Malaria Challenge Agent for Malaria

Overseen By Joel A Goldberg, M.D.

Age: 18 - 65

Sex: Any

Trial Phase: Phase 1

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must not be taking: Immunosuppressants, Antibiotics, Antimalarials, others

Disqualifiers: Pregnancy, Immunodeficiency, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

200 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to understand how malaria, a disease caused by parasites from mosquito bites, develops in humans and spreads back to mosquitoes. Researchers will study the body's immune response to malaria using a specific parasite called P. vivax (also known as the P. vivax challenge agent). Healthy individuals living in the Washington DC area who do not live alone during the study are suitable candidates for this trial. Participants will receive the parasite through an IV and will be closely monitored with blood tests and mosquito bite evaluations.

As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the unique opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. You must not use systemic antibiotics or medications with potential antimalarial effects, or any investigational products, within 28 days before the trial starts. Also, you cannot use medications that significantly prolong the QT interval during the study.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the P. vivax challenge agent in this trial is under study to assess its safety and effectiveness in inducing malaria in a controlled setting. The goal is to gain insights into how malaria affects the body and spreads. This agent is part of a Phase 1 trial, indicating it is in the early stages of safety testing. These studies primarily aim to evaluate how well participants tolerate the treatment and identify any side effects.

Although specific information on this agent's safety is limited, Phase 1 trials are generally designed to minimize risks and closely monitor participants. Side effects, if they occur, are typically mild and temporary. The trial includes careful monitoring, such as daily health checks and multiple blood tests, to ensure participant safety. Participants will also take chloroquine, an FDA-approved medication for treating malaria, to clear the infection, adding an extra layer of safety to the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the P. vivax challenge agent because it offers a new way to study malaria caused by Plasmodium vivax. Unlike traditional treatments that focus on curing the infection, this approach involves controlled infection of volunteers to understand the disease better and test new interventions. It allows scientists to evaluate how the parasite is transmitted to mosquitoes and to study the body's response to infection. This could lead to more effective prevention and treatment strategies in the future, potentially changing how we combat malaria.

What evidence suggests that this trial's treatments could be effective for malaria?

Research has shown that developing a test agent for P. vivax, a type of malaria, is crucial for understanding how malaria spreads and how the body responds. This trial will use different arms with the P. vivax challenge agent derived from either PvHMB-CCE001 or PvHMB-CCE002 to study its safety and infectivity. The P. vivax parasite can cause recurring infections, making it difficult to control. Studies indicate that treatments like tafenoquine are effective against P. vivax, significantly reducing the chance of the infection returning. Tafenoquine has been proven to be 96% effective in protecting against this type of malaria. This supports the idea that understanding and controlling P. vivax can aid in better managing malaria. ^{1 3 6 7 8}

Who Is on the Research Team?

Joel A Goldberg, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

This trial is for healthy adults who have never had malaria. They will be part of a study at the NIH Clinical Center to test how safe and effective two types of Plasmodium vivax (a malaria parasite) are in causing controlled malaria infection, which could help develop vaccines.

Inclusion Criteria

Agreement to long-term storage of study samples for future research

Malaria comprehension exam passed prior to study activities

Suitable accommodation and reliable access to the NIHCC for the duration of the study in the opinion of the investigator

Exclusion Criteria

I have not taken long-term immune-weakening drugs in the last 6 months.

Planned travel to a P. vivax-endemic area during the study period

Rh blood group negative for persons of childbearing potential

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Inoculation and Initial Monitoring

Participants are inoculated with the P. vivax challenge agent and monitored for initial symptoms and safety

10 days

Daily visits for blood tests

Inpatient Monitoring and Treatment

Participants are admitted to the NIH clinic for intensive monitoring and begin antimalarial treatment with chloroquine

3-6 days

Inpatient stay with multiple daily blood tests

Mosquito Feeding Assays

Participants are subjected to mosquito feeding assays to evaluate transmission of P. vivax

Concurrent with inpatient stay

Up to 4 mosquito feeding sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

Follow-up visits at 1 and 3 weeks post-discharge

What Are the Treatments Tested in This Trial?

Interventions

• P. vivax challenge agent

Trial Overview The trial involves giving participants one of two P. vivax challenge agents intravenously to induce malaria. The effects will be monitored to find the right dose, understand transmission via mosquitoes, and gather data for future vaccine studies.

How Is the Trial Designed?

Group I: P. vivax challenge agent derived from PvHMB-CCE002 Pilot Arm Experimental Treatment 1 Intervention

1-2 subjects will undergo IBSM to establish the safety and infectivity of the P. vivax challenge agent derived PvHMB-CCE002 challenge agent.

Group II: P. vivax challenge agent derived from PvHMB-CCE002 Main Arm Experimental Treatment 1 Intervention

Up to 16 subjects will undergo IBSM to further develop the P. vivax challenge agent derived from PvHMB-CCE002 model including to evaluate transmission to mosquitoes using feeding assays and assess the host response to P. vivax infection.

Group III: P. vivax challenge agent derived from PvHMB-CCE001 Pilot Arm Experimental Treatment 1 Intervention

1-2 subjects will undergo IBSM to establish the safety and infectivity of the P. vivax challenge agent derived from PvHMB-CCE001.

Group IV: P. vivax challenge agent derived from PvHMB-CCE001 Main Arm Experimental Treatment 1 Intervention

Up to 16 subjects will undergo IBSM to further develop the P. vivax challenge agent derived PvHMB-CCE001 model including to evaluate transmission to mosquitoes using feeding assays and assess the host response to P. vivax infection.

