HealthyPhase 1NCT01552330
Pharmacokinetic Study of Primaquine and Pyronaridine-Artesunate in Healthy Subjects
A Phase 1 study testing Primaquine and Pyronaridine-artesunate in people with Healthy, run by University of Oxford at 1 site in Thailand.
Trial summary
The observed changes of P. falciparum sensitivity to artemisinin lead to the intensification of early detection as well as treatment monitoring in malaria infection. It is widely accepted that the development of resistance can be delayed by the use of combination therapy, especially combinations that include… Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Primaquine and Pyronaridine-artesunate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 1 siteThailand
- Study dates
- May 2012to Oct 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
- Males and Females aged between 18 years to 60 years.
- Males and Females weighing between 45-64 kilograms.
- A female is eligible to enter and participate in this study if she is:
- of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy
- or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU/mL or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy
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- or of childbearing potential, has a negative serum pregnancy test at screening and prior to start the study drug in each period, and abstain from sexual intercourse or agrees to using effective contraceptive methods (e.g., intrauterine device, hormonal contraceptive drug, tubal ligation or female barrier method with spermicide) during the study until completion of the follow-up procedures
- A male is eligible to enter and participate in this study if he: agrees to abstain from (or use a condom during) sexual intercourse with females of childbearing potential or lactating females; or is willing to use a condom/spermicide, during the study until completion of the follow-up procedures.
- Provide a signed and dated written informed consent prior to study participation.
- Normal electrocardiogram (ECG) with QTc <450 msec.
- Willingness and ability to comply with the study protocol for the duration of the trial.
Who cannot join
- Females who are pregnant, trying to get pregnant, or are lactating.
- The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
- A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
- Subjects with a personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes (heart failure, hypokalemia) or with a family history of sudden cardiac death.
- A creatinine clearance <70 mL/min as determined by Cockcroft-Gault equation:
- CLcr (mL/min) = (140 - age) Wt / (72 Scr) (multiply answer by 0.85 for females) Where age is in years, weight (wt) is in kg, and serum creatinine (Scr) is in units of mg/dL [Cockcroft, 1976].
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- History of alcohol or substance abuse or dependence within 6 months of the study.
- Use of prescription or non-prescription drugs except paracetamol at doses of up to 2 grams/day, including vitamins, herbal and dietary supplements (including St. John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication until the completion of the follow-up procedure, unless in the opinion of investigator, the medication will not interfere with the study procedures or compromise subject safety; the investigator will take advice from the manufacturer representative as necessary.
- The subject has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of study medication.
- The subject is unwilling to abstain from ingesting alcohol within 48 hours prior to the first dose of study medication until collection of the final pharmacokinetic sample during each regimen.
- Subjects who have donated blood to the extent that participation in the study would result in more than 300 mL blood donated within a 30-day period. Note: This does not include plasma donation.
- Subjects who have a history of allergy to the study drug or drugs of this class, or a history of drug or other allergy that, in the opinion of the investigator, contraindicates participation in the trial. In addition, if heparin is used during pharmacokinetic sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
- Lack of suitability for participation in this study, including but not limited to, unstable medical conditions, systemic disease manifested by tendency to granulocytopenia e.g. rheumatoid arthritis and lupus erythematosus that in the opinion of the investigator would compromise their participation in the trial.
- AST or ALT > 1 x upper limit of normal (ULN).
- Subjects with history of renal disease, hepatic disease, and/or cholecystectomy
- G6PD deficient detected by Beutler's dye test.
- Abnormal methemoglobin level.
- History of antimalarial drugs use including but not limited to mefloquine, chloroquine, primaquine, artesunate, piperaquine and pyronaridine treatment within 12 months.
- Subject who received quinacrine in last 30 days.
Trial locations and contacts
1 site in 1 country.
Thailand1 site
Hospital of Tropical Diseases, Faculty of Tropical Medicine, Mahidol University
Bangkok, 10400
About this study
Official title: Open-Label Study to Evaluate Potential Pharmacokinetic Interaction of Orally Administered Primaquine and Pyronaridine-Artesunate in Healthy Adult Subjects
The observed changes of P. falciparum sensitivity to artemisinin lead to the intensification of early detection as well as treatment monitoring in malaria infection. It is widely accepted that the development of resistance can be delayed by the use of combination therapy, especially combinations that include artemisinin derivatives (acts). As the resistance problem is considered extremely serious; as a consequence, who has recommended that all monotherapy for malaria should be stopped.
