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BioavailabilityPhase 1NCT04866602

Atoguanil BA Study

A Phase 1 study testing Atoguanil and Malarone in people with Bioavailability, run by Medicines for Malaria Venture at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This trial aims to characterise the pharmacokinetic (PK) profile and estimate drug exposure from Atoguanil in comparison to Malarone®. Read more about this study

Who is it for?
Ages 18 to 55 yearsHealthy volunteers can take part
Conditions the study is for
Bioavailability
What is being tested?
Atoguanil and Malarone
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
1 siteUnited Kingdom
Study dates
17 Nov 2021to 18 Mar 2022
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 55 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • Healthy male or female (of childbearing and non-childbearing potential) aged 18 to 55 years, inclusive. Efforts will be made to ensure a reasonable gender balance.
  • Satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination, vital signs and clinical laboratory evaluation (haematology, biochemistry, coagulation, and urinalysis) that is reasonably likely to interfere with the participant's participation in or ability to complete the trial as assessed by the Investigator.
  • Participant has a body weight of 50 to 80 kg and a body mass index (BMI) of 18.0-25.0 kg/m2, inclusive at screening.
  • All participants must comply with the contraception criteria in Section 5.5.
  • Participants must agree not to donate sperm or ova from the time of the first administration of trial medication until three months after the end of the systemic exposure of the trial drug (for this trial, this is until Day 22 of Period 2).
  • Participants are non-smokers (fewer than 100 lifetime cigarettes and zero cigarettes in the past 6 months).
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  • Participants who are able to provide written, personally signed, and dated informed consent to participate in the trial, in accordance with the ICH Good Clinical Practice (GCP) Guideline E6 (R2) (2016) and applicable regulations, before completing any trial-related procedures.
  • Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, restrictions, and other trial procedures. Participants must be willing to complete all meals, which may contain meat (in particular, the high fat, high calorie breakfast on dosing days).
  • Participants who are willing to comply with the latest site guidelines regarding COVID-19 safety precautions, measures and testing

