MalariaPhase 2NCT02880241
MMV390048 POC in Patients With P. Vivax and P. Falciparum Malaria
A Phase 2 study testing MMV390048 in people with Malaria, run by Medicines for Malaria Venture at 2 sites in Ethiopia.
Trial summary
The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Malaria
- What is being tested?
- MMV390048
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 2 sitesEthiopia
- Study dates
- 20 Oct 2017to 24 Sep 2018
- Phase
- Phase 2
- 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
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Body weight between 40 kg and 90 kg inclusive
- Presence of P. vivax or P. falciparum monoinfection confirmed by:
- Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature ≥38°C, or history of fever in the previous 48 hours for P. vivax and 24 hours for P. falciparum and,
- Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood
- Written informed consent provided by the patient in accordance with local practice. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations.
- Ability to swallow oral medication
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- The patient is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned
- Willing to be hospitalized for at least 72 hours or until malarial parasites are not detected by microscopy on 2 consecutive occasions whichever comes later and return to clinic for all follow-up visits
- Women must be of non-childbearing potential (WNCBP) as per one of the following definitions:
- postmenopausal defined as having age-appropriate, natural (spontaneous) amenorrhea for at least 12 months prior to screening in the absence of an alternative medical cause for the amenorrhea, or
- premenopausal with irreversible surgical sterilization by hysterectomy and/or bilateral oophorectomy or salpingectomy at least 6 months prior to screening (as determined by subject medical history)
- Sexually active men must agree to comply with strict appropriate contraception rules (barrier contraception, e.g. condom) or complete abstinence when this is in line with the preferred and usual lifestyle of the patient. The contraception coverage in this situation should ensure full elimination of MMV390048, i.e. until 120 days after MMV390048 administration to the enrolled male patient (covering a full sperm cycle of 90 days starting after 5 x t½ of the drug). Abstinent patients must agree to use the above-mentioned contraceptive methods if they start sexual relationships during the study, and to continue these methods until 120 days after study medication.
Who cannot join
- Patients with signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2012
- Mixed Plasmodium infection
- Vomiting more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or diarrhea equivalent to three or more watery stools per day
- Women who are nursing (lactating)
- Presence of other serious or chronic clinical condition requiring hospitalisation
- Severe malnutrition (defined as a body mass index [BMI] of less than 16 kg/m2 as per local guidelines)
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- Presence of concurrent febrile illness (e.g. typhoid fever)
- Known history or evidence of clinically significant:
- cardiovascular disease (including arrhythmia, QTcF interval >450 msec, personal or family history of long QT syndrome, PR interval >200msec; any relevant intra-ventricular heart block [QRS >120msec]),
- respiratory conditions (including active tuberculosis),
- history of jaundice or other hepatic dysfunction,
- renal insufficiency,
- gastrointestinal disorder, or any condition that may affect absorption of the study medication (e.g. vomiting or diarrhea),
- immunological disorders (including known pre-existing HIV infection),
- endocrine disorders (including any type of diabetes mellitus whether controlled or not, diabetes insipidus, uncontrolled hypo- or hyperthyroidism, endocrine reproductive disorders not requiring concurrent medication, disorders of adrenal function),
- infectious conditions (other than minor skin or soft tissue infections or confirmed minor lower urinary tract infection),
- malignancy,
- psychiatric or neurological disorders (including a history of convulsions, major head trauma, focal neurological signs, psychosis, bipolar or major depressive disorder), or
- any other disorder or condition that in the opinion of the investigator may render the patient unfit for participation in the trial, may limit his/her ability to provide informed consent, may interfere with protocol adherence or place the patient at increased risk through participation in the study
- Known to have any of the following markers of active hepatitis:
- Hepatitis A IgM (HAV-IgM),
- Hepatitis B surface antigen (HBsAg), or
- Hepatitis C antibody (HCV Ab) and HCV RNA
- Have received any antimalarial treatment (alone or in combination) during the following periods before screening (list of prohibited medication is provided in Appendix 2):
- Piperaquine, mefloquine, naphthoquine or sulphadoxine-pyrimethamine within 6 weeks prior to screening
- Amodiaquine, chloroquine, pyronaridine or tafenoquine within 4 weeks prior to screening
