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Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum

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Descriptive Information
Brief Title † Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum
Official Title † Sanaria PfSPZ Challenge With Pyrimethamine Chemoprophylaxis (PfSPZ-CVac Approach): Phase 1 Dose Escalation Trial to Determine Safety and Development of Protective Efficacy After Exposure to Only Pre-erythrocytic Stages of Plasmodium Falciparum
Brief Summary Background: People get malaria from bites from infected mosquitos. Researchers are studying a vaccine strategy. They will give people malaria parasites by injecting them with live infectious malaria parasites with antimalarial medications and then see if this strategy prevents malaria infection while off antimalarial medications. Objective: To see if combining a high dose of live, infectious malaria parasites (known as Sanaria PfSPZ Challenge) and two FDA approved drugs that kill malaria parasites (pyrimethamine [PYR] OR chloroquine [CQ]) is safe and can provide people protection against malaria. Eligibility: Healthy adults ages 18-50 who: - are not pregnant or breastfeeding or planning on becoming pregnant while in the study - are not infected with HIV, Hepatitis B or Hepatitis C - have reliable early morning access to the NIH Clinical Center - are able to come to the outpatient clinic frequently, sometimes daily Design: - Participants will be screened with medical history and physical exam. They will have heart, blood, and urine tests. - Participants will have blood drawn for tests at most visits. - Participants will keep track of their temperature and symptoms during some sections of the study. - Participants will join one part of the study. Part 1 is one month: - Participants will get the parasites by an injection into a vein on day 1 and receive antimalarial medications. - They will have daily visits on days 7-14 - They will take another antimalarial at visits on days 15-17. - The final visit will be on day 29. Part 2 is seven months: - For the first 3 months, participants will get the parasite injection into a vein for 3 injections in total. Each injection will occur once per month while taking an antimalarial drug. - They will have daily visits on days 7-14 after the first injection, and on days 7-11 after the second and third injection. - They will have a final (fourth) injection around month 6 without any antimalarial medication. - After this fourth injection, participants may have up to 21 daily visits from day 7 after injection until end of study. Part 3 is one month: - Participants will get the parasites by injection into a vein on day 1 without antimalarial medications. - They will have visits almost every day starting day 7 from injection. - They will take an antimalarial medication when they are diagnosed with malaria - They will return for final end of study visit on days 27-29.
Detailed Description Human studies have shown that immunization by the bite Plasmodium falciparum (Pf) sporozoite(SPZ)-infected mosquitoes under drug coverage with chloroquine, an approach called chemoprophylaxis with sporozoites (CPS) or infection treatment vaccination (ITV), can provide high level, long term protection against homologous controlled human malaria infection (CHMI). The Sanaria PfSPZ chemoprophylaxis vaccination (PfSPZ CVac) approach duplicates this with an injectable SPZ regimen. In both approaches, whether mosquitoes or syringes are used for SPZ administration, when chloroquine is used as the chemoprophylactic agent, transient, limited, asexual erythrocytic stage is seen in the majority of participants. Thus the question remains whether the significant protective efficacy seen can be achieved with pre-erythrocytic (sporozoite/liver stage) exposure only. Previously, we performed a phase 1 study to investigate the safety, tolerability, immunogenicity, and protective efficacy of Sanaria PfSPZ CVac with chloroquine (sporozoites, liver, and blood stage) or pyrimethamine with chloroquine (sporozoites and liver stage only) to further describe stage specific sterile protection (NIAID protocol #15-I-0169). In this study, we demonstrated that pyrimethamine is safe to administer, well tolerated, and can prevent subpatent and patent parasitemia (qPCR and blood smear negative) 100% of the time during Sanaria PfSPZ CVac. The study also duplicated the results previously reported with Sanaria PfSPZ CVac with chloroquine in terms of safety profile and protective efficacy against homologous CHMI. Although a combination of Sanaria PfSPZ CVac with pyrimethamine and PfSPZ Challenge at 51,200 PfSPZ did not provide significant protection against homologous CHMI, we demonstrated that protective immunity can develop without any evidence of blood stage exposure during PfSPZ CVac. Building on these results and taking the lessons learned from other pre-erythrocytic vaccine studies and models that have shown the importance of reaching a minimal antigen threshold required for the development of sterile immunity, this proposed study will assess the safety, tolerability, immunogenicity, and protective efficacy of increasing the dose of Sanaria PfSPZ Challenge sporozoites while receiving similar doses of pyrimethamine. Additionally, we will explore the impact of increasing the number Sanaria PfSPZ Challenge sporozoites while under chloroquine prophylaxis on heterologous protection. The results of this study will contribute to understanding the targets and mechanisms of immunity against Pf malaria infection and how the degree of exposure to the parasite (pre-erythrocytic or erythrocytic stage only or both) impacts these responses and subsequent protective efficacy.