Current WHO guidelines recommend that the drug combination regimens using ACT with effective partner medicines should be used to decrease the risk of development or spreading of artemisinin resistance.
Read the detailed description
Current WHO guidelines recommend that the drug combination regimens using ACT with effective partner medicines should be used to decrease the risk of development or spreading of artemisinin resistance.
Pyronaridine (PP) and artesunate (AS) are antimalarial agents with a history of clinical use both separately and in combination with other drugs. Each drug has powerful anti-schizonticidal actions. The action of artesunate is a rapid knock-down of the parasites, after which the drug is rapidly cleared as it has a short systemic half-life. Pyronaridine is also effective in the short-term but has an intermediate blood half-life thus providing a sustained schizonticidal effect. The aim of the fixed dose combination of pyronaridine and artesunate (PA or PYRAMAX®) in the treatment of uncomplicated acute malaria is to provide a rapid reduction in parasitemia with a short-term regimen, thereby improving compliance and reducing the risk of recrudescence through the slower elimination of pyronaridine. Doses have been selected to be in line with current prescribing practice for these agents when used as mono-therapy.
Primaquine (PQ) is an effective gametocytocide for P. falciparum transmission prevention and as tissue killing for the radical cure in P. vivax and P. ovale infection. It will be given only in the presence of other antimalarials, so it is necessary to study the drug interactions between primaquine, pyronaridine and artesunate. It is inevitable that in the near future, pyronaridine-artesunate (PA) and primaquine (PQ) combination treatment will become necessary. These drugs are metabolized by cytochrome P450 enzymes which potentially causes pharmacokinetic alteration and clinically significant drug-drug interactions that can lead to unanticipated adverse reactions or therapeutic failures because of the suboptimal exposure of the parasite.
This study is planned to evaluate potential pharmacokinetic interaction of orally administered primaquine and pyronaridine-artesunate (PYRAMAX®) in healthy adult subjects. The results of these interaction studies are important in order to provide clinical guidance for the optimum combination primaquine and pyronaridine-artesunate (PYRAMAX®) treatment regimens in malaria infections.
- Conditions
- Healthy
- Being tested
- Primaquine and Pyronaridine-artesunate
- Keywords
- Primaquine, Pyronaridine-artesunate
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Primaquine and Pyronaridine-artesunateDrug
Also called Pyramax
Subject will receive primaquine (PQ) then receive pyronaridine-artesunate (PA)after 1 week washout period and receive PQ together with PA for the third regimen after 8 weeks washout period
Primaquine:
- Dosage: 2 tablets and
Pyronaridine-Artesunate:
- Dosage: 3 tablets
Primaquine and Pyronaridine-ArtesunateDrug
Also called Pyramax
Subject will receive primaquine (PQ) then receive PQ together dihydroartemisinin-piperaquine (DHA-PQP) after 1 week washout period and receive DHA-PQP for the third regimen after 8 weeks washout period.
Primaquine:
- Dosage: 2 tablets and
Pyronaridine-Artesunate:
- Dosage: 3 tablets
| Study group | Role | What they receive |
|---|---|---|
| Group A | Experimental | Primaquine only followed by Pyronaridine-Artesunate and followed by Primaquine together with Pyronaridine-Artesunate. Receives: Drug: Primaquine and Pyronaridine-artesunate |
| Group B | Active comparator | Primaquine only followed by Primaquine together Pyronaridine-Artesunate and followed by Pyronaridine-Artesunate only. Receives: Drug: Primaquine and Pyronaridine-Artesunate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Area under curve for Primaquine
Area under the concentration-time curve (AUC) for primaquine when given alone or together with Pyronaridine-Artesunate.
Measured: 42 days
Area under cure for Pyronaridine-Artesunate
Area under the concentration-time curve (AUC) for pyronaridine when given alone as Pyronaridine-Artesunate (PA) or together with primaquine.