P. vivax challenge agent is already approved in United States for the following indications:

Approved in United States as Krintafel for:

• Radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older

Approved in United States as Arakoda for:

• Prophylaxis of malaria in adults aged 18 years and older

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

In a phase I clinical trial involving 467 healthy adult volunteers, a single 300-mg dose of tafenoquine showed no significant pharmacodynamic effects on the retina, indicating it is safe for ocular health.

Both tafenoquine and placebo groups had similar rates of retinal changes, with only 0.3% of tafenoquine recipients showing any retinal disruption, which was not clinically significant and did not affect vision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers. Ackert, J., Mohamed, K., Slakter, JS., et al.[2020]

The review discusses various strategies and efforts aimed at eliminating P. vivax malaria, highlighting the challenges and progress made in this area.

It emphasizes the importance of understanding the unique biology and transmission dynamics of P. vivax to develop effective interventions for its eradication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards the elimination of Plasmodium vivax malaria: Implementing the radical cure. Thriemer, K., Ley, B., von Seidlein, L.[2023]

There are emerging concerns about primaquine resistance in Plasmodium vivax, particularly in regions like the South Pacific and Southeast Asia, where strains may have spread due to increased population mobility over the last 50 years.

While there is currently no strong evidence of acquired primaquine resistance, the potential for its future emergence is significant, and monitoring for relapses after primaquine treatment could be crucial for early detection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primaquine resistance in Plasmodium vivax. Collins, WE., Jeffery, GM.[2019]

Tafenoquine, recently approved for treating Plasmodium vivax malaria, does not show the same neurotoxic effects as older 8-aminoquinoline drugs like pamaquine and plasmocid, based on a review of both non-clinical and clinical literature.

Unlike some older malaria treatments that caused specific neurological damage in Rhesus monkeys and humans, there is no evidence of similar neurotoxicity associated with tafenoquine or primaquine, suggesting they are safer options for malaria treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafenoquine and primaquine do not exhibit clinical neurologic signs associated with central nervous system lesions in the same manner as earlier 8-aminoquinolines. Berman, J., Brown, T., Dow, G., et al.[2023]

Tafenoquine is an effective oral anti-malarial drug approved for the radical cure of P. vivax malaria and for malaria prophylaxis, demonstrating its dual action against both liver and blood stages of the parasite.

The exact mechanism of tafenoquine's action is not fully understood, but it may involve inhibiting haematin polymerization and inducing mitochondrial dysfunction in the malaria-causing organisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafenoquine: First Global Approval. Frampton, JE.[2019]

Artefenomel demonstrated effective antimalarial activity in a study involving 8 healthy participants, with all individuals showing initial parasite clearance within 48 hours after a single 200-mg dose.

Despite the initial success, 7 out of 8 participants experienced recrudescence of the malaria parasite 11-14 days post-treatment, indicating the need for further clinical development and potential adjustments in dosing strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection. Collins, KA., Abd-Rahman, AN., Marquart, L., et al.[2022]

In a study involving 329 patients with P. vivax malaria, a single dose of tafenoquine (300 mg or 600 mg) combined with chloroquine significantly improved relapse-free efficacy at 6 months compared to chloroquine alone, achieving rates of 89.2% and 91.9%, respectively.

The safety profile of tafenoquine was comparable to that of primaquine and chloroquine, with no significant increase in serious adverse events, indicating that tafenoquine is a promising option for preventing malaria relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study. Llanos-Cuentas, A., Lacerda, MV., Rueangweerayut, R., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9849360/

The challenges of Plasmodium vivax human malaria infection ... This article summarizes the challenges and progress with continuous culture of P. vivax, the different challenge protocols (mosquito bite & blood stage ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1710775

Single-Dose Tafenoquine to Prevent Relapse ... Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06607003?term=AREA%5BConditionSearch%5D(Malaria%20OR%20%22%22)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING)&rank=10

NCT06607003 | Induced Blood-Stage Malaria in Healthy ... Up to 16 subjects will undergo IBSM to further develop the P. vivax challenge agent derived PvHMB-CCE001 model including to evaluate transmission to mosquitoes ...

4. cdc.gov cdc.gov/mmwr/volumes/68/wr/mm6846a4.htm

Guidance for Using Tafenoquine for Prevention and ... Tafenoquine kills both the liver and blood stages of the parasite, broadening its applicability for chemoprophylaxis to all species of malaria.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9347252/

Tafenoquine for Plasmodium vivax malaria - PubMed Central The protective efficacy of TQ against all malaria infections was 97 per cent and for P. vivax malaria was 96 per cent. Elmes et al15 assessed the efficacy ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06607003

NCT06607003 | Induced Blood-Stage Malaria in Healthy ... Single-center, open-label, phase 1 study to characterize the safety and infectivity of Plasmodium vivax (P. vivax) challenge agent for induced blood-stage ...

7. mmv.org mmv.org/sites/default/files/uploads/docs/press_releases/US_FDA_approves_Krintafel.pdf

US FDA approves Krintafel (tafenoquine) for the radical ... vivax malaria. Hence, a single P. vivax infection can give rise to multiple episodes of malaria, in the absence of a new mosquito bite. These.

8. thelancet.com thelancet.com/journals/lanchi/article/PIIS2352-4642(21)00328-X/fulltext

Tafenoquine exposure assessment, safety, and relapse ... The safety profile was as expected based on data from adults with P vivax malaria, with the exception of post-dose vomiting, which was ...