AzTrials
AzTrials

Malaria,FalciparumCHMI-trans2NCT03454048

Controlled Human Malaria Infection Model for Evaluation of Transmission-blocking Interventions - Study 2

A study testing Piperaquine (low dose), Piperaquine (high dose) and Sulfadoxine pyrimethamine in people with Malaria,Falciparum and Gametocytes, run by Radboud University Medical Center at 1 site in Netherlands.

Completed

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

Official record
Search all trials

Trial summary

This is a single-center, open label study. The primary aim of this project is to develop a controlled human malaria infection transmission model ("CHMI-trans") or "challenge model" to evaluate the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs to block malaria parasite transmission by… Read more about this study

Who is it for?
Ages 18 to 35 yearsHealthy volunteers can take part
What is being tested?
Piperaquine (low dose), Piperaquine (high dose) and Sulfadoxine pyrimethamine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
1 siteNetherlands
Study dates
7 May 2018to 20 Nov 2018
Phase
Interventional
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 35 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • In order to be eligible to participate in this study, a subject must meet all of the following criteria:
  • Subject is aged ≥ 18 and ≤ 35 years and in good health.
  • Subject has adequate understanding of the procedures of the study and is able and willing (in the investigator's opinion) to comply with all study requirements.
  • Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly.
  • Subject is able to communicate well with the investigator and is available to attend all study visits, lives in proximity to the trial centre (<10 km) or (if >10km) is willing to stay in a hotel close to the trial centre during part of the study (from day 4 (blood stage challenge) 5 (sporozoite challenge) post-infection until T1+4 provided that the subject has had 2 consecutive negative 18S qPCR tests (at least 24 hours apart) following T1 treatment; or until day T3+3).
  • The subject will remain within the Netherlands during the challenge period, will not travel to a malaria-endemic area during the study period, and is reachable (24/7) by mobile telephone throughout the entire study period.
Show all 12Show fewer
  • Subject agrees to their general practitioner being informed and contacted about their participation in the study and agrees to sign a form to request the release by their General Practitioner (GP), and medical specialist when necessary, to the investigator(s), of any relevant medical information concerning possible contra-indications for participation in the study.
  • The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period and for a defined period thereafter according to current Sanquin guidelines.
  • For female subjects: subject agrees to use continuous adequate contraception** and not to breastfeed for the duration of study.
  • Subject agrees to refrain from intensive physical exercise (disproportionate to the subject's usual daily activity or exercise routine) during the malaria challenge period until day 38 after infection.
  • Subject agrees to avoid additional triggers that may cause elevations in liver enzymes including alcohol from baseline up to 1 week post treatment (T3).
  • Subject has signed written informed consent to participate in the trial. (*Acceptable forms of contraception include: established use of oral, injected or implanted hormonal contraceptives; intrauterine device or intrauterine system; barrier methods (condoms or diaphragm with additional spermicide); male partner's sterilisation (with appropriate post-vasectomy documentation of absence of sperm in the ejaculate); true abstinence when this is in line with the preferred and usual lifestyle of the subject; Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.)

Who cannot join

  • A potential subject who meets any of the following criteria will be excluded from participation in this study:
  • Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, haematological, infectious, immunodeficient, psychiatric and other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following.
  • 1.1. Body weight <50 kg or Body Mass Index (BMI) <18 or >30 kg/m2 at screening. 1.2. A heightened risk of cardiovascular disease, as determined by: an estimated ten year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of clinically significant arrhythmia's, prolonged QT-interval or other clinically relevant ECG abnormalities; or a positive family history of cardiac events in 1st or 2nd degree relatives <50 years old.
  • 1.3. A medical history of functional asplenia, sickle cell trait/disease, thalassaemia trait/disease or G6PD-deficiency.
  • 1.4. History of epilepsy in the period of five years prior to study onset, even if no longer on medication.
  • 1.5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) 1.6. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period.
Show all 19Show fewer
  • 1.7. Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (allowable timeframe for use at the Investigator's discretion).
  • 1.8. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.
  • 1.9. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year.
  • 1.10. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine or amphetamines at screening or at inclusion, or positive urine toxicology test for cannabis at inclusion.
  • For female subjects: positive urine pregnancy test at screening and/or at the baseline visit.
  • Abnormal ALT/AST values on baseline
  • Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study.
  • Known hypersensitivity to or contra-indications (including co-medication) for use of sulfadoxine-pyrimethamine, piperaquine, chloroquine, Malarone®, artemether-lumefantrine, primaquine or history of severe (allergic) reactions to mosquito bites.
  • Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.
  • Being an employee or student of the department of Medical Microbiology of the Radboudumc or the department of Internal Medicine.
  • Any other condition or situation that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol.
  • For cohort B (blood stage challenge): Received a blood transfusion in the past.
  • For cohort B (blood stage challenge): Women of childbearing potential with a screening test positive for erythrocyte anti-Rh(c) and/or anti-Rh(e) antibodies.