Who cannot join

  • Female detected to be pregnant, breast feeding or who is likely to become pregnant during the trial.
  • Male participants with a female partner(s) who is (are) pregnant or lactating from the time of the administration of trial medication.
  • Evidence or history of clinically significant haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including drug or food allergies, anaphylaxis or other severe allergic reactions but excluding untreated, asymptomatic, seasonal allergies at the time of dosing).
  • Current or relevant history of physical or psychiatric illness (in particular, anxiety disorders) that may require treatment or make the participant unlikely to fully comply with the requirements or complete the trial, or any condition that presents undue risk from the investigational product or trial procedures.
  • Any surgical or medical condition possibly affecting drug absorption (e.g. cholecystectomy, gastrectomy, bowel disease, etc.), distribution, metabolism or excretion or any food intolerance.
  • Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participant at risk because of the participation in the trial may influence the result of the trial, or the participant's ability to participate in the trial.
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  • History of photosensitivity.
  • History or clinical evidence of substance and/or alcohol abuse within the 12 months before screening. Alcohol abuse is defined as regular weekly intake of more than 14 units for males and females (using alcohol tracker http://www.nhs.uk/Tools/Pages/NHSAlcoholtracker.aspx).
  • Treatment with an investigational drug within 90 days or 5 half-lives preceding the first dose of trial medication (or as determined by the local requirement, whichever is the longer).
  • Donation of blood or blood products (excluding plasma) within 90 days prior to trial medication administration.
  • Has used any medication listed on the Flockhart table (http://medicine.iupui.edu/clinpharm/ddis/main-table/) that is either a moderate or strong inhibitor or inducer of CYP450 within 30 days or 5 half-lives (whichever is longer) prior to the planned first day of dosing.
  • Additionally, participants must not have consumed other substances known to be potent inhibitors or inducers of CYP P450s . This includes food or drink products containing cranberry, pomegranate, star fruit, grapefruit, pomelos, exotic citrus fruits or Seville oranges (including marmalade and juices made from these fruits) in the two weeks before the planned first trial drug administration.
  • Has used any other prescription medication (excluding hormonal contraception, hormone replacement therapy) within 14 days or 10 half-lives (whichever is longer) prior to Day 1 of the dosing period that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
  • Has used any over-the-counter medication (including multivitamin, herbal, or homeopathic preparations; excluding paracetamol - up to 4g paracetamol per day permitted) during the 7 days or 10 half-lives of the drug (whichever is longer) prior to Day 1 of the dosing period, that the Investigator judges is likely to interfere with the trial or pose an additional risk in participating.
  • Use of herbal supplements at least 30 days prior to the first dose of trial medication.
  • Known hypersensitivity reaction to atovaquone or proguanil.
  • Any clinically significant abnormal laboratory, vital signs or other safety findings as determined by medical history, physical examination or other evaluations conducted at screening or on admission.
  • 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.
  • 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:
  • Sinus node dysfunction.
  • Clinically significant PR (PQ) interval prolongation.
  • Intermittent second- or third-degree AV block.
  • Complete bundle branch block.
  • Sustained cardiac arrhythmia's including (but not limited to) atrial fibrillation or supraventricular tachycardia; 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 (males and females).
  • Any other ECG abnormalities in the standard 12-lead ECG and 24-hour 12 lead Holter 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 investigator.
  • 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.
  • 19. Confirmed positive results from urine drug screen (amphetamines, benzodiazepines, cocaine, cannabinoids, opiates, barbiturates, and methadone) or from the alcohol breath test at screening or on admission.
  • 20. A positive human immunodeficiency virus (HIV) I and II antibodies, hepatitis B surface antigen (HBsAg), anti-Hepatitis core antibody (anti HBc Ig G [and anti HBc IgM if IgG is positive]), or hepatitis C virus (HCV) antibody at screening.
  • 21. Participants have veins unsuitable for intravenous puncture or cannulation on either arm (e.g. veins that are difficult to locate access or puncture veins with a tendency to rupture during or after puncture).
  • 22. Participants with difficulty in swallowing multiple tablets at a time.
  • 23. Any conditions which in the opinion of the Investigator would make the participant unsuitable for enrolment or could interfere with the participants' participation in or completion of the trial.
  • 24. Participants who have received or are planning on receiving a COVID-19 vaccination as per section 6.3.1.

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site

  • Richmond Pharmacology Limited

    London, SE1 1YR

Other trials in United Kingdom

About this study

Official title: A Randomised, Open Label 2-period Crossover Study to Evaluate the Relative Bioavailability of Atoguanil Compared to Malarone® in Healthy Adult Participants in the Fed State

This trial aims to characterise the pharmacokinetic (PK) profile and estimate drug exposure from Atoguanil in comparison to Malarone®.

Read the detailed description

After being informed about the study and potential risks, all adult participants giving written informed consent will be screened within 30 days prior to entering the trial on Day -1 to determine eligibility for study entry. The trial will establish whether the PK profile of both atovaquone (ATV), proguanil (PG) and cycloguanil (CG) from Atoguanil is similar to Malarone® and whether exposure of ATV from Atoguanil indicates that at least a 2-fold reduction in ATV dose compared with Malarone® is feasible (i.e. that the bioavailability of ATV in Atoguanil is approximately double that of ATV in Malarone®).

