Malaria, FalciparumPhase 1NCT02281344
MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants
A Phase 1 study testing MMV390048 20mg in people with Malaria, Falciparum, run by Medicines for Malaria Venture at 1 site in Australia.
Trial summary
A single-centre, open-label, study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection. Read more about this study
- Who is it for?
- Ages 18 to 55 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Malaria, Falciparum
- What is being tested?
- MMV390048 20mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteAustralia
- Study dates
- Oct 2014to 19 Dec 2014
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Participants who do not live alone from Day 0 until at least the end of the antimalarial drug treatment, and are contactable and available for the duration of the trial (≤4 months)
- Body weight ≥50kg, body mass index between 18.0 and 32.0 kg/m2, inclusive
- Healthy by clinical assessment
- Normal vital signs
- Normal 12-lead electrocardiogram
- Lab tests in normal range
- Agrees to use a double barrier method of contraception including condom plus diaphragm or condom plus intrauterine device or condom plus stable oral / transdermal / injectable hormonal contraceptive by female partner for ≥14 days prior to the first dose of study drug until 90 days after the last dose
- Written informed consent before any study procedure
Who cannot join
- History of malaria or participation in a previous malaria challenge study
- Must not have travelled to or lived >2 weeks in a malaria-endemic area in past 12 months nor plan to travel to one during study
- Evidence of increased cardiovascular disease risk
- History of splenectomy
- Presence / history of drug hypersensitivity, or allergic disease diagnosed and treated or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion
- Presence of current / suspected serious chronic diseases such as cardiac or autoimmune disease, diabetes, progressive neurological disease, severe malnutrition, acute or progressive hepatic or renal disease, psoriasis, rheumatoid arthritis, asthma, epilepsy or obsessive compulsive disorder, skin carcinoma excluding non-spreadable skin cancers such as basal cell and squamous cell carcinoma, schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis
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- History of photosensitivity
- History of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis, including depression or receiving psychiatric drugs or hospitalized in past 5 yrs for psychiatric illness, history of suicide attempt or confinement for danger to self/others
- Frequent headache and/or migraine, recurrent nausea, and/or vomiting (≥2 / month)
- Acute infectious disease/fever in 5 days pre-inoculation with malaria parasites
- Acute illness in 4 weeks pre-screening which may compromise subject safety
- Any significant intercurrent disease, in particular liver, renal, cardiac, pulmonary, neurologic, rheumatologic, or autoimmune disease by history, physical exam or lab test
- Clinically significant disease or any condition that might affect drug absorption distribution or excretion
- Participation in any investigational study in last 12 weeks
- Any blood sampling/donation in last 8 weeks
- Unwilling to defer blood donation for 6 months
- Any blood donation, in 1 month before inclusion.
- Medical requirement for intravenous immunoglobulin or blood transfusion
- Ever had a blood transfusion
- Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension
- History or presence of alcohol abuse (≥40g per day) or drug habituation, or any prior intravenous use of an illicit substance
- Smoking ≥5 cigarettes or equivalent /day and unable to stop smoking during confinement period
- Poppy seeds in 24h pre-screening
- Excessive consumption of xanthine bases, including red bull, chocolate
- Any medication (including St John's Wort) in 14 days pre-study or within 5 times the medication half-life if longer
- Vaccination in the last 28 days
- Any corticosteroids, anti-inflammatory, immunomodulators or anticoagulants. Any currently or previous immunosuppressive therapy, including systemic steroids including adrenocorticotrophic hormone or inhaled steroids in dosages associated with hypothalamic-pituitary-adrenal axis suppression or chronic use of inhaled high potency corticosteroids
- Recent or current systemic therapy with an antibiotic / potential antimalarial
- Likely to be noncompliant, or unable to cooperate
- Not contactable in case of emergency throughout and for 2 weeks after end of study
- Staff directly involved in study conduct
- Without good peripheral venous access