Measured: 42 days
Secondary outcomes (4)
Area under curve for Artesunate
Area under the concentration-time curve (AUC) for Artesunate/DHA when given alone as Pyronaridine-Artesunate or together with primaquine.
Measured: 42 days
Maximum concentration and Area under curve for Primaquine and its metabolites
Primaquine enantiomers and Pyronaridine Cmax; carboxyprimaquine (and other detectable major metabolites) Cmax, AUC.
Measured: 42 days
Assesment of safe and tolerability of Pyronaridine-Artesunate
Collecting number of adverse events, clinical laboratory, and vital signs assessments, ECG.
Measured: 42 days
Pharmacogenetic polymorphisms
Pharmacogenetic polymorphisms in the case of unusually high or low drug levels.
Measured: 42 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Mar 2012 (estimated)
- Study startMay 2012
- Primary completionOct 2012
- Study completionOct 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Podjanee Jittamala, MD, Principal investigator, Mahidol University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01552330
- Sponsor's protocol ID
- SP-C-016-11
- Status last verified
- Aug 2013
- First submitted
- 1 Mar 2012
- Last updated
- 28 Aug 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Jittamala P, Pukrittayakamee S, Ashley EA, Nosten F, Hanboonkunupakarn B, Lee SJ, Thana P, Chairat K, Blessborn D, Panapipat S, White NJ, Day NP, Tarning J. Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects. Antimicrob Agents Chemother. 2015 Jan;59(1):505-13. doi: 10.1128/AAC.03829-14. Epub 2014 Nov 10.
PubMed 25385096
Study at a glance
From the registry record, last updated by the sponsor on 28 Aug 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Open-Label Study to Evaluate Potential Pharmacokinetic Interaction of Orally Administered Primaquine and Pyronaridine-Artesunate in Healthy Adult Subjects
- ClinicalTrials.gov ID
- NCT01552330
- Acronym / sponsor ID
- SP-C-016-11
- Conditions
- Healthy
- Keywords
- Primaquine, Pyronaridine-artesunate
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- May 2012
- Primary completion
- Oct 2012 (actual)
- Study completion
- Oct 2012 (actual)
- First posted
- 13 Mar 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The observed changes of P. falciparum sensitivity to artemisinin lead to the intensification of early detection as well as treatment monitoring in malaria infection. It is widely accepted that the development of resistance can be delayed by the use of combination therapy, especially combinations that include artemisinin derivatives (acts). As the resistance problem is considered extremely serious; as a consequence, who has recommended that all monotherapy for malaria should be stopped.
Current WHO guidelines recommend that the drug combination regimens using ACT with effective partner medicines should be used to decrease the risk of development or spreading of artemisinin resistance.
Detailed description
Current WHO guidelines recommend that the drug combination regimens using ACT with effective partner medicines should be used to decrease the risk of development or spreading of artemisinin resistance.
Pyronaridine (PP) and artesunate (AS) are antimalarial agents with a history of clinical use both separately and in combination with other drugs. Each drug has powerful anti-schizonticidal actions. The action of artesunate is a rapid knock-down of the parasites, after which the drug is rapidly cleared as it has a short systemic half-life. Pyronaridine is also effective in the short-term but has an intermediate blood half-life thus providing a sustained schizonticidal effect. The aim of the fixed dose combination of pyronaridine and artesunate (PA or PYRAMAX®) in the treatment of uncomplicated acute malaria is to provide a rapid reduction in parasitemia with a short-term regimen, thereby improving compliance and reducing the risk of recrudescence through the slower elimination of pyronaridine. Doses have been selected to be in line with current prescribing practice for these agents when used as mono-therapy.
Primaquine (PQ) is an effective gametocytocide for P. falciparum transmission prevention and as tissue killing for the radical cure in P. vivax and P. ovale infection. It will be given only in the presence of other antimalarials, so it is necessary to study the drug interactions between primaquine, pyronaridine and artesunate. It is inevitable that in the near future, pyronaridine-artesunate (PA) and primaquine (PQ) combination treatment will become necessary. These drugs are metabolized by cytochrome P450 enzymes which potentially causes pharmacokinetic alteration and clinically significant drug-drug interactions that can lead to unanticipated adverse reactions or therapeutic failures because of the suboptimal exposure of the parasite.
