Evaluate the Infectivity Equivalence of Current and New Lots of Plasmodium Falciparum Strain NF54

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT03882528
• Collaborator: (none)
• Enrollment: 12
• Location: 1
• Arm: 1
• Actual Duration (Months): 2.4
• Patients Per Site Per Month: 5

Study Details

Study Description

Brief Summary

Objectives:

Primary:

• To characterize the infectivity of the new lot of Plasmodium falciparum strain 3D7 within the standard WRAIR CHMI model as compared to the current lot (historical data)

Secondary:

• To assess safety of the new lot of P falciparum parasites

• To assess the kinetics of detecting parasitemia and parasite clearance by quantitative polymerase chain reaction (qPCR) as compared to blood smear

• To obtain plasma samples to restore the testing control pool for malaria serology testing and for future malaria research

Condition or Disease	Intervention/Treatment	Phase
Malaria,Falciparum	Biological: Plasmodium falciparum malaria parasite	Phase 1

Detailed Description

This is a single center, open label CHMI study. CHMI will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. After the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Unless previously diagnosed and fully treated, subjects will be required to stay in a hotel for a maximum of 12 nights starting on or around the evening of Day 7 post challenge.

All subjects diagnosed with malaria infection based on smears will be prescribed a standard malaria treatment regimen to begin on the day that parasitemia is detected. Subjects who do not become parasitemic (via smear) by Day 19 will be empirically treated for malaria.

After the hotel phase, all challenged subjects will have a final scheduled follow-up visit on Day 28 (±7 days).

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Screening
• Official Title: Bridging Trial to Evaluate the Infectivity Equivalence of Current and New Lots of Plasmodium Falciparum Strain NF54 (Clone 3D7) Within the WRAIR Controlled Human Malaria Infection (CHMI) Model
• Actual Study Start Date: Mar 4, 2019
• Actual Primary Completion Date: Apr 25, 2019
• Actual Study Completion Date: May 16, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Infective controls Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear.	Biological: Plasmodium falciparum malaria parasite; Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).

Outcome Measures

Primary Outcome Measures

1. To Characterize the Infectivity of a New Lot of Plasmodium Falciparum Strain 3D7 Developing Parasitemia Within the Standard WRAIR CHMI Model. [Within 2 weeks]

   Number of challenged subjects exposed to the new lot of Plasmodium falciparum strain 3D7 parasites developing parasitemia (defined as 2 unambiguous malaria parasites on a single smear).

Secondary Outcome Measures

1. Diagnostic Efficacy; Time to Parasitemia by Blood Smear Method After the P Falciparum Challenge [Within 2-3 weeks]

   Time to parasitemia by blood smear method after the P falciparum challenge. Time to parasitemia is defined as the time from CHMI to a first positive malaria parasite result. Parasitemia was defined as the presence of 2 unambiguous malaria parasites on a single smear. Beginning on Day 1 after their challenge, subjects were seen and evaluated daily by a study investigator and blood was drawn for determination of parasitemia by qPCR. Beginning on Day 5 and through Day 19 after their challenge, blood from these daily draws was utilized to generate blood smears to evaluate the development of malaria infection. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. However, only blood smears were used for diagnosis during this trial and evaluation of treatment success.

2. Diagnostic Efficacy; Time to Parasitemia (Days) by qPCR Method After the P Falciparum Challenge [Within 2-3 weeks]

   Time to parasitemia by qPCR method after the P falciparum challenge. Time to parasitemia is defined as the time from CHMI to a first positive malaria parasite result. Parasitemia was defined as the presence of 2 unambiguous malaria parasites on a single smear. On Day 0, subjects were evaluated by qPCR once prior to challenge, to establish a baseline. Beginning on Day 1 through Day 19 after their challenge, subjects were seen and evaluated daily by a study investigator and blood was drawn for determination of parasitemia by qPCR. Beginning on Day 5 and going through Day 19 after their challenge, blood from these daily draws was utilized to generate blood smears to evaluate the development of malaria infection. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. However, only blood smears were used for diagnosis during this trial and evaluation of treatment success.

3. Diagnostic Efficacy; Quantification of Parasite Clearance Time (PCT) by Blood Smear and qPCR Methods After Initiation of Antimalarial Treatment [Within 6 weeks]

   Time to Clearance was determined for all subjects for both smear and qPCR. Time to Clearance was defined as the time (in Days) from malaria diagnosis to confirmed clearance of parasitemia. Confirmed clearance of parasitemia by malaria smear was defined as the observation of 3 sequential negative (no parasites observed) daily smears. Confirmed clearance of parasitemia by qPCR was defined as 2 sequential daily (approximately 24 hours apart) negative qPCR assay results. For clarity, the day of the final test in each sequence (smear, PCR) was used as the day of confirmed clearance for calculation purposes.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• To be eligible for this study, you must meet ALL of the following conditions:

• You are between the ages of 18 and 50 years old.