Conditions
Bioavailability
Being tested
Atoguanil, Malarone
Keywords
Pharmacokinetics, Bioavailability, Malaria prevention, Malaria
Medical subject headings
Malaria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AtoguanilDrug

    Also called Atovaquone + Proguanil

    Atovaquone + Proguanil free base:125 mg: 87 mg, 4 tablets

  • MalaroneDrug

    Also called Atovaquone + Proguanil

    Atovaquone + Proguanil HCl: 250 mg: 100 mg, 4 tablets

Study groups in NCT04866602
Study groupRoleWhat they receive
AtoguanilExperimentalAtovaquone 500 mg + Proguanil 348 mg
Receives: Drug: Atoguanil
Malarone®Active comparatorAtovaquone 1000 mg + Proguanil HCl 400 mg
Receives: Drug: Malarone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Ratio of maximum observed plasma concentration (Cmax) of ATV, PG and CG from Atoguanil in comparison to Malarone.

    Blood samples are collected at indicated time points to measure the maximum observed plasma concentration (Cmax) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods.

    Measured: ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

  2. Ratio of the area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) of ATV, PG and CG for Atoguanil compared to Malarone

    Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to last detectable plasma concentration (AUC0-t) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods

    Measured: ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

  3. Ratio of area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72h), of ATV, PG and CG for Atoguanil compared to Malarone.

    Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to 72 hours (AUC0-72h) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods

    Measured: Measured from 0 to 72 hours ATV/PG/CG evaluation: At pre-dose -1 and then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

  4. Ratio of the area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) [ATV only] for Atoguanil compared to Malarone

    Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) for pharmacokinetic analysis of ATV. Pharmacokinetic parameters are determined using standard non-compartmental methods.

    Measured: Measured from 0 to 168 hours (ATV) ATV evaluation: At pre-dose -1, and then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168 hours post-dose

  5. Ratio of the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf), of ATV, PG and CG for Atoguanil compared to Malarone

    Blood samples are collected at indicated time points to measure the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) for pharmacokinetic analysis of ATV, PG and CG. Pharmacokinetic parameters are determined using standard non-compartmental methods.

    Measured: ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Apr 2021
  2. Study start17 Nov 2021
  3. Primary completion18 Mar 2022
  4. Study completion18 Mar 2022

Resources

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
Basic science
Allocation
Randomised
Intervention model
Crossover
Model description
In Period 1, 16 participants will be enrolled and randomised to one of two treatments in a ratio of 1:1, and to the alternative treatment in Period 2, as described below: * Treatment 1: Single dose of Atoguanil . (Atovaquone 500 mg + Proguanil 348 mg administered as 4 tablets of 125 mg: 87 mg). * Treatment 2: Single dose of Malarone® . (Atovaquone 1000 mg + Proguanil HCl 400 mg administered as 4 tablets of 250 mg: 100 mg), Both doses are administered in the fed state and with 240mL of drinking water.
Masking
None (open label)
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04866602
Sponsor's protocol ID
MMV_SMC_19_02
Status last verified
May 2022
First submitted
20 Apr 2021
Last updated
5 May 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: De-Identified individual participant data for all primary and secondary outcome measures will be made available.

Publications

  • Kuemmerle A, Gossen D, Marx MW, Lorch U, Szramowska M, Kumar A, Singh D, Singh S, Ramachandruni H, Thankachen B, Kore S, Gaaloul ME, Borghini-Fuhrer I, Chalon S. A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil) versus atovaquone-proguanil hydrochloride (Malarone(R)) in healthy adult participants. Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec;397(12):9823-9832. doi: 10.1007/s00210-024-03245-x. Epub 2024 Jun 25.

    PubMed 38918235

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Atoguanil and Malarone in people with Bioavailability, run by Medicines for Malaria Venture at 1 site in United Kingdom.

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 9 inclusion and 34 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 5 May 2022. 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 United Kingdom. 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?

Ratio of maximum observed plasma concentration (Cmax) of ATV, PG and CG from Atoguanil in comparison to Malarone. (time frame: ATV evaluation: Measured pre-dose -1 hours, then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72, 168, 336, 504 hours post-dose. PG/CG evaluation: At pre-dose -1 then 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 48, 72 hours post-dose). 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?

On the ClinicalTrials.gov record for NCT04866602, 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 5 May 2022.

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