Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Trial to Determine Safety and Protective Efficacy of Sanaria PfSPZ Challenge With Concurrent Pyrimethamine Treatment That Inhibits Development of Asexual B...

Malaria Clinical Trial

Official title: Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Trial to Determine Safety and Protective Efficacy of Sanaria PfSPZ Challenge With Concurrent Pyrimethamine Treatment That Inhibits Development of Asexual Blood Stages of Plasmodium Falciparumc

Status Completed

Clinical Trial Summary

Background:

• Malaria is a severe infection caused by a parasite. People can get malaria if a mosquito that carries the parasite bites them. Although malaria does not occur in the United States, many people in Africa, Asia, and South America do get malaria. In some cases, malaria can cause death. In 2013 alone, 584,000 people died due to malaria. Researchers want to find ways to prevent and treat malaria.

Objective:

• To find out if combining live, infectious malaria parasites (known as Sanaria PfSPZ Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] and chloroquine [CQ]) is safe and can provide people protection against malaria. The Sanaria PfSPZ Challenge has been used in other studies without significant side effects.

Eligibility:

• Healthy people ages 18-50 who weigh less than 170 pounds and are not pregnant or breastfeeding

• No history of hepatitis B, hepatitis C, or HIV infection

• Not currently enrolled in a clinical trial that involves a research drug or vaccine

• Have not traveled to an area with high malaria transmission within the last 5 years

• Never diagnosed with malaria in the past

Design:

• Participants will be in 1 of 4 groups.

• Participants will receive a combination of injections and drugs. What combination they will receive will depend on what group they are in. This combination of injections and drugs may include:

• Injections of Sanaria PfSPZ Challenge (live, infectious malaria parasites) into a vein

• FDA approved antimalarial drug called chloroquine (CQ)

• FDA approved antimalarial drug called pyrimethamine (PYR)

• FDA approved antimalarial drug called Malarone

• The study will last approximately 3-7 months (depending on which group participants are in).

• There will be up to 68 study visits for three groups. One group will have up to 27 study visits. During the study visits, participants may have:

• Medical history review

• Physical exams

• Electrocardiogram (ECG): soft electrodes will be placed on the skin. A machine will record the heart s electrical signals to evaluate heart function.

• Blood and urine tests

• Medication given in the clinic under direct observation

• Injection of Sanaria PfSPZ Challenge into a vein

• Participants will receive a diary, thermometer, and ruler to record their body temperature and any symptoms.

Clinical Trial Description

Human studies have shown that immunization by the bite PfSPZ-infected mosquitoes under drug coverage with chloroquine, an approach called chemoprophylaxis with sporozoites (CPS), infection treatment vaccination (ITV), or chemoprophylaxis vaccination (CVac) can provide high level, long term protection against homologous controlled human malaria infection (CHMI). The Sanaria PfSPZ-CVac approach duplicates this with an injectable sporozoite (SPZ) regimen (aseptic, purified, cryopreserved SPZ). In both approaches, whether mosquitoes or a syringe are used for SPZ administration, when chloroquine is used as the chemoprophylactic agent, transient, limited, asexual erythrocytic stage (AES) parasitemia develops. However, exposure to liver stage parasites only, without having any parasites completing liver stage development and entering the blood, thereby reducing the potential to induce blood stage immunity, likewise has been shown in animal studies to induce protective immunity upon subsequent challenge with homologous parasites, indicating that the transient parasitemia is not integral to inducing protection. To achieve this requires a different partner drug regimen that includes activity against liver stage parasites.

Our approach, using PfSPZ-CVac with pyrimethamine (PYR), will assess this in humans. This phase 1 study will investigate the safety, tolerability, immunogenicity, and protective efficacy following liver stage only parasite exposure of direct venous inoculation (DVI) with aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (Sanaria PfSPZ Challenge), under chloroquine and pyrimethamine chemoprophylaxis, to induce stage specific sterile protection. By adding pyrimethamine chemoprophylaxis to chloroquine, liver stages will develop but should be killed before merozoites are released into the blood stream. The subjects will thus be exposed only to liver stage parasites (qPCR and blood smear negative). With this strategy, we will determine if protective immunity can develop without exposure to AES parasites and additionally whether it will minimize clinical symptoms associated with blood stage exposure. The timing of the pyrimethamine dose is critical to ensure the efficacy of pyrimethamine as causal prophylaxis, yet still allow for maximal antigenic exposure of liver-stage parasites to the host. An additional potential benefit of preventing AES parasitemia is the elimination of the immunosuppression associated with AES parasitemia.

This trial will be the first step in establishing a new regimen for the PfSPZ-CVac approach, exposure to liver stage parasites without subsequent blood stage parasites, assessing protection against homologous CHMI. In future trials, the two-drug regimen can be assessed for protection against heterologous Pf infection and longevity of protection. The results of the study will contribute to understanding the targets and mechanisms of immunity against Pf malaria infection. ;

Related Conditions & MeSH terms

• Malaria

• NCT number: NCT02511054
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 1
• Start date: July 21, 2015
• Completion date: June 1, 2017