Piperaquine Granule Formulation Relative Bioavailability and Food Effect Study in Healthy Volunteers.

Study Overview
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Brief Summary
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This trial aims to characterise the pharmacokinetic (PK) profile and estimate drug exposure of a single oral dose of piperaquine (PQP) in a dispersible granule formulation compared to the PQP hard tablet formulation in the fasted state (Part 1), to advise the selection of dose when the PQP granule formulation is administered in a fed state in healthy adult participants. Part 2 will assess the effect on different types of meal composition on the PK of a single dose of PQP granule formulation in healthy adult participants.

Detailed Description
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Adult participants who give written informed consent will be screened within 45 days to determine their eligibility before entering the trial on Day -1. The trial will initially establish the pharmacokinetic (PK) profile and estimated drug exposure of a single oral dose of PQP in a dispersible granule formulation compared to the PQP hard tablet formulation in the fasted state (Part 1). In the second study part, and based on the PK results of Part 1, it is intended to administer the same dose level of 320 mg PQP dispersible granules concomitant with different fed conditions. However, if from Part 1 of the study it is shown that PQP dispersible granules formulation provides a significant improvement in Cmax values in the fasted state, this dose level may be adjusted for Part 2, in order to take into account a potential 3-fold increase in exposure which is the observed food effect when film-coated tablets (Eurartesim®) are administered with a high fat/high calorie meal. Such dose adjustment will be based on the safety and preliminary PK interim results of the granule formulation in the fasted state. The PQP dose selected in Part 2 (as dispersible granules formulation) will take into account a 3-fold factor increase in exposure when administered with food (see above) with such predicted exposure in the presence of food being not higher than after the administration of 960 mg PQP in tablet of Eurartesim® in adult subjects dosed in fasting conditions. Furthermore, sufficient data will be available to address key questions on both, safety and PK parameters to enable the review and recommendation by the SRC for the optimal dose of the granule formulation to be administered in Part 2.

Official Title
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A Randomized, Open Label, Two-part, Parallel-group, Phase I Study to Evaluate the Pharmacokinetics of Piperaquine Oral Dispersible Granules Formulation Compared to Piperaquine Hard Tablets Administered as a Single Dose in Fasting Condition (Part 1) and of Piperaquine Oral Dispersible Granules Formulation Administered as Single Dose in Various Fed States (Part 2) in Healthy Adult Participants

Conditions
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Malaria

Intervention / Treatment
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* Drug: Piperaquine Phosphate
* Drug: Piperaquine Phosphate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must fulfil all of the following criteria to be eligible for enrolment in this trial: Female or Male aged ≥18 years to ≤55 years at the date of signing informed consent. Ability to provide written, personally signed, and dated informed consent to participate in the trial, in accordance with the ICH Good Clinical Practice (GCP) and applicable regulations, before any trial-related procedures. An understanding, ability, and willingness to fully comply with trial procedures and restrictions. Female participants must agree to follow contraceptive requirements as indicated in Section 13.2.2, from at least 30 days prior to first dosage to 16 weeks after last dosage. Agrees not to donate sperm or ova from the time of the first administration of trial medication until twelve weeks after the end of the systemic exposure of the trial drug. Participants must have a body weight of 50 kg or greater and a BMI between 18.0 kg/m² - 30.0 kg/m² (inclusive) at screening. Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by; medical history, physical examination, vital signs, 12-lead electrocardiogram (ECG) and clinical laboratory evaluation that is reasonably likely to interfere with the participant's participation in or ability to complete the trial as assessed by the Investigator. Exclusion Criteria: Participants will be excluded from enrolment in this trial if they fulfil any of the criteria below: Prior screen failure or randomisation in this trial. NOTE: Participants who initially failed due to temporary non-medically significant issues are eligible for re-screening once the cause has resolved. Female participant who is pregnant (from history, examination or confirmed by a positive serum pregnancy test at screening and/or on Day -1) or breastfeeding. Male participants with a female partner(s) who is (are) pregnant or lactating at screening and/or on Day -1, or is (are) expected to be during the trial period. Has a mental incapacity or language barriers precluding adequate understanding, co-operation, or compliance with the trial requirements. Unable or unwilling to follow a standardised diet and meal schedule or unable to fast, as required during the trial. Has milk intolerance. Unable to swallow tablets. Has veins on either arm that are unsuitable for intravenous puncture or cannulation (e.g., veins that are difficult to locate, or a tendency to rupture during puncture). Known or suspected intolerance or hypersensitivity to the investigational products, any closely related compound, or any of the stated ingredients. History of significant allergic reaction (e.g., anaphylaxis, angioedema) to any product (food, pharmaceutical, etc) but excluding untreated, asymptomatic, seasonal allergies. Donated blood or blood products (excluding plasma) within 90 days prior to trial medication administration. Has received or plans to receive a COVID-19 vaccination within two weeks before to one week after trial last visit. Treated with medication containing PQP within 90 days or five half-lives preceding the dose of trial medication (whichever is the longer). Ingested herbal remedies or dietary supplements containing St. John's Wort in the 30 days before the planned Day 1 of the dosing Part. Taking medicinal products that are known to prolong the QTc interval (see http://www.crediblemeds.org/). An up-to-date list will be in the study specific manual. Use of any medication that is either a moderate or strong inhibitor or inducer of CYP3A4 within 30 days or five half-lives (whichever is longer) prior to the planned day of dosing (see Drug Development and Drug Interactions, Table of Substrates, Inhibitors and Inducers, FDA). Anup to date list will be in the study specific manual. Use of any other prescription medication (excluding hormonal contraception and hormone replacement therapy) within 14 days or ten half-lives (whichever is longer) prior to Day 1 of the dosing Part that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating. Use of any over-the-counter medication (including multivitamin, herbal, or homeopathic preparations; excluding paracetamol - up to 3 g of paracetamol per day permitted while participants are in-house, whereas while participants are outpatients a maximum of 1 g paracetamol per day will be allowed) during the seven days or ten half-lives of the drug (whichever is longer) prior to Day 1 of the dosing Part, that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating. Ingested any poppy seeds within the 24 hours prior to screening or admission. Current use of tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products in any form (e.g., gum, patch, electronic cigarettes). History or clinical evidence of substance and/or alcohol abuse within the two years before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units (for both males and females). Participants must have not consumed other substances known to be potent inhibitors or inducers of CYP34A system such as grapefruit or cranberry juice containing products in the 30 days before the planned IMP administration. Any history of seizures, epilepsy, photosensitivity or documented retinopathy. The history or presence of any of the following cardiac conditions: known structural cardiac abnormalities; family history of long QT syndrome; cardiac syncope or recurrent, idiopathic syncope; exercise related clinically significant cardiac events. Has vital signs consistently outside of the normal range at screening or Day-1. Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG or clinically important abnormalities that may interfere with the interpretation of QTc interval changes. This includes participants with any of the following (at screening or Day -1): sinus node dysfunction clinically significant PR (PQ) interval prolongation (>220ms) second- or third-degree atrioventricular (AV) block sustained cardiac arrhythmia's including (but not limited to) atrial fibrillation or supraventricular tachycardia, or any symptomatic arrhythmia, with the exception of isolated extra-systoles abnormal T-wave morphology which may impact on the QT/QTc assessment QT interval corrected using the Fridericia's formula (QTcF) >450 ms any other ECG abnormalities in the standard 12-lead ECG or an equivalent assessment which in the opinion of the Investigator will interfere with the ECG analysis Participants with borderline abnormalities may be