm Pyramax 1 day; Pyramax (pyronaridine tetraphosphate 180mg:artesunate 60mg) will be administered, once per day according to body weight for one day (Arm C)	Drug: Pyronaridine tetraphosphate 180mg:artesunate 60mg; ACT; Other Names: Pyramax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-adjusted APR at Day 28 (based on slide assessment by microscopy)	To assess the efficacy of each dosing regimen PCR-adjusted Adequate parasitological response (APR) at Day 28	Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PCR-adjusted APR	To assess the efficacy of each dosing regimen PCR-adjusted APR at Day 63	63 days
PCR-unadjusted APR	To assess the efficacy of each dosing regimen PCR-unadjusted APR at Day 63	63 days
Rate of recurrent infections, recrudescence and new infections	To assess the efficacy of each dosing regimen on rate of recurrent infections, recrudescence and new infections	63 days
Proportion of parasite free participants	Proportion of participants who are parasite free by 4-8 hours, Day 1, Day 2 and Day 3 post first dosing	4 days
Gametocyte incidence	The area under the curve (AUC) up to Day 14 (post first dose) of gametocytes in participants with gametocytes at baseline, and separately in participants without gametocytes at baseline	14 days
Adverse Events	Number (%) of patients and number of events with:TEAEs,serious TEAEs,study drug related TEAEs,study drug related serious TEAEs,malaria-related TEAEs,malaria-related serious TEAEs; Number (%) of patients with TEAEs and drug-related TEAEs by maximum severity, based on Grade 1 to Grade 5 (CTCAE V4.03) severity grading Adverse events will be coded by MedDRA primary system organ class and preferred term.; Hepatotoxicity related TEAEs o The number and percentage of patients with hepatotoxicity related TEAEs, based on the Standard MedDRA Query (SMQ) narrow search "Drug-related hepatic disorders" will be summarised and clinical biochemistry parameters	63 days
Clinical laboratory data - Haematology	Haemoglobin, haematocrit, erythrocytes, platelets, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils will be summarised over time, as absolute values and changes from baseline with the number of observations, mean, standard deviation, median, quartiles, minimum and maximum. SI units will be used to summarise the data.	63 days
Clinical laboratory data - Biochemistry	Total and conjugated bilirubin will be summarised over time, as absolute values and changes from baseline with the number of observations, mean, standard deviation, median, quartiles, minimum and maximum. SI units will be used to summarise the data.	63 days
Clinical laboratory data - Liver Enzymes	Alanine aminotransaminase (ALT), Aspartate aminotransaminase (AST), Alkaline Phosphatase will be summarised over time, as absolute values and changes from baseline with the number of observations, mean, standard deviation, median, quartiles, minimum and maximum. IU/L units will be used to summarise the data	63 days
Clinical laboratory data - Liver Enzyme Elevations	The number (%) of participants with liver enzyme elevations after first drug administration as defined below will be summarised.; ALT or AST > 3 x Upper Limit of Normal (ULN); ALT or AST > 5 x ULN; ALT or AST > 8 x ULN; ALT or AST > 3 x ULN and bilirubin > 2 x ULN at the same time point (when conjugated bilirubin fraction is missing); ALT or AST > 3 x ULN and bilirubin > 2 x ULN, together with a conjugated bilirubin fraction >35% (Potential Hy's law cases), at the same time point	63 days
Vital signs - Blood pressure	Supine systolic and diastolic blood pressure (mm Hg) absolute values and changes from baseline will be summarised by time point with the number of observations, mean, standard deviation, median, minimum and maximum, and quartiles	63 days
Vital signs - Pulse rate	Pulse rate (bpm) absolute values and changes from baseline will be summarised by time point with the number of observations, mean, standard deviation, median, minimum and maximum, and quartiles	63 days
Vital signs - Temperature	Temperature (degrees Celsius) absolute values and changes from baseline will be summarised by time point with the number of observations, mean, standard deviation, median, minimum and maximum, and quartiles	63 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parasite free by qPCR quantification	To estimate the proportion of participants who are parasite free by qPCR quantification.	63 days
PCR-adjusted APR by qPCR	To estimate PCR-adjusted APR by qPCR.To estimate PCR-unadjusted APR by qPCR. To estimate the rate of recurrent infections, recrudescences and new infections by qPCR until Day 63 (post first dose) by KM analysis.	63 days
Percentage change in gametocytaemia.	In participants with positive detection of gametocytes by reverse transcriptase (RT)-PCR at baseline, to evaluate percentage reduction in gametocytaemia.	63 days
AUC of gametocytaemia by RT-PCR	To estimate area under the curve (AUC) up to Day 14 of gametocytaemia by RT-PCR, in participants with positive RT-PCR at baseline and separately in participants with negative RT-PCR at baseline	14 days
Relationship between artesunate and pyronaridine concentration and efficacy	To explore the relationship between artesunate and pyronaridine concentration and efficacy (PCR-adjusted APR at Day 28, based on slide assessment by microscopy)	28 days

Collaborators and Investigators

• Sponsor: Shin Poong Pharmaceutical Co. Ltd.
• Collaborators: Medicines for Malaria Venture
• Investigators: Study Director: Jang Sik Shin, Shin Poong

Publications and helpful links

General Publications

• Dabira ED, Hachizovu S, Conteh B, Mendy A, Nyang H, Lawal B, Ndiath MO, Mulenga JM, Mwanza S, Borghini-Fuhrer I, Arbe-Barnes S, Miller R, Shin J, Duparc S, D'Alessandro U, Manyando C, Achan J. Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial. Clin Infect Dis. 2022 Jan 29;74(2):180-188. doi: 10.1093/cid/ciab425.

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 3, 2018
• Primary Completion (ANTICIPATED): October 1, 2019
• Study Completion (ANTICIPATED): October 1, 2019

Study Registration Dates

• First Submitted: September 13, 2018
• First Submitted That Met QC Criteria: January 18, 2019
• First Posted (ACTUAL): January 24, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2019
• Last Update Submitted That Met QC Criteria: September 27, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Asymptomatic malaria
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria; Malaria, Falciparum; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Artesunate; Pyronaridine
• Other Study ID Numbers: SP-C-026-18

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No