• You are willing and able to participate in all planned study visits for the duration of the study.

• You are in good general health based on your medical history, physical examination, EKG, and screening laboratories.

• You are able to understand and sign this informed consent.

• You pass the written test called the 'Assessment of Understanding' with a score of at least 80% (8 out of 10 questions correct).

• You agree not to donate blood during the study and for 3 years after the malaria challenge.

• You agree not to travel to place(s) where there is malaria during the time of the study.

• If you are a female, you must agree to consistently use effective birth control (e.g., oral or implanted contraceptives, intrauterine device (IUD), diaphragm with spermicide, abstinence, cervical cap) during the period from the day of screening (today) through 3 months after the malaria challenge.

• You must be willing to take anti-malarial treatment after CHMI, if indicated.

• You must agree to stay in a pre-determined hotel near the NMRC CTC during the designated post-CHMI follow-up period from approximately 7 days after malaria challenge until antimalarial treatment is completed, if indicated.

• If you are an active duty military or federal employee, you must have approval from your supervisory chain to participate. The appropriate approval form will be provided to you.

Exclusion Criteria:

• You must not have any of the following:

• Any history of malaria infection or having been given a malaria vaccine

• Any history travel to a country with falciparum malaria in the past 6 months, or planned travel to such an area during the course of the study

• Any history of having lived in an area with falciparum malaria for more than 5 years.

• Any use of medications that prevent or treat malaria during the 1 month prior to challenge or planned use during the study (outside of the drugs provided by the study team).

• Any serious medical illness or condition involving the heart, liver, lungs, or kidneys

• Any significant risk for developing heart disease in the next 5 years. The risk for developing heart disease in the next 5 years will be determined by a combination of the following factors: high blood pressure, smoking, weight, family history of heart disease and the presence of diabetes

• Any medical illness or condition involving your blood or immune system (to include sickle cell trait or thalassemia trait)

• Any abnormal (as determined by a physician) screening laboratory test results

• Any history of neurologic disease (including migraines or seizures)

• Any history of psoriasis (itchy skin rash) or porphyria (rare disturbance of metabolism), since these conditions could get worse after treatment with chloroquine (a medication for treating malaria).

• You have had your spleen removed

• Any past or current infection with HIV, Hepatitis C, or Hepatitis B

• Any use of investigational drugs or vaccines within 1 month before starting the study

• Any allergy to or inability to take the anti-malaria medications used in this study

• Any history of allergic reaction to mosquito bites that required hospitalization

• You must not be pregnant or nursing, or have any plans to become pregnant or breastfeed during the period from now through 3 months after malaria challenge

• Any chronic use of steroids or other medications that affect the immune system in the 6 months before malaria challenge. Inhaled and topical (used on the skin) steroids are allowed.

• You plan to have surgery between enrollment and 3 months after malaria challenge.

• Any active alcohol or drug abuse

• You have any other physical or psychologic condition or laboratory abnormality that the study doctor thinks may increase your risk of having side effects or compromise the results of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Walter Reed Army Institute of Research	Silver Spring	Maryland	United States	20910

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command

Investigators

• Principal Investigator: James E Moon, MD, Walter Reed Army Institute of Research (WRAIR)

Study Documents (Full-Text)

• Study Protocol - Feb 13, 2019
• Statistical Analysis Plan - Sep 30, 2019
• Informed Consent Form - Feb 21, 2019

More Information

Publications

None provided.

• Responsible Party: U.S. Army Medical Research and Development Command
• ClinicalTrials.gov Identifier: NCT03882528
• Other Study ID Numbers: S-18-02
• First Posted: Mar 20, 2019
• Last Update Posted: Mar 30, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum

Study Results

Participant Flow

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Overall Participants	12
Age, Customized (years) [Mean (Standard Deviation) ]
Age	28.7 (7.73)
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 25%
Not Hispanic or Latino	9 75%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 8.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 25%
White	7 58.3%
More than one race	1 8.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	12 100%

Outcome Measures

1. Primary Outcome

Title	To Characterize the Infectivity of a New Lot of Plasmodium Falciparum Strain 3D7 Developing Parasitemia Within the Standard WRAIR CHMI Model.
Description	Number of challenged subjects exposed to the new lot of Plasmodium falciparum strain 3D7 parasites developing parasitemia (defined as 2 unambiguous malaria parasites on a single smear).
Time Frame	Within 2 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Measure Participants	12
9 Days post-challenge	0 0%
10 Days post-challenge	1 8.3%
11 Days post-challenge	5 41.7%
12 Days post-challenge	5 41.7%
13 Days post-challenge	0 0%
14 Days post-challenge	1 8.3%