included if the deviations do not pose a safety risk, and if agreed between the appointed cardiologist and the PI. Positive test results for alcohol or drugs of abuse at screening or Day -1. Electrolyte imbalances, particularly results that are out of reference intervals for potassium, calcium or magnesium. Has a positive test for Hepatitis B surface Antigen (HBsAg), Hepatitis C Antibody (HCV Ab), or Human Immunodeficiency Virus Antibody (HIV Ab) at screening. Presence of malaria parasites by blood smear. Has total bilirubin, ALT or AST consistently >upper limit of normal (ULN) at screening (up to two repeats may be taken during the screening period; participants may be included if two out of the three total results are ≤ULN), or has total bilirubin >ULN on Day -1 (mild variations from baseline may be allowed if considered not clinically significant by the Investigator). Has a haemoglobin, platelet count, total white blood cell count, lymphocyte or monocyte count < lower limit of normal (LLN) (up to two repeats may be taken during the screening period and on Day -1 (participants may be included if two out of the three total results are greater or equal to LLN), at screening. Where there is a clear diurnal effect on the result participants may be included if variations are considered not clinically relevant by the Investigator. Current or recurrent disease (e.g., cardiovascular, haematological, neurological, endocrine, immunological, renal, hepatic or gastrointestinal or other conditions, including cholecystectomy or gastrectomy) that could affect the action, absorption, distribution, metabolism or excretion of PQP or could affect clinical assessments or clinical laboratory evaluations. Current or relevant history of physical or psychiatric illness that are not stable or may require a change in treatment, or use of prohibited therapies during the trial,that make the participant unlikely to fully comply with the requirements of the trial or to complete the trial, or any condition that presents undue risk from the investigational product or trial procedures. Any other abnormal findings on vital signs, ECG, physical examination or laboratory assessments that the Investigator judges as likely to interfere with the trial or pose an additional risk in participating. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of participation in the trial, or may influence the result of the trial or the participant's ability to participate in the trial. Any conditions which in the opinion of the Investigator would make the participant unsuitable for enrolment or could interfere with the participation in or completion of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part 1: PQP tablet / dispersible granule administered in fasting condition of at least 10 hours. Group 1: PQP hard tablet, 320 mg (N=12) Group 2: PQP dispersible granule, 320 mg (N=12) Transition to Part 2: To minimize the risk to healthy participants, a decision on transitioning from Part 1 to Part 2, will be taken by the Safety Review Committee (SRC), based on the safety and preliminary PK interim report of the granule formulation, compared to the PQP hard tablet, with safety data obtained up to Day 15 and PK data obtained up to Day 8. If necessary, doses may be readjusted for the Part 2 to assess the food effect. Part 2: PQP dispersible granule administered in fed conditions (planned as 320 mg) Group 3: High-fat meal (N=12) Group 4: Low-fat meal representative of African diet (N=12) Group 5: Whole milk 250 ml (N=12)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Part 1 (fasted) : Group 1 PQP hard tablet, 320mg (N=12)<br>Group 1: Piperaquine hard tablet, 320mg (administered in fasting condition of at least 10 hours) (N=12) | Drug: Piperaquine Phosphate<br>* PQP hard tablet 320 mg; single dose (320 mg) given orally with 240 ml of water<br>|
| Experimental: Part 1 (Fasted): Group 2: PQP dispersible granules 320mg (N=12)<br>Group 2: Piperaquine dispersible granules 320mg administered in fasting condition of at least 10 hours (N=12) | Drug: Piperaquine Phosphate<br>* PQP dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single dose (320 mg) given orally<br>|
| Experimental: Part 2 (Fed): Group 3 - high fat: PQP dispersible granule (planned as 320 mg) (N=12)<br>Group 3: Piperaquine dispersible granules 320mg administered in fed conditions - High-fat meal (N=12) | Drug: Piperaquine Phosphate<br>* PQP dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single dose (320 mg) given orally<br>|
| Experimental: Part 2 Fed): Group 4 - low fat: PQP dispersible granule (planned as 320 mg) (N=12)<br>Group 4: Piperaquine dispersible granules 320mg administered in fed conditions - Low-fat meal representative of African diet (N=12) | Drug: Piperaquine Phosphate<br>* PQP dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single dose (320 mg) given orally<br>|