This study is planned to evaluate potential pharmacokinetic interaction of orally administered primaquine and pyronaridine-artesunate (PYRAMAX®) in healthy adult subjects. The results of these interaction studies are important in order to provide clinical guidance for the optimum combination primaquine and pyronaridine-artesunate (PYRAMAX®) treatment regimens in malaria infections.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A | Experimental | Drug: Primaquine and Pyronaridine-artesunatePrimaquine only followed by Pyronaridine-Artesunate and followed by Primaquine together with Pyronaridine-Artesunate. |
| Group B | Active comparator | Drug: Primaquine and Pyronaridine-ArtesunatePrimaquine only followed by Primaquine together Pyronaridine-Artesunate and followed by Pyronaridine-Artesunate only. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (11 listed)
- Healthy as judged by a responsible physician with no abnormality identified on a medical evaluation including medical history and physical examination.
- Males and Females aged between 18 years to 60 years.
- Males and Females weighing between 45-64 kilograms.
- A female is eligible to enter and participate in this study if she is:
- A male is eligible to enter and participate in this study if he: agrees to abstain from (or use a condom during) sexual intercourse with females of childbearing potential or lactating females; or is willing to use a condom/spermicide, during the study until completion of the follow-up procedures.
Key exclusion criteria (19 listed)
- Females who are pregnant, trying to get pregnant, or are lactating.
- The subject has evidence of active substance abuse that may compromise safety, pharmacokinetics, or ability to adhere with protocol instructions.
- A positive pre-study hepatitis B surface antigen, positive hepatitis C antibody, or positive human immunodeficiency virus-1 (HIV-1) antibody result at screening.
- Subjects with a personal history of cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes (heart failure, hypokalemia) or with a family history of sudden cardiac death.
- A creatinine clearance <70 mL/min as determined by Cockcroft-Gault equation:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Primaquine and Pyronaridine-artesunateAlso: PyramaxSubject will receive primaquine (PQ) then receive pyronaridine-artesunate (PA)after 1 week washout period and receive PQ together with PA for the third regimen after 8 weeks washout period Primaquine: - Dosage: 2 tablets and Pyronaridine-Artesunate: - Dosage: 3 tablets | Drug | Group A |
| Primaquine and Pyronaridine-ArtesunateAlso: PyramaxSubject will receive primaquine (PQ) then receive PQ together dihydroartemisinin-piperaquine (DHA-PQP) after 1 week washout period and receive DHA-PQP for the third regimen after 8 weeks washout period. Primaquine: - Dosage: 2 tablets and Pyronaridine-Artesunate: - Dosage: 3 tablets | Drug | Group B |
Primary outcome
Area under curve for Primaquine
Time frame: 42 days
Area under the concentration-time curve (AUC) for primaquine when given alone or together with Pyronaridine-Artesunate.
Area under cure for Pyronaridine-Artesunate
Time frame: 42 days
Area under the concentration-time curve (AUC) for pyronaridine when given alone as Pyronaridine-Artesunate (PA) or together with primaquine.
4 secondary outcomes
Area under curve for Artesunate
Time frame: 42 days
Maximum concentration and Area under curve for Primaquine and its metabolites
Time frame: 42 days
Assesment of safe and tolerability of Pyronaridine-Artesunate
Time frame: 42 days
Pharmacogenetic polymorphisms
Time frame: 42 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Aug 2013.
- Derived from this study: PubMed 25385096Jittamala P, Pukrittayakamee S, Ashley EA, Nosten F, Hanboonkunupakarn B, Lee SJ, Thana P, Chairat K, Blessborn D, Panapipat S, White NJ, Day NP, Tarning J. Pharmacokinetic interactions between primaquine and pyronaridine-artesunate in healthy adult Thai subjects. Antimicrob Agents Chemother. 2015 Jan;59(1):505-13. doi: 10.1128/AAC.03829-14. Epub 2014 Nov 10.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Podjanee Jittamala, MD principal investigator
Mahidol University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Primaquine and Pyronaridine-artesunate in people with Healthy, run by University of Oxford at 1 site in Thailand.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Aug 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area under curve for Primaquine (time frame: 42 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01552330, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2013.