2. Secondary Outcome

Title	Diagnostic Efficacy; Time to Parasitemia by Blood Smear Method After the P Falciparum Challenge
Description	Time to parasitemia by blood smear method after the P falciparum challenge. Time to parasitemia is defined as the time from CHMI to a first positive malaria parasite result. Parasitemia was defined as the presence of 2 unambiguous malaria parasites on a single smear. Beginning on Day 1 after their challenge, subjects were seen and evaluated daily by a study investigator and blood was drawn for determination of parasitemia by qPCR. Beginning on Day 5 and through Day 19 after their challenge, blood from these daily draws was utilized to generate blood smears to evaluate the development of malaria infection. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. However, only blood smears were used for diagnosis during this trial and evaluation of treatment success.
Time Frame	Within 2-3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Measure Participants	12
Mean (Standard Deviation) [days]	11.6 (1.00)

3. Secondary Outcome

Title	Diagnostic Efficacy; Time to Parasitemia (Days) by qPCR Method After the P Falciparum Challenge
Description	Time to parasitemia by qPCR method after the P falciparum challenge. Time to parasitemia is defined as the time from CHMI to a first positive malaria parasite result. Parasitemia was defined as the presence of 2 unambiguous malaria parasites on a single smear. On Day 0, subjects were evaluated by qPCR once prior to challenge, to establish a baseline. Beginning on Day 1 through Day 19 after their challenge, subjects were seen and evaluated daily by a study investigator and blood was drawn for determination of parasitemia by qPCR. Beginning on Day 5 and going through Day 19 after their challenge, blood from these daily draws was utilized to generate blood smears to evaluate the development of malaria infection. In addition to smears, subjects were also evaluated for the presence of parasitemia via qPCR. However, only blood smears were used for diagnosis during this trial and evaluation of treatment success.
Time Frame	Within 2-3 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Measure Participants	12
Mean (Standard Deviation) [days]	7.3 (0.65)

4. Secondary Outcome

Title	Diagnostic Efficacy; Quantification of Parasite Clearance Time (PCT) by Blood Smear and qPCR Methods After Initiation of Antimalarial Treatment
Description	Time to Clearance was determined for all subjects for both smear and qPCR. Time to Clearance was defined as the time (in Days) from malaria diagnosis to confirmed clearance of parasitemia. Confirmed clearance of parasitemia by malaria smear was defined as the observation of 3 sequential negative (no parasites observed) daily smears. Confirmed clearance of parasitemia by qPCR was defined as 2 sequential daily (approximately 24 hours apart) negative qPCR assay results. For clarity, the day of the final test in each sequence (smear, PCR) was used as the day of confirmed clearance for calculation purposes.
Time Frame	Within 6 weeks

Outcome Measure Data

Analysis Population Description

Unless previously diagnosed and fully treated, subjects stayed in a hotel starting on the evening of Day 9 post challenge. Subjects diagnosed with malaria were treated on the day parasitemia was detected. Subjects not parasitemic by Day 19 were treated for malaria and released from the hotel. These subjects had clinic daily for completion of treatment and blood collection until treatment efficacy criteria were met. All challenged subjects had a final follow-up visit on Day 28 (±7 days).

Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
Measure Participants	12
Blood smear Method	1.2 (0.39)
qPCR method	3.0 (0.60)

Adverse Events

Time Frame	Day 1 through Day 35
Adverse Event Reporting Description	Subjects were seen and evaluated daily and adverse event reporting collected
Arm/Group Title	Infective Controls
Arm/Group Description	Controlled Human Malaria Infection (CHMI) will consist of exposure to Plasmodium falciparum sporozoites through the bites of infected mosquitoes. Beginning 5 days after the challenge, subjects will be evaluated daily for the development of malaria infection using a blood smear. Plasmodium falciparum malaria parasite: Laboratory cultured Plasmodium falciparum strain 3D7 delivered via the bite of 5 infected mosquitoes with salivary gland scores of at least 2+ (11-100 sporozoites observed).
All Cause Mortality
	Infective Controls
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	Infective Controls
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Infective Controls
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Cardiac disorders
Tachycardia	2/12 (16.7%)
Gastrointestinal disorders
Diarrhea	2/12 (16.7%)
Abdominal Pain	1/12 (8.3%)
General disorders
Administration site pruritus	8/12 (66.7%)
Administration site erythema	1/12 (8.3%)
Fatigue	2/12 (16.7%)
Pyrexia	2/12 (16.7%)
Infections and infestations
Malaria	12/12 (100%)
Viral upper respiratory tract infection	1/12 (8.3%)
Influenza	1/12 (8.3%)
Investigations
Alanine Aminotransferase Elevation	1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Myalgia	1/12 (8.3%)
Back Pain	1/12 (8.3%)
Nervous system disorders
Headache	4/12 (33.3%)
Syncope	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Erythema	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.