G6PD NormalPhase 1NCT01668433
Pharmacokinetic and in Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD Normal and G6PD Deficiency
A Phase 1 study testing Regimens (Primaquine, Methylene blue) in people with G6PD Normal and G6PD Deficient, run by University of Oxford at 1 site in Thailand.
Trial summary
The emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thai border and more recently on the Myanmar-Thai border jeopardizes the renewed global efforts of control and elimination of malaria. Read more about this study
- Who is it for?
- Ages 18 to 60 yearsHealthy volunteers can take part
- Conditions the study is for
- G6PD Normal, G6PD Deficient, Healthy
- What is being tested?
- Regimens (Primaquine, Methylene blue)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteThailand
- Study dates
- Jul 2013to Oct 2014
- 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
- For G6PD normal group, healthy males and females as judged by a physician with no abnormality identified on a medical evaluation including medical history and physical examination with laboratory diagnosis of G6PD normal.
- For G6PD deficient group, healthy males with laboratory diagnosis of G6PD deficiency grade 3 with enzyme activity 10-60%.
- Subjects aged between 18 years to 60 years.
- Subjects who have Hb ≥ 11 mg/dl.
- 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
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- 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
- or of childbearing potential, has a negative serum pregnancy test at screening and urine pregnancy test 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.
- Read, comprehend, and write at a sufficient level to complete study-related materials.
- 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.
- 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 hypertension, cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de points (heart failure, hypokalemia).
- Subjects 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].
- History of alcohol or substance abuse or dependence within 6 months of the study: History of regular alcohol consumption averaging >7 drinks/wk for women or >14 drinks/wk for men. One drink is equivalent to 12 g alcohol = 5 oz (150 mL) of wine or 12 oz (360 mL) of beer or 1.5 oz (45 mL) of 80 proof distilled spirits within 6 months of screening.
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- 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 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.
- The subject is unwilling to abstain from the ingestion of grapefruit containing products for 72 hours prior to the start of dosing until collection of the final pharmacokinetic sample during each period.
- 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.
- Those who, in the opinion of the investigator, have a risk of non-compliance with study procedures.
- AST or ALT >1.5 upper limit of normal (ULN).
- Subjects with history of renal disease, hepatic disease, and/or cholecystectomy.
- Abnormal methaemoglobin level.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Open Label Randomized Controlled Trial Pharmacokinetic and Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD Normal and G6PD Deficiency
The emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thai border and more recently on the Myanmar-Thai border jeopardizes the renewed global efforts of control and elimination of malaria. Containment of this severe threat requires reduction of transmission of the resistant phenotype by adding gametocytocidal drugs to the treatment of falciparum malaria. Mathematical models also predict that transmission blocking will be required if the goal of malaria elimination is to be achieved. The only drug currently available with strong gametocytocidal properties against the more mature gametocytes is primaquine. However, the oxidative properties of primaquine readily causes acute haemolysis in glucose 6 phosphate dehydrogenase (G6PD) deficiency, the degree of which appears to be inversely related to G6PD enzyme activity. Because of these safety concerns, primaquine is not widely deployed in treatment regimens for falciparum malaria, even in areas with documented artemisinin resistance. Methylene blue, which does not exert its action through an oxidative mechanism, is a promising alternative as a gametocytocidal adjuvant to artemisinin combination therapies (ACTs). Paul Ehrlich discovered methylene blue as the first synthetic drug ever to treat malaria. In contrast with primaquine, the thiazine dye methylene blue asserts its properties as an oxidizing agent only at very high doses, whereas at pharmacologic doses it has reducing agent properties and is for this reason used as a medication for the treatment of methemoglobinemia. A recent laboratory study identified methylene blue as a potent inhibitor of gametocyte development across all stages, almost fully abolishing P. falciparum transmission to mosquitoes at concentrations readily achievable in humans. In addition, a recent clinical study in 180 children with uncomplicated falciparum malaria in Burkina Faso showed that, compared to artesunate-amodiaquine alone, addition of the cheap drug methylene blue to either artesunate or amodiaquine importantly reduced gametocyte carrier rates measured at days 3, 7, and 14 of follow-up. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. The current series of studies will investigate further methylene blue as a potential gametocytocidal drug in the treatment of uncomplicated falciparum malaria.