Study Phase Phase 1
Study Type † Interventional
Study Design †
Primary Outcome Measure † The incidence and severity of local and systemic adverse events occurring after PfSPZ CVac (Arms 1, 2 and 3)
Secondary Outcome Measure † P. falciparum blood stage infection defined as detection of at least 2 P. falciparum parasites by microscopic examination of 0.5 UL of blood or one positive real time NIH qPCR after homologous PfSPZ CHMI via DVI (Arm 2 and 4a)
Condition † Malaria
Intervention † DrugChloroquine Phosphate
Study Arms / Comparison Groups 1 (N=8-12)Arm 1a, 1b and 1 d (and if needed Arms 1 c, 1 e and 1f) will receive 1 dose of NF54 Sanaria PfSPZ Challenge AND 2 doses of pyrimethamine (50 mg and if needed 75 mg) administered on 2 and 3 days post injection timed to eliminate parasites in the liver-stage of development, after hepatocyte invasion and development, but prior to full maturation and release into the bloodstream. 2 (N=28)Arm 2 will receive three vaccinations, 28 days apart, with the regimen determined in the pilot of NF54 Sanaria PfSPZ Challenge AND pyrimethamine, two doses given on days 2 and 3 post injection. The target regimen is 200,000 PfSPZ with 50 mg of pyrimethamine on days 2 and 3 post DVI (Arm 1 d). Approximately 12 weeks after the last injection, subjects will receive a 4th injection of a lower dose of Sanaria PfSPZ Challenge without any antimalarial medication to determine if they have developed protection against malaria. If diagnosed with malaria infection per protocol subjects will be treated with Malarone for three consecutive days in accordance with FDA guidelines. 3 (N=7) Arm 3 will receive three vaccinations, 28 days apart, using NF54 Sanaria PfSPZ Challenge (50,000 or higher number of sporozoites, as used in Arm 2, if safety data from other studies is available) with continuous suppressive prophylaxis with the blood-stage antimalarial drug chloroquine [weekly dosing beginning 2 days prior to first Sanaria PfSPZ Challenge (1g (600 mg base) loading dose then 500 mg (300 mg base) maintenance dosing weekly) thereafter] and continuing throughout CVac, last dose on day 5 after 3rd NF54 Sanaria PfSPZ Challenge to prevent development of patent parasitemia detectable by thick blood smear and clinical malaria. Approximately 12 weeks after the last injection, subjects will receive a 4th injection of a lower dose of Sanaria PfSPZ Challenge without any antimalarial medication to determine if they have developed protection against malaria. 4 Arm 4a (N=8); Arm 4b (N=6). Arms 4a and 4b (lnfectivity Controls for CHMI) will be the challenge control group. This group will join the study for administration of Sanaria PfSPZ Challenge, NF54 and 7G8 respectively, at CHMI. This group will not receivechloroquine or pyrimethamine. Upon diagnosis with malaria infection per protocol subjects will be treated with Malarone for three consecutive days in accordance with FDA guidelines.
Publications *

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information
Recruitment Status † Drug
Estimated Enrollment † 200
Start Date † June 5, 2017
Completion Date June 15, 2018
Primary Completion Date December 30, 2017
Eligibility Criteria † - INCLUSION CRITERIA: - Age greater than or equal to 18 and less than or equal to 50 years. - In good general health and without clinically significant medical history - Malaria comprehension exam completed, passed (a score of greater than or equal to 80% or per investigator s discretion) and reviewed prior to enrollment - Reliable access to the clinical trial center and availability to participate for duration of study - Females of childbearing potential must be willing to use reliable contraception (as defined below) from 21 days prior to study day -2 to 28 days following last Sanaria PfSPZ Challenge exposure - Subject to the judgment and discretion of the PI, female participants who meet ANY ONE of the criteria listed immediately below, may not be required to take any additional measures to avoid pregnancy. Such participants will be counseled on risks at the time of consent and at appropriate points (e.g. when pregnancy testing occurs) during the study: - Females who have had their uterus, and/or BOTH ovaries removed - Females who have had BOTH fallopian tubes surgically 'tied' or removed - Females who are above the age of 45 and have spontaneously had no menses at any point during the past 12 or more consecutive months (i.e. have reached menopause) - Females who, in the conservative and reasonable judgment of the PI (e.g. due to sexual orientation or serious life choice (such as being celibate clergy or transgender), during the entire trial will NOT participate in any potentially reproductive sexual contact - Females who, in the conservative and reasonable judgment of the PI, are in a monogamous stable relationship with a male who has undergone vasectomy at least 4 months prior or another procedure/medical condition that deems the male sterile -Subject to the judgment and discretion of the PI, female participants who DO NOT meet ANY of the criteria listed above, will be appropriately counseled on reproductive risks and pregnancy avoidance, and will be required to adhere to the following measures and agree to 2 methods of pregnancy prevention as noted below: - CATEGORY 1: a highly effective hormonal method to prevent pregnancy [e.g. CONSISTENT, CONTINUOUS use of contraceptive pill, patch, ring, implant or injection], and/or IUD or equivalent - IN ADDITION TO CATEGORY 2: a barrier method to be used at the time of potentially reproductive sexual activity (e.g. [male/female condom, 'cap,' or diaphragm] + spermicide). EXCLUSION