- Positive for: hepatitis B surface antigen, anti-hepatitis B core antibodies, anti-hepatitis C virus antibodies, or anti-human immunodeficiency virus 1/2 antibodies
- glucose-6-phosphate dehydrogenase deficiency
- Positive urine drug screen or alcohol urine or breath test
- Cardiac/QT risk: Known pre-existing prolongation of the QTcB/QTcF interval considered clinically significant. Family history of sudden death or of congenital prolongation of the corrected QT interval interval or known congenital prolongation of the corrected QT interval or any clinical condition known to prolong the corrected QT interval interval. History of symptomatic cardiac arrhythmias or with clinically relevant bradycardia. Electrolyte disturbances, particularly hypokalaemia, hypocalcaemia or hypomagnesaemia. Clinically relevant 12-lead electrocardiogram abnormality at screening or which will interfere with the analysis, or history of clinically significant abnormalities
- Known hypersensitivity to MMV390048 or any of its excipients or 4-aminoquinolines, artemether or other artemisinin derivatives, lumefantrine, or other arylaminoalcohols
- Unwillingness to abstain from citrus (grapefruit, Seville orange, etc.) or juice, as well as quinine containing foods/beverages for the study period
- Lactose intolerance
- Unwilling to restrict exposure to direct sunlight during the study. Must use sunglasses and sunblock for the study period
Trial locations and contacts
1 site in 1 country.
Australia1 site
Q-Pharm Clinics, Royal Brisbane and Women's Hospital
Brisbane, Queensland, 4006
About this study
Official title: A Proof-of-concept Study to Assess the Effect of MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants.
A single-centre, open-label, study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection.
Read the detailed description
Study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection. There will be two or more cohorts of 8 subjects. In the first cohort a single dose of 20 mg of MMV390048 will be investigated. Depending on the data obtained, the dose in Cohort 2 may be adjusted but will not exceed the maximum tolerated dose (or highest achieved dose based on a predefined exposure cap) as determined in an ongoing single ascending dose study. Each participant will be inoculated on Day 0 with ~1,800 viable parasites of Plasmodium falciparum-infected human erythrocytes intravenously. On an outpatient basis, participants will be monitored daily until positive for presence of malaria parasites. Once positive they will be monitored twice-daily until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when quantification of all participants is ≥ 1,000 parasites/mL. If the quantification of any participant is ≥ 5,000 parasites/mL, and is accompanied by a clinical symptom score >5, or if clinical or parasitological evidence of malaria occurs in any participant before all participants have reached the treatment threshold (quantification of ≥ 1,000), then treatment of that participant will begin within a 24 h period.
Following treatment with MMV390048, participants will be followed up as inpatients for at least 72 hours to ensure tolerance of the treatment and clinical response, then on an outpatient basis if clinically well for monitoring of safety and clearance of malaria parasites. Compulsory treatment with Riamet® (artemether-lumefantrine) will start on day 16 (±3 days) post study treatment unless required earlier. Early intervention can occur if either poor responses or fast responses are seen following MMV390048 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. Pre-emptive treatment with Riamet® can commence whenever necessary. Participants will be treated with a single dose (45 mg) of primaquine (Primacin™) at the end of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present.
- Conditions
- Malaria, Falciparum
- Being tested
- MMV390048 20mg
- Keywords
- induced blood stage malaria infection
- Medical subject headings
- Malaria, Falciparum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MMV390048 20mgDrug
Supplied as a powder to be prepared as a suspension for oral use
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1 | Experimental | Cohort 1 will receive a single dose of 20mg MMV390048. Receives: Drug: MMV390048 20mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose
Pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites.
The area under the plasma concentration time curve from time zero to the last measured time point.
Measured: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
Secondary outcomes (3)
Parasite Reduction Rate (PRR) Following MMV390048 Treatment
The clearance of malaria parasitemia by Polymerase Chain Reaction (PCR) measurement.