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Radboud university medical center

    Nijmegen, Gelderland, 6525 GA

Other trials in Netherlands

About this study

Official title: Controlled Human Malaria Infection Study to Assess Gametocytemia and Mosquito Transmissibility in Participants Challenged With Plasmodium Falciparum by Sporozoite or Blood Stage Challenge to Establish a Model for the Evaluation of Transmission-blocking Interventions

This is a single-center, open label study. The primary aim of this project is to develop a controlled human malaria infection transmission model ("CHMI-trans") or "challenge model" to evaluate the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs to block malaria parasite transmission by assessing infectiousness of Plasmodium falciparum (Pf) gametocyte carriers for Anopheles mosquitoes.

Read the detailed description

A total of 24 volunteers, in two cohorts (n=12), will be randomly assigned to two groups per cohort (n=6). Cohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes (groups 1 and 2). Cohort B will be subjected to a standard blood stage challenge with ~2,800 Pf-infected erythrocytes by intravenous injection (groups 3 and 4).

Treatment is subsequently initiated to induce gametocytemia (treatment 1, T1) and to clear pathogenic asexual parasites whilst leaving gametocytes unaffected (treatment 2 and 3, T2 and T3). At the end of the study, treatment of all parasite stages is provided following national treatment guidelines (end treatment, ET).

Once malaria infections are detected by 18S qPCR positive (sporozoite challenge) or on day 8 (blood stage challenge), all volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Using blood samples taken twice daily, the initial clearance of parasitemia will be carefully monitored. After T1, volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. On day 21 or when a recrudescence occurs after T2, volunteers in group 1 and 3 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg) and group 2 and 4 (LD-PIP/LD-PIP2/SP) with sulfadoxine-pyrimethamine (1000mg/50mg). These treatment regimens cure asexual parasitemia while leaving immature and mature gametocytes unaffected. To ensure the radical clearance of all parasite stages, all volunteers will receive a final treatment (ET) according to national guidelines with atovaquone/proguanil (Malarone®) on day 36. Daily blood samples will allow detailed quantification of gametocytes, gametocyte sex ratio and ex vivo assessments of gametocyte fitness. Additionally, blood samples will be obtained for Direct Membrane Feeding Assay (DMFA) and volunteers will be subjected to Direct Skin Feeding Assays (DFA). These assays will provide evidence on the infectivity of volunteers.

Being tested
Piperaquine (low dose), Piperaquine (high dose), Sulfadoxine pyrimethamine, Atovaquone Proguanil, malaria challenge infection, P. falciparum 3D7
Medical subject headings
Malaria, Falciparum

What participants receive

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

  • Piperaquine (low dose)Drug

    Also called piperaquine phosphate

    subcurative regimen (480 mg)

  • Piperaquine (high dose)Drug

    Also called piperaquine phosphate

    Curative regimen (960mg)

  • Sulfadoxine pyrimethamineDrug

    Also called Fansidar

    Curative regimen (1000mg/50mg)

  • Atovaquone ProguanilDrug

    Also called Malarone

    Curative regimen (1000/400 mg, for 3 days)