CRITERIA: - Currently is breast-feeding (if female). - Pregnancy as determined by a positive urine or serum human choriogonadotropin (beta- hCG) test at any point during the study (if female). - Recent travel to a malaria endemic area within 5 years of enrollment - Planned travel to a malaria endemic area (as defined by the Center for Disease Control) during the study period - Reported history of confirmed malaria diagnosis on peripheral blood smear or by clinical history in the past 10 years. - Hemoglobin, WBC, platelets, ALT, and creatinine outside of local lab normal range (subjects may be included at the investigator s discretion for not clinically significant values outside of normal range) - Abnormal urinalysis as defined by positive urine glucose, protein, and red blood cells. Subject can be included if investigator determine the abnormality is not clinically significant . - BMI 35 - Anticipated use during the study period, or use within the following periods prior to enrollment: - Investigational malaria vaccine within the last five years - Malaria chemoprophylaxis within 6 months - Chronic systemic immunosuppressive medications (>14 days) within 6 months (e.g.cytotoxic medications, oral/parental corticosteroids >0.5 mg/kg/day prednisone or equivalent). Corticosteroid nasal spray for allergic rhinitis and topical corticosteroids for mild, uncomplicated dermatitis are allowed. - Blood products or immunoglobulins within 6 months - Systemic antibiotics with antimalarial effects within 30 days (such as clindamycin, doxycycline) - Investigational or non-registered product or vaccine within 30 days - Receipt of a live vaccine within 28 days or a killed vaccine within the 14 days prior to Sanaria PfSPZ Challenge - Medications known to interact with pyrimethamine, chloroquine, atovaquone, proguanil (during the study period only) - Reported history of: - Sickle cell disease, sickle cell trait, or other hemoglobinopathies - Splenectomy or functional asplenia - Systemic anaphylaxis - Any allergic reactions to study drugs - Documented history of chronic or active neurologic disease (including seizures, uncontrolled migraine headaches) - Psoriasis or porphyria - Ocular diseases including retinopathy or visual field defects - Clinically significant medical condition, physical examination findings, other clinically significant abnormal laboratory results, or past medical history that may have clinically significant implications for current health status and participation in the study in the opinion of the Investigator. A clinically significant condition or process includes but is not limited to: - A process that would affect the immune response, or requires medication that affects the immune response - Any contraindication to repeated phlebotomy - A condition or process in which signs or symptoms could be confused with reactions to malaria challenge and/or infection, including dermatologic abnormalities at the site of sporozoite inoculation - A chronic or subclinical condition which could be exacerbated by administration of any of the PfSPZ-CVac components or malaria infection - History of, or known active cardiac disease including: (1) prior myocardial infarction (heart attack); (2) angina pectoris; (3) congestive heart failure; (4) valvular heart disease; (5) cardiomyopathy; (6) pericarditis; (7) stroke or transient ischemic attack; (8) exertional chest pain or shortness of breath; or ( 9) other heart conditions under the care of a doctor - Clinically significant ECG findings, as determined by the expert study cardiologist - Moderate or high risk for coronary heart disease (CHD) based on NHANES I cardiovascular risk assessment - Acute illness at the time of enrollment - Infection with HIV, Hepatitis B, Hepatitis C - Psychiatric condition that precludes compliance with the protocol including but not limited to: - Psychosis within the past 3 years - Ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years - Suspected or known current alcohol or drug abuse as defined by the American Psychiatric Association in the DSM V at the discretion of the PI - Clinical trial staff and/or Sanaria Inc. employees with direct involvement in the conduct of the trial are excluded from participation. - Participating in other clinical trials involving investigational interventions or off label medication use during the study period (excluding participation in the optional long term follow up visits). Participation in other trials such as observational or imaging studies will be discussed with the investigators. - Any other finding that, in the judgment of the Investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety or reactogenicity, or a subject s ability to give informed consent, or increase the risk of having an adverse outcome from participating in the study.
Gender All
Ages 18 Years - 50 Years
Accepts Healthy Volunteers Accepts Healthy Volunteers
Contacts †† Sara A Healy, M.D., (240) 747-7497, sara.healy@nih.gov
Location Countries † United States
Administrative Information
NCT ID † NCT03083847
Organization ID 170067
Secondary IDs †† 17-I-0067
Responsible Party Sponsor
Study Sponsor † National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators ††
Investigators † Principal Investigator: Sara A Healy, M.D., National Institute of Allergy and Infectious Diseases (NIAID)
Information Provided By
Verification Date April 10, 2017
First Received Date † March 14, 2017
Last Updated Date June 6, 2017
† Required WHO trial registration data element.
†† WHO trial registration data element that is required only if it exists.
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