- Any artemisinin derivative (artesunate, artemether, arteether or dihydroartemisinin), quinine, halofantrine, lumefantrine and any other anti-malarial treatment or antibiotic with antimalarial activity (including cotrimoxazole, tetracyclines, quinolones and fluoroquinolones and azithromycin) within 14 days prior to screening
- Any herbal products or traditional medicines during the 7 days prior to screening
- Receipt of an investigational drug within 8 weeks or 5 half-lives (whichever is longer) prior to screening
- Current participation in any other clinical trial
- A history of regular abuse of alcohol, or use of drugs of abuse during the past 6 months, or any clinical signs of substance abuse
- Neutrophil count <1,000/µL
- Elevated liver function tests as follows:
- AST/ALT >2 x the upper limit of normal (ULN), regardless of the level of total bilirubin
- AST/ALT >1.5 and ≤2 x ULN and total bilirubin >ULN
- AST/ALT >ULN and ≤1.5 x ULN
- and total bilirubin >1.5 and ≤2 x ULN,
- and conjugated bilirubin ≥35% of the total bilirubin
- Total bilirubin >2 x ULN, regardless of the level of AST/ALT
- Hb level <8g/dL
- Serum creatinine levels >2 x ULN
- Platelet level <50,000/mm3.
Trial locations and contacts
2 sites in 1 country.
Ethiopia2 sites
University of Gondar Hospital/Maksegnit Health Centre
Gonder, Amhara, 6200
Jimma University Referral Hospital/Agaro District Hospital
Jimma, Oromiya
About this study
Official title: An Open Label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose of MMV390048 in Adult Patients With Acute, Uncomplicated Plasmodium Vivax or Falciparum Malaria Monoinfection Over a 35 Day Period
The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub-type. The results of this trial will identify active, well-tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.
Read the detailed description
The present Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human IBSM human challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub type.
The results of this trial will identify active, well tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.
Preclinical studies using SCID mice inoculated with P. falciparum-infected red blood cells link doses and exposures to the efficacy of MMV390048.38 The active dose in the SCID model causing maximum effect (ED90) against the parasites is 1 mg/kg/day. The MPC derived from the SCID data was 39 ng/ml.39 A human dose for the treatment of P. falciparum was sought that could maintain blood concentrations above 39 ng/ml (100 nM) for 8 days. Assuming linear pharmacokinetics and based on observed data from the Phase I exploratory formulation study in human volunteers, a dose of approximately 20 mg would be estimated to achieve the pharmacodynamic target drug concentration in humans based on the preclinical efficacy data generated in the SCID mice model. For new antimalarial drugs the translation of a predicted efficacious dose from the SCID mouse to the human challenge model and in turn to the treatment of acute, uncomplicated P. vivax or P. falciparum is unknown. To minimise the risk to patients and to ensure the highest probability of success, the maximum safe dose (as determined in healthy volunteers) that maintains a toxicokinetic safety margin to the repeat dose studies was selected for the first cohort in this study. This dose is expected to exceed the predicted MPC on Day 8 and provide significant target coverage at the site of action.
- Conditions
- Malaria
- Being tested
- MMV390048
- Medical subject headings
- Malaria
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MMV390048Drug
Tablets of 20mg each
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1A - P. vivax malaria | Experimental | A single oral dose of up to 120mg MMV390048 Receives: Drug: MMV390048 |
| Cohort 1B - P. falciparum malaria | Experimental | A single oral dose of up to 120mg MMV390048 Receives: Drug: MMV390048 |
| Cohort 2A - P. vivax malaria | Experimental | A single oral dose (to be determined) of MMV390048 Receives: Drug: MMV390048 |
| Cohort 2B - P. falciparum malaria | Experimental | A single oral dose (to be determined) of MMV390048 Receives: Drug: MMV390048 |
| Cohort 3A - P. vivax malaria | Experimental | A single oral dose (to be determined) of MMV390048 Receives: Drug: MMV390048 |
| Cohort 3B - P. falciparum malaria | Experimental | A single oral dose (to be determined) of MMV390048 Receives: Drug: MMV390048 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) for P. Vivax
The absence of parasitaemia (thick smear) on Day 14, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure. Parasitaemia was defined as a P. vivax asexual forms count >0
Measured: On Day 14 post-dose
For P. Falciparum: PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)
Number of participants meeting PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)
Measured: On Day 14 post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Aug 2016 (estimated)
- Study start20 Oct 2017
- Primary completion1 Jan 2018
- Study completion24 Sep 2018
Why it stopped: Due to a Medicines for Malaria Venture (MMV) strategic business decision
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 (1)Papers the sponsor has linked to this study.
