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

Trial Summary

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.

What data supports the effectiveness of the drug P. vivax challenge agent, Krintafel, Arakoda for treating malaria?

Tafenoquine, marketed as Krintafel and Arakoda, has been approved for the radical cure and prevention of Plasmodium vivax malaria. It is effective against different stages of the malaria parasite, including those in the liver and blood, and has been shown to prevent relapse in patients. ^{1 2 3 4 5}

How is the drug tafenoquine unique in treating malaria?

Tafenoquine (Krintafel, Arakoda) is unique because it is a long-acting drug that targets both the liver and blood stages of the malaria parasite, Plasmodium vivax, and is used for both treatment and prevention. Unlike other treatments, it is a single-dose therapy, which makes it more convenient for patients. ^{3 4 5 6 7}

What is the purpose of this trial?

Background: Malaria is a disease caused by parasites transmitted to people by mosquitoes. Around the world, there were 241 million cases and 627,000 deaths from malaria in 2020. Researchers are working to develop vaccines and treatments for this disease. Objective: To learn how malaria develops in people; how the body's immune system reacts to malaria; and how malaria spreads from people to mosquitoes. Eligibility: Healthy people in the Washington DC area, aged 18 to 54 years. They cannot live alone during parts of the study. Design: Participants will be infected with a parasite that causes malaria. The parasite will be in donated blood; it will be given through an IV. Participants will likely develop symptoms within a week after the injection. Researchers will call daily to check on their health. After about 6 days, participants will come to the NIH clinic each day for blood tests. Participants will check in to the NIH clinic around 10 days after the injection. They will stay in the clinic 3 to 6 days. They will have multiple blood tests every day. Participants will be bitten by mosquitoes up to 4 times. Cups containing mosquitoes will be held against their skin for 15 minutes. Participants will begin taking chloroquine close to the end of their clinic stay. Chloroquine is a pill taken by mouth once or twice a day for 3 days. It is FDA-approved to treat malaria. Participants will have follow-up visits 1 and 3 weeks after discharge....

Research Team

Joel A Goldberg, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Randomized Placebo-Controlled Trial Evaluating the Ophthalmic Safety of Single-Dose Tafenoquine in Healthy Volunteers. [2020]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Tafenoquine: First Global Approval. [2019]

4. England 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Antimalarial Activity of Artefenomel Against Asexual Parasites and Transmissible Gametocytes During Experimental Blood-Stage Plasmodium vivax Infection. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Towards the elimination of Plasmodium vivax malaria: Implementing the radical cure. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Primaquine resistance in Plasmodium vivax. [2019]