- Conditions
- G6PD Normal, G6PD Deficient, Healthy
- Being tested
- Regimens (Primaquine, Methylene blue)
- Keywords
- G6PD, Primaquine, Methylene blue
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Regimens (Primaquine, Methylene blue)Drug
Primaquine 45 mg single dose Or Methylene Blue 600 mg single dose followed by Methylene Blue 600 mg single dose or Primaquine 45 mg single dose.
| Study group | Role | What they receive |
|---|---|---|
| G6PD Normal | Active comparator | Subjects will be given either primaquine, 45 mg single dose or methylene blue, 600 mg single dose with a washout period of 7 days then followed by either methylene blue, 600 mg single dose or primaquine, 45 mg single dose. Receives: Drug: Regimens (Primaquine, Methylene blue) |
| G6PD deficiency | Experimental | Subjects will be given either primaquine, 45 mg single dose or methylene blue, 600 mg single dose with a washout period of 7 days then followed by either methylene blue, 600 mg single dose or primaquine, 45 mg single dose. Receives: Drug: Regimens (Primaquine, Methylene blue) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacokinetic profile of Primaquine
Maximum concentration (Cmax), Area under the concentration curve (AUC 0-24), Elimination rate constant (PRQ-λz), and Elimination half life (t1/2) for primaquine when given standard dose in G6PD normal and G6PD deficiency
Measured: 7 days
Pharmacokinetic profile of Carboxyprimaquine
Maximum concentration (Cmax), area under the concentration curve (AUC 0-24), elimination rate constant (PRQ-λz), and elimination half life (t1/2) for carboxyprimaquine (primaquine metabolite) when given standard dose in G6PD normal and G6PD deficiency
Measured: 7 days
Pharmacokinetic profile of Methylene blue
Maximum concentration(Cmax), area under the concentration curve (AUC 0-24) elimination rate constant (MB-λz), and elimination half life (t1/2) for methylene blue when given standard dose in G6PD normal and G6PD deficiency
Measured: 7 days
Oocysts production in mosquitoes
Reduction of oocysts production in mosquitoes fed with gametocytes which were exposed to methylene blue and primaquine
Measured: 7 days
Methaemoglobin, Hematocrit and Hemoglobin levels
Methaemoglobin, hematocrit and hemoglobin level when given primaquine and methylene blue in G6PD normal and G6PD deficiency
Measured: 7 days
Secondary outcomes (1)
Safety of Primaquine and Methylene Blue
Safety and tolerability parameters, including adverse events, clinical laboratory, and vital signs assessments
Measured: 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Aug 2012 (estimated)
- Study startJul 2013
- Primary completionOct 2014
- Study completionOct 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for G6PD NormalStudies 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
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01668433
- Sponsor's protocol ID
- FTM1201
- Status last verified
- Nov 2015
- First submitted
- 1 Aug 2012
- Last updated
- 3 Nov 2015
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Nov 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Open Label Randomized Controlled Trial Pharmacokinetic and Vitro Transmission Blocking Activities Study of Primaquine Compare to Methylene Blue in Healthy Volunteer Both G6PD Normal and G6PD Deficiency
- ClinicalTrials.gov ID
- NCT01668433
- Acronym / sponsor ID
- FTM1201
- Conditions
- G6PD Normal, G6PD Deficient, Healthy
- Keywords
- G6PD, Primaquine, Methylene blue
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Study start
- Jul 2013
- Primary completion
- Oct 2014 (actual)
- Study completion
- Oct 2014 (actual)
- First posted
- 20 Aug 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 emergence of partial artemisinin resistance in Plasmodium falciparum on the Cambodia-Thai border and more recently on the Myanmar-Thai border jeopardizes the renewed global efforts of control and elimination of malaria. Containment of this severe threat requires reduction of transmission of the resistant phenotype by adding gametocytocidal drugs to the treatment of falciparum malaria. Mathematical models also predict that transmission blocking will be required if the goal of malaria elimination is to be achieved. The only drug currently available with strong gametocytocidal properties against the more mature gametocytes is primaquine. However, the oxidative properties of primaquine readily causes acute haemolysis in glucose 6 phosphate dehydrogenase (G6PD) deficiency, the degree of which appears to be inversely related to G6PD enzyme activity. Because of these safety concerns, primaquine is not widely deployed in treatment regimens for falciparum malaria, even in areas with documented artemisinin resistance. Methylene blue, which does not exert its action through an oxidative mechanism, is a promising alternative as a gametocytocidal adjuvant to artemisinin combination therapies (ACTs). Paul Ehrlich discovered methylene blue as the first synthetic drug ever