- Other trials for MalariaStudies 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 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- Medicines for Malaria Venture
- Sponsor type
- University, hospital or other
- Collaborators
- University of Gondar, Jimma University
- Responsible party
- Sponsor
- Investigators
- Esayas Gudina, MD, Principal investigator, Jimma UniversityMezgebu Silamsaw, MD, Principal investigator, University of Gondar
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02880241
- Sponsor's protocol ID
- MMV_MMV390048_16_02
- Status last verified
- Oct 2021
- First submitted
- 23 Aug 2016
- Last updated
- 9 Dec 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Mohammed R, Asres MS, Gudina EK, Adissu W, Johnstone H, Marrast AC, Donini C, Duparc S, Yilma D. Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria. Am J Trop Med Hyg. 2022 Dec 5;108(1):81-84. doi: 10.4269/ajtmh.22-0567. Print 2023 Jan 11.
PubMed 36509063
Study at a glance
From the registry record, last updated by the sponsor on 9 Dec 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open Label Study to Assess the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose of MMV390048 in Adult Patients With Acute, Uncomplicated Plasmodium Vivax or Falciparum Malaria Monoinfection Over a 35 Day Period
- ClinicalTrials.gov ID
- NCT02880241
- Acronym / sponsor ID
- MMV_MMV390048_16_02
- Conditions
- Malaria
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to a Medicines for Malaria Venture (MMV) strategic business decision
- Enrolment
- 8 participants (actual)
- Lead sponsor
- Medicines for Malaria VentureUniversity, hospital or other
- Collaborators
- University of Gondar, Jimma University
- Study start
- 20 Oct 2017 (actual)
- Primary completion
- 1 Jan 2018 (actual)
- Study completion
- 24 Sep 2018 (actual)
- First posted
- 26 Aug 2016 (estimated)
- Results
- Posted 9 Dec 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The present proof-of-concept Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human Induced Blood-Stage Malaria (IBSM) challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub-type. The results of this trial will identify active, well-tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.
Detailed description
The present Phase IIa study aims to confirm, in patients, the observed activity of MMV390048 against P. falciparum in pre-clinical models and the human IBSM human challenge model, and to determine the activity against P. vivax malaria in patients, both over 14 and 28 days. Additional aims are to characterise the safety of MMV390048 in patients. Patient safety will be monitored for up to 35 days post-dose including pharmacokinetic assessments. The study will investigate descending single doses of MMV390048 in response to results obtained in the first cohort/dose in each malaria sub type.
The results of this trial will identify active, well tolerated doses for investigation in combination with a partner drug within a Phase IIb clinical trial.