Measured: From dosing up to Day 21 Post-dose
MMV390048 Maximum Plasma Concentration (Cmax)
Maximum Plasma Concentration (Cmax) of MMV390048
Measured: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
MMV390048 Time to Maximum Plasma Concentration (Tmax)
Time to Maximum Plasma Concentration (Tmax) of MMV390048
Measured: From dosing up to Day 21 Post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Nov 2014 (estimated)
- Study startOct 2014
- Primary completion19 Dec 2014
- Study completion19 Dec 2014
Why it stopped: Inconsistent and unpredictable exposures were observed. Drug needed to be reformulated.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Malaria, FalciparumStudies of the same condition, open and under way.
- 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
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medicines for Malaria Venture
- Sponsor type
- University, hospital or other
- Collaborators
- Q-Pharm Pty Limited
- Responsible party
- Sponsor
- Investigators
- James McCarthy, Dr., Principal investigator, Q-Pharm Pty Limited
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02281344
- Sponsor's protocol ID
- QP14C11
- Status last verified
- May 2020
- First submitted
- 30 Oct 2014
- Last updated
- 9 Jun 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Sinxadi P, Donini C, Johnstone H, Langdon G, Wiesner L, Allen E, Duparc S, Chalon S, McCarthy JS, Lorch U, Chibale K, Mohrle J, Barnes KI. Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers. Antimicrob Agents Chemother. 2020 Mar 24;64(4):e01896-19. doi: 10.1128/AAC.01896-19. Print 2020 Mar 24.
PubMed 31932368Burel JG, Apte SH, McCarthy JS, Doolan DL. Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential. PLoS Negl Trop Dis. 2016 Dec 8;10(12):e0005031. doi: 10.1371/journal.pntd.0005031. eCollection 2016 Dec.
PubMed 27930660
Study at a glance
From the registry record, last updated by the sponsor on 9 Jun 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Proof-of-concept Study to Assess the Effect of MMV390048 Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Participants.
- ClinicalTrials.gov ID
- NCT02281344
- Acronym / sponsor ID
- QP14C11
- Conditions
- Malaria, Falciparum
- Keywords
- induced blood stage malaria infection
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Inconsistent and unpredictable exposures were observed. Drug needed to be reformulated.
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Medicines for Malaria VentureUniversity, hospital or other
- Collaborators
- Q-Pharm Pty Limited
- Study start
- Oct 2014 (actual)
- Primary completion
- 19 Dec 2014 (actual)
- Study completion
- 19 Dec 2014 (actual)
- First posted
- 3 Nov 2014 (estimated)
- Results
- Posted 9 Jun 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A single-centre, open-label, study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection.
Detailed description
Study using induced blood stage malaria infection to characterize the activity of MMV390048 against early Plasmodium falciparum blood stage infection. There will be two or more cohorts of 8 subjects. In the first cohort a single dose of 20 mg of MMV390048 will be investigated. Depending on the data obtained, the dose in Cohort 2 may be adjusted but will not exceed the maximum tolerated dose (or highest achieved dose based on a predefined exposure cap) as determined in an ongoing single ascending dose study. Each participant will be inoculated on Day 0 with ~1,800 viable parasites of Plasmodium falciparum-infected human erythrocytes intravenously. On an outpatient basis, participants will be monitored daily until positive for presence of malaria parasites. Once positive they will be monitored twice-daily until treatment, for adverse events and the unexpected early onset of symptoms, signs or parasitological evidence of malaria. On the day designated for commencement of treatment, participants will be admitted to the study unit and monitored. The threshold for commencement of treatment will be when quantification of all participants is ≥ 1,000 parasites/mL. If the quantification of any participant is ≥ 5,000 parasites/mL, and is accompanied by a clinical symptom score >5, or if clinical or parasitological evidence of malaria occurs in any participant before all participants have reached the treatment threshold (quantification of ≥ 1,000), then treatment of that participant will begin within a 24 h period.