to treat malaria. In contrast with primaquine, the thiazine dye methylene blue asserts its properties as an oxidizing agent only at very high doses, whereas at pharmacologic doses it has reducing agent properties and is for this reason used as a medication for the treatment of methemoglobinemia. A recent laboratory study identified methylene blue as a potent inhibitor of gametocyte development across all stages, almost fully abolishing P. falciparum transmission to mosquitoes at concentrations readily achievable in humans. In addition, a recent clinical study in 180 children with uncomplicated falciparum malaria in Burkina Faso showed that, compared to artesunate-amodiaquine alone, addition of the cheap drug methylene blue to either artesunate or amodiaquine importantly reduced gametocyte carrier rates measured at days 3, 7, and 14 of follow-up. This effect was seen both in patients with and without P. falciparum gametocytaemia at baseline. The current series of studies will investigate further methylene blue as a potential gametocytocidal drug in the treatment of uncomplicated falciparum malaria.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| G6PD Normal | Active comparator | Drug: Regimens (Primaquine, Methylene blue)Subjects will be given either primaquine, 45 mg single dose or methylene blue, 600 mg single dose with a washout period of 7 days then followed by either methylene blue, 600 mg single dose or primaquine, 45 mg single dose. |
| G6PD deficiency | Experimental | Drug: Regimens (Primaquine, Methylene blue)Subjects will be given either primaquine, 45 mg single dose or methylene blue, 600 mg single dose with a washout period of 7 days then followed by either methylene blue, 600 mg single dose or primaquine, 45 mg single dose. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- For G6PD normal group, healthy males and females as judged by a physician with no abnormality identified on a medical evaluation including medical history and physical examination with laboratory diagnosis of G6PD normal.
- For G6PD deficient group, healthy males with laboratory diagnosis of G6PD deficiency grade 3 with enzyme activity 10-60%.
- Subjects aged between 18 years to 60 years.
- Subjects who have Hb ≥ 11 mg/dl.
- A female is eligible to enter and participate in this study if she is:
Key exclusion criteria (16 listed)
- Females who are pregnant, trying to get pregnant, or are lactating.
- 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 hypertension, cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de points (heart failure, hypokalemia).
- Subjects 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].
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 |
|---|---|---|
| Regimens (Primaquine, Methylene blue)Primaquine 45 mg single dose Or Methylene Blue 600 mg single dose followed by Methylene Blue 600 mg single dose or Primaquine 45 mg single dose. | Drug | G6PD Normal, G6PD deficiency |
Primary outcome
Pharmacokinetic profile of Primaquine
Time frame: 7 days
Maximum concentration (Cmax), Area under the concentration curve (AUC 0-24), Elimination rate constant (PRQ-λz), and Elimination half life (t1/2) for primaquine when given standard dose in G6PD normal and G6PD deficiency
Pharmacokinetic profile of Carboxyprimaquine
Time frame: 7 days
Maximum concentration (Cmax), area under the concentration curve (AUC 0-24), elimination rate constant (PRQ-λz), and elimination half life (t1/2) for carboxyprimaquine (primaquine metabolite) when given standard dose in G6PD normal and G6PD deficiency
Pharmacokinetic profile of Methylene blue
Time frame: 7 days
Maximum concentration(Cmax), area under the concentration curve (AUC 0-24) elimination rate constant (MB-λz), and elimination half life (t1/2) for methylene blue when given standard dose in G6PD normal and G6PD deficiency
Oocysts production in mosquitoes
Time frame: 7 days
Reduction of oocysts production in mosquitoes fed with gametocytes which were exposed to methylene blue and primaquine
Methaemoglobin, Hematocrit and Hemoglobin levels
Time frame: 7 days
Methaemoglobin, hematocrit and hemoglobin level when given primaquine and methylene blue in G6PD normal and G6PD deficiency
1 secondary outcome
Safety of Primaquine and Methylene Blue
Time frame: 1 month
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 3 Nov 2015.
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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.
The record lists no contact. Use the official record to reach the sponsor.
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 Regimens (Primaquine, Methylene blue) in people with G6PD Normal and G6PD Deficient, 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 12 inclusion and 16 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 3 Nov 2015. 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?
Pharmacokinetic profile of Primaquine (time frame: 7 days). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 3 Nov 2015.