Preclinical studies using SCID mice inoculated with P. falciparum-infected red blood cells link doses and exposures to the efficacy of MMV390048.38 The active dose in the SCID model causing maximum effect (ED90) against the parasites is 1 mg/kg/day. The MPC derived from the SCID data was 39 ng/ml.39 A human dose for the treatment of P. falciparum was sought that could maintain blood concentrations above 39 ng/ml (100 nM) for 8 days. Assuming linear pharmacokinetics and based on observed data from the Phase I exploratory formulation study in human volunteers, a dose of approximately 20 mg would be estimated to achieve the pharmacodynamic target drug concentration in humans based on the preclinical efficacy data generated in the SCID mice model. For new antimalarial drugs the translation of a predicted efficacious dose from the SCID mouse to the human challenge model and in turn to the treatment of acute, uncomplicated P. vivax or P. falciparum is unknown. To minimise the risk to patients and to ensure the highest probability of success, the maximum safe dose (as determined in healthy volunteers) that maintains a toxicokinetic safety margin to the repeat dose studies was selected for the first cohort in this study. This dose is expected to exceed the predicted MPC on Day 8 and provide significant target coverage at the site of action.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Cohort 1A - P. vivax malaria | Experimental | Drug: MMV390048A single oral dose of up to 120mg MMV390048 |
| Cohort 1B - P. falciparum malaria | Experimental | Drug: MMV390048A single oral dose of up to 120mg MMV390048 |
| Cohort 2A - P. vivax malaria | Experimental | Drug: MMV390048A single oral dose (to be determined) of MMV390048 |
| Cohort 2B - P. falciparum malaria | Experimental | Drug: MMV390048A single oral dose (to be determined) of MMV390048 |
| Cohort 3A - P. vivax malaria | Experimental | Drug: MMV390048A single oral dose (to be determined) of MMV390048 |
| Cohort 3B - P. falciparum malaria | Experimental | Drug: MMV390048A single oral dose (to be determined) of MMV390048 |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (12 listed)
- Body weight between 40 kg and 90 kg inclusive
- Presence of P. vivax or P. falciparum monoinfection confirmed by:
- Fever, as defined by axillary temperature ≥37.5°C or oral/rectal/tympanic temperature ≥38°C, or history of fever in the previous 48 hours for P. vivax and 24 hours for P. falciparum and,
- Microscopically confirmed parasite infection: 1,000 to 40,000 asexual parasite count/µL blood
- Written informed consent provided by the patient in accordance with local practice. If the patient is unable to write, witnessed consent is permitted according to local ethical considerations.
Key exclusion criteria (42 listed)
- Patients with signs and symptoms of severe / complicated malaria according to the World Health Organisation Criteria 2012
- Mixed Plasmodium infection
- Vomiting more than three times in the 24 hours prior to inclusion in the study or inability to tolerate oral treatment, or diarrhea equivalent to three or more watery stools per day
- Women who are nursing (lactating)
- Presence of other serious or chronic clinical condition requiring hospitalisation
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 |
|---|---|---|
| MMV390048Tablets of 20mg each | Drug | Cohort 1A - P. vivax malaria, Cohort 1B - P. falciparum malaria, Cohort 2A - P. vivax malaria, Cohort 2B - P. falciparum malaria, Cohort 3A - P. vivax malaria, Cohort 3B - P. falciparum malaria |
Primary outcome
Number of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) for P. Vivax
Time frame: On Day 14 post-dose
The absence of parasitaemia (thick smear) on Day 14, irrespective of axillary temperature, in patients who did not previously meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure. Parasitaemia was defined as a P. vivax asexual forms count >0
For P. Falciparum: PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)
Time frame: On Day 14 post-dose
Number of participants meeting PCR-adjusted Crude Adequate Clinical and Parasitological Response (ACPR)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Dec 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 36509063Mohammed R, Asres MS, Gudina EK, Adissu W, Johnstone H, Marrast AC, Donini C, Duparc S, Yilma D. Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria. Am J Trop Med Hyg. 2022 Dec 5;108(1):81-84. doi: 10.4269/ajtmh.22-0567. Print 2023 Jan 11.
- Individual participant dataSharing planned: No
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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.
Esayas Gudina, MD principal investigator
Jimma University
Mezgebu Silamsaw, MD principal investigator
University of Gondar
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing MMV390048 in people with Malaria, run by Medicines for Malaria Venture at 2 sites in Ethiopia.
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 42 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 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Ethiopia. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 Dec 2021). 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?
Number of Participants With Crude Adequate Clinical and Parasitological Response (ACPR) for P. Vivax (time frame: On Day 14 post-dose). 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 NCT02880241, 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 9 Dec 2021.