| Experimental: Part 2 (Fed): Group 5 - whole milk: PQP dispersible granule (planned as 320 mg) (N=12)<br>Group 5: Piperaquine dispersible granules 320mg administered in fed conditions - Whole milk 250 ml (N=12) | Drug: Piperaquine Phosphate<br>* PQP dispersible granules 320 mg dose equivalent dispersed in 25 ml of water; single dose (320 mg) given orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative bioavailability (Frel) of the Maximum Observed Plasma Concentration (Cmax) of the PQP dispersible granule compared to the PQP hard tablet in the fasted state (Frel Cmax). | Blood samples are analysed for PQP concentrations at the indicated time points to determine the maximum observed plasma concentration (Cmax) for PQP dispersible granule (test) and PQP hard tablet (reference) in the fasted state. Pharmacokinetic parameters are determined using standard non-compartmental analysis. Frel Cmax is calculated as the ratio of Cmax of the PQP dispersible granule compared to the PQP hard tablet in the fasted state. | Plasma samples taken pre-dose -0.5 hours, then 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, Day 5, Day 8, Day 15, Day 22 and Day 30 post-dose. | 
| Relative bioavailability (Frel) of the Area Under the Plasma Concentration-time Curve From Time Zero to 72h hours (AUC0-72h) of the PQP dispersible granule compared to the PQP hard tablet in the fasted state (Frel AUC0-72h). | Blood samples are analysed for PQP concentrations at the indicated time points to calculate the area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72h) for PQP dispersible granule (test) and PQP hard tablet (reference) in the fasted state. Pharmacokinetic parameters are determined using standard non-compartmental analysis. Frel AUC0-72h is calculated as the ratio of AUC0-72h of the PQP dispersible granule compared to the PQP hard tablet in the fasted state. | Plasma samples taken pre-dose -0.5 hours, then 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, Day 5, Day 8, Day 15, Day 22 and Day 30 post-dose. | 
| Relative bioavailability (Frel) of the Area Under the Plasma Concentration-time Curve From Time Zero to the last quantifiable concentration (AUC0-t) of the PQP dispersible granule compared to the PQP hard tablet in the fasted state (Frel AUC0-t). | Blood samples are analysed for PQP concentrations at the indicated time points to calculate the area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC0-t) for PQP dispersible granule (test) and PQP hard tablet (reference) in the fasted state. Pharmacokinetic parameters are determined using standard non-compartmental analysis. Frel AUC0-t is calculated as the ratio of AUC0-t of the PQP dispersible granule compared to the PQP hard tablet in the fasted state. | Plasma samples taken pre-dose -0.5 hours, then 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, Day 5, Day 8, Day 15, Day 22 and Day 30 post-dose. | 
| Relative bioavailability (Frel) of the Area Under the Plasma Concentration-time Curve From Time Zero to 168 hours (AUC0-168h) of the PQP dispersible granule compared to the PQP hard tablet in the fasted state (Frel AUC0-168h. | Blood samples are analysed for PQP concentrations at the indicated time points to calculate the area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) for PQP dispersible granule (test) and PQP hard tablet (reference) in the fasted state. Pharmacokinetic parameters are determined using standard non-compartmental analysis. Frel AUC0-168h is calculated as the ratio of the AUC0-168h of the PQP dispersible granule compared to the PQP hard tablet in the fasted state. | Plasma samples taken pre-dose -0.5 hours, then 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, Day 5, Day 8, Day 15, Day 22 and Day 30 post-dose. | 
| Relative bioavailability (Frel) of the Area Under the Plasma Concentration-time Curve From Time Zero extrapolated to infinity (AUC0-∞) of the PQP dispersible granule compared to the PQP hard tablet in the fasted state (Frel AUC0-∞). | Blood samples are analysed for PQP concentrations at the indicated time points to calculate the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-∞) for PQP dispersible granule (test) and PQP hard tablet (reference) in the fasted state. Pharmacokinetic parameters are determined using standard non-compartmental analysis. Frel AUC0-∞ is calculated as the ratio of the AUC0-∞ of the PQP dispersible granule compared to the PQP hard tablet in the fasted state. | Plasma samples taken pre-dose 0.5 hours, then 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 48, Day 5, Day 8, Day 15, Day 22 and Day 30 post-dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetics, Malaria prevention, Bioavailability, Malaria, Food effect, Oral granule formulation