  • malaria challenge infection, P. falciparum 3D7Other

    Also called 3D7 Plasmodium falciparum

    malaria challenge infection by P. falciparum 3D7-infected mosquito bites

  • Blood stage malaria challenge infection, P. falciparum 3D7Other

    Also called P. falciparum 3D7-infected human erythrocytes

    1. falciparum 3D7-infected human erythrocytes administered intravenously for the purpose controlled human malaria infection.
Study groups in NCT03454048
Study groupRoleWhat they receive
Group 1 (Cohort A) LD-PIP/LD-PIP2/PIPExperimentalCohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 1 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg).
Receives: Drug: Piperaquine (low dose); Drug: Piperaquine (high dose); Drug: Atovaquone Proguanil; Other: malaria challenge infection, P. falciparum 3D7
Group 2 (Cohort A) LD-PIP/LD-PIP2/SPExperimentalCohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 2(LD-PIP/LD-PIP2/SP) will be curatively treated with sulfadoxine-pyrimethamine (1000mg/50mg).
Receives: Drug: Piperaquine (low dose); Drug: Sulfadoxine pyrimethamine; Drug: Atovaquone Proguanil; Other: malaria challenge infection, P. falciparum 3D7
Group 3 (Cohort B) LD-PIP/LD-PIP2/PIPExperimentalCohort B will be subjected to a standard blood stage challenge with ~2,800 Pf-infected erythrocytes by intravenous injection. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 3 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg)
Receives: Drug: Piperaquine (low dose); Drug: Piperaquine (high dose); Drug: Atovaquone Proguanil; Other: Blood stage malaria challenge infection, P. falciparum 3D7
Group 4 (Cohort B) LD-PIP/LD-PIP2/SPExperimentalCohort B will be subjected to a standard blood stage challenge with ~2,800 Pf-infected erythrocytes by intravenous injection. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 4 (LD-PIP/LD-PIP2/SP) will be curatively treated with sulfadoxine-pyrimethamine (1000mg/50mg).
Receives: Drug: Piperaquine (low dose); Drug: Sulfadoxine pyrimethamine; Drug: Atovaquone Proguanil; Other: Blood stage malaria challenge infection, P. falciparum 3D7

What is being measured

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

  1. Frequency of Adverse Events in the CHMI-trans Model

    Frequency of adverse events in the CHMI-trans model.

    Measured: up to day 51 after challenge infection

  2. Gametocyte Prevalence

    Number of individuals in each study arm that show prevalence of gametocytes as defined by quantitative reverse-transcriptase PCR (qRT-PCR) for CCp4 (female) and PfMGET (male) mRNA with a threshold of 5 gametocytes/mL for positivity.

    Measured: up to day 51 after challenge infection

  3. Magnitude of Adverse Events in the CHMI-trans Model

    symptoms will be ranked as (1) mild, (2) moderate, or (3) severe, depending on their intensity according to the following scale:

    • Mild (grade 1): awareness of symptoms that are easily tolerated and do not interfere with usual daily activity
    • Moderate (grade 2): discomfort that interferes with or limits usual daily activity
    • Severe (grade 3): disabling, with subsequent inability to perform usual daily activity, resulting in absence or required bed rest

    Measured: up to day 51 after challenge infection

Secondary outcomes (5)

  1. Peak Density Gametocytes

    Peak density of gametocytes by qRT-PCR.

    Measured: up to day 51 after challenge infection

  2. AUC Gametocytes

    The area under the curve of gametocyte density versus time. The median AUC was calculated for both cohorts. Since onset of gametocytaemia differs depending on method of infection a window of 15 days was used to calculate AUC, from the time-point where a minimum of 50% of participants within a cohort had detectable gametocytemia.

    Measured: up to day 51 after challenge infection

  3. Gametocyte Commitment

    The gametocyte commitment rate is estimated by dividing the peak gametocyte by the peak of asexual parasites.

    Measured: up to day 51 after challenge infection

  4. Gametocyte Sex-ratio

    Proportion of male gametocytes

    Measured: up to day 51 after challenge infection

  5. Number of Participants Infectious for Mosquitoes Through DFA

    Prevalence of gametocyte infectiousness for Anopheles mosquitoes through Direct Feeding Assays (Direct Skin Feeding Assay, DFA).

    Measured: up to day 51 after challenge infection

Timeline

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

  1. First posted5 Mar 2018
  2. Study start7 May 2018
  3. Primary completion1 Nov 2018
  4. Study completion20 Nov 2018

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 N/A
Primary purpose
Other
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03454048
Sponsor's protocol ID
CHMI-trans2
Acronym
CHMI-trans2
Status last verified
Mar 2020
First submitted
27 Feb 2018
Last updated
7 Jul 2020
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Alkema M, Reuling IJ, de Jong GM, Lanke K, Coffeng LE, van Gemert GJ, van de Vegte-Bolmer M, de Mast Q, van Crevel R, Ivinson K, Ockenhouse CF, McCarthy JS, Sauerwein R, Collins KA, Bousema T. A Randomized Clinical Trial to Compare Plasmodium falciparum Gametocytemia and Infectivity After Blood-Stage or Mosquito Bite-Induced Controlled Malaria Infection. J Infect Dis. 2021 Oct 13;224(7):1257-1265. doi: 10.1093/infdis/jiaa157.

    PubMed 32239171

Questions about this trial

What is this clinical trial studying?

A study testing Piperaquine (low dose), Piperaquine (high dose) and Sulfadoxine pyrimethamine in people with Malaria,Falciparum and Gametocytes, run by Radboud University Medical Center at 1 site in Netherlands.

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 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Jul 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 Netherlands. 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.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Mar 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?

Frequency of Adverse Events in the CHMI-trans Model (time frame: up to day 51 after challenge infection). The study lists 3 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 NCT03454048, 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 7 Jul 2020.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in