Following treatment with MMV390048, participants will be followed up as inpatients for at least 72 hours to ensure tolerance of the treatment and clinical response, then on an outpatient basis if clinically well for monitoring of safety and clearance of malaria parasites. Compulsory treatment with Riamet® (artemether-lumefantrine) will start on day 16 (±3 days) post study treatment unless required earlier. Early intervention can occur if either poor responses or fast responses are seen following MMV390048 treatment. This is to ensure participant safety and to avoid participant inconvenience if useful data cannot be obtained. Pre-emptive treatment with Riamet® can commence whenever necessary. Participants will be treated with a single dose (45 mg) of primaquine (Primacin™) at the end of their Riamet® treatment if gametocytes are identified, to ensure complete clearance of any gametocytes present.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 | Experimental | Drug: MMV390048 20mgCohort 1 will receive a single dose of 20mg MMV390048. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Participants who do not live alone from Day 0 until at least the end of the antimalarial drug treatment, and are contactable and available for the duration of the trial (≤4 months)
- Body weight ≥50kg, body mass index between 18.0 and 32.0 kg/m2, inclusive
- Healthy by clinical assessment
- Normal vital signs
- Normal 12-lead electrocardiogram
Key exclusion criteria (40 listed)
- History of malaria or participation in a previous malaria challenge study
- Must not have travelled to or lived >2 weeks in a malaria-endemic area in past 12 months nor plan to travel to one during study
- Evidence of increased cardiovascular disease risk
- History of splenectomy
- Presence / history of drug hypersensitivity, or allergic disease diagnosed and treated or history of a severe allergic reaction, anaphylaxis or convulsions following any vaccination or infusion
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 |
|---|---|---|
| MMV390048 20mgSupplied as a powder to be prepared as a suspension for oral use | Drug | Cohort 1 |
Primary outcome
MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose
Time frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
Pharmacokinetic-pharmacodynamic relationship of MMV390048 on clearance of Plasmodium falciparum parasites from the blood in healthy participants following infection with blood stage parasites. The area under the plasma concentration time curve from time zero to the last measured time point.
3 secondary outcomes
Parasite Reduction Rate (PRR) Following MMV390048 Treatment
Time frame: From dosing up to Day 21 Post-dose
MMV390048 Maximum Plasma Concentration (Cmax)
Time frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.
MMV390048 Time to Maximum Plasma Concentration (Tmax)
Time frame: From dosing up to Day 21 Post-dose
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Jun 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 31932368Sinxadi P, Donini C, Johnstone H, Langdon G, Wiesner L, Allen E, Duparc S, Chalon S, McCarthy JS, Lorch U, Chibale K, Mohrle J, Barnes KI. Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers. Antimicrob Agents Chemother. 2020 Mar 24;64(4):e01896-19. doi: 10.1128/AAC.01896-19. Print 2020 Mar 24.
- Derived from this study: PubMed 27930660Burel JG, Apte SH, McCarthy JS, Doolan DL. Plasmodium vivax but Not Plasmodium falciparum Blood-Stage Infection in Humans Is Associated with the Expansion of a CD8+ T Cell Population with Cytotoxic Potential. PLoS Negl Trop Dis. 2016 Dec 8;10(12):e0005031. doi: 10.1371/journal.pntd.0005031. eCollection 2016 Dec.
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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.
James McCarthy, Dr. principal investigator
Q-Pharm Pty Limited
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 MMV390048 20mg in people with Malaria, Falciparum, run by Medicines for Malaria Venture at 1 site in Australia.
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 8 inclusion and 40 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: stopped early, as of the sponsor's last update on 9 Jun 2020. 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 Australia. 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?
Yes. Results are posted in the registry (first posted 9 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
MMV390048 Area Under the Plasma Concentration Versus Time Curve (AUClast) up to Day 21 Post-dose (time frame: At pre-dose, and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 (D1), 30, 36, 48 (D2), 72 (D3), and 144 hours (D6) and Days 8, 10, 14, 18 and D21.). 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 NCT02281344, which also lists 2 linked publications.
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 9 Jun 2020.