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Trial record 229 of 309 for:    hepatitis b | Recruiting, Not yet recruiting, Available Studies

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

This study is currently recruiting participants.
Verified July 17, 2017 by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Sponsor:
ClinicalTrials.gov Identifier:
NCT03083847
First Posted: March 20, 2017
Last Update Posted: July 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
  Purpose

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
  • have not been diagnosed with malaria within the past 10 years

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.

Condition Intervention Phase
Malaria Drug: Chloroquine Phosphate Drug: Pyrimethamine Biological: Sanaria PfSPZ Challenge Phase 1

National Institute of Allergy and Infectious Diseases (NIAID) has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Primary Outcome Measures:
  • The incidence and severity of local and systemic AEs and SAEs occurring after PfSPZ CVac (Arms 1, 2, 3, 5) [ Time Frame: One (1) to seven (7) Months ]
  • P. falciparum blood stage infection defined as detection of p. falciparum parasites by qPCR (real time NIH qPCR and sensitive retrospective LMIV qPCR) following Sanaria PfSPZ Challenge (Arms 1, 2) [ Time Frame: One (1 ) to seven (7) months ]
  • Incidence of clinical malaria diagnosis occurring after PfSPZ-CVac- chloroquine requiring treatment with additional antimalaria (Arms 3 and 5) [ Time Frame: Seven (7) months ]

Secondary Outcome Measures:
  • 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) [ Time Frame: One to seven (7) months ]
  • P. falciparum blood stage infection defined as detection of at least 2 P. falciparum parasites by microscopic examination of 0.5 microliter of blood or one positive real time NIH qPCR after heterologous PfSPZ CHMI(7GB) via DVI. (Arm 2b, 3 and 4b... [ Time Frame: One to seven (7) months ]

Estimated Enrollment: 230
Actual Study Start Date: June 5, 2017
Estimated Study Completion Date: June 15, 2018
Estimated Primary Completion Date: December 30, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Arm 1 is a pilot arm to determine dose of sporozoites and prrimethamine for Arm 2
Drug: Pyrimethamine
Pyrimethamine is a folic acid antagonist that has been commonly used as antimalarial drug for both treatment and prevention of malaria, usually in combination with sulfadoxine in adults, pregnant women, and children worldwide (Organization April 2013 (rev. January 2014 )). Similar to chloroquine, pyrimethamine (in combination with sulfa drugs) was a drug of choice for malaria treatment and prophylaxis for decades because it was safe, well tolerated, affordable and highly effective; however, due to widespread resistance, pyrimethamine and pyrimethamine combinations have fallen out of favor for clinical use.
Biological: Sanaria PfSPZ Challenge
Sanaria Inc has manufactured two strains of Sanaria PfSPZ Challenge: NF54 and 7G8. The Sanaria PfSPZ Challenge contains fully infectious PfSPZ purified from the salivary glands of Anopheles stephensi mosquitoes raised under aseptic conditions. The infectious PfSPZ are formulated in cryoprotectant to maintain potency for an extended period. Sanaria PfSPZ Challenge (NF54) is known to be susceptible to chloroquine, pyrimethamine, atovaquone, artesunate, but not mefloquine. Sanaria PfSPZ Challenge (7G8) is known to be susceptible to mefloquine, atovaquone, artemether and artesunate but not to chloroquine or pyrimethamine.
Experimental: 2 and 3
Arms 2 (2a, 2b) and 3 are main study arms under pyrimethamine only for Arm 2; and chloroquine prophylaxis only for Arm 3
Drug: Chloroquine Phosphate
Chloroquine phosphate is FDA approved for suppressive treatment(prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a bloodstage schizonticide, highly active against replicating forms of bloodstage drug-sensitive parasites
Drug: Pyrimethamine
Pyrimethamine is a folic acid antagonist that has been commonly used as antimalarial drug for both treatment and prevention of malaria, usually in combination with sulfadoxine in adults, pregnant women, and children worldwide (Organization April 2013 (rev. January 2014 )). Similar to chloroquine, pyrimethamine (in combination with sulfa drugs) was a drug of choice for malaria treatment and prophylaxis for decades because it was safe, well tolerated, affordable and highly effective; however, due to widespread resistance, pyrimethamine and pyrimethamine combinations have fallen out of favor for clinical use.
Experimental: 4
Arm 4 (4a, 4b) is the infectivity control arm for Arms 2 and 3 during CHMI
Drug: Chloroquine Phosphate
Chloroquine phosphate is FDA approved for suppressive treatment(prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a bloodstage schizonticide, highly active against replicating forms of bloodstage drug-sensitive parasites
Biological: Sanaria PfSPZ Challenge
Sanaria Inc has manufactured two strains of Sanaria PfSPZ Challenge: NF54 and 7G8. The Sanaria PfSPZ Challenge contains fully infectious PfSPZ purified from the salivary glands of Anopheles stephensi mosquitoes raised under aseptic conditions. The infectious PfSPZ are formulated in cryoprotectant to maintain potency for an extended period. Sanaria PfSPZ Challenge (NF54) is known to be susceptible to chloroquine, pyrimethamine, atovaquone, artesunate, but not mefloquine. Sanaria PfSPZ Challenge (7G8) is known to be susceptible to mefloquine, atovaquone, artemether and artesunate but not to chloroquine or pyrimethamine.
Experimental: 5
Arm 5 is a pilot arm to determine a safe dose of sporozoites under chloroquine prophylaxis for Arm 3
Drug: Chloroquine Phosphate
Chloroquine phosphate is FDA approved for suppressive treatment(prophylaxis) and for acute attacks of malaria due to P. vivax, P. malariae, P. ovale, and susceptible strains of Pf. Chloroquine is a bloodstage schizonticide, highly active against replicating forms of bloodstage drug-sensitive parasites
Biological: Sanaria PfSPZ Challenge
Sanaria Inc has manufactured two strains of Sanaria PfSPZ Challenge: NF54 and 7G8. The Sanaria PfSPZ Challenge contains fully infectious PfSPZ purified from the salivary glands of Anopheles stephensi mosquitoes raised under aseptic conditions. The infectious PfSPZ are formulated in cryoprotectant to maintain potency for an extended period. Sanaria PfSPZ Challenge (NF54) is known to be susceptible to chloroquine, pyrimethamine, atovaquone, artesunate, but not mefloquine. Sanaria PfSPZ Challenge (7G8) is known to be susceptible to mefloquine, atovaquone, artemether and artesunate but not to chloroquine or pyrimethamine.

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 a significant protection level against homologous CHMI, we demonstrated that some subjects did develop protective immunity 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 the same, or, if needed to successfully prevent parasitemia, a higher dose of pyrimethamine. Unlike the first study, however, pyrimethamine will be administered by itself as the partner drug, and will not be co-administered with chloroquine. The efficacy of PfSPZ-CVac with pyrimethamine will be assessed against CHMI with homologous parasites (Arm 2a) and CHMI with heterologous parasites (Arm 2b). Additionally, we will explore the impact of increasing the dose of Sanaria PfSPZ Challenge sporozoites while receiving chloroquine alone prophylaxis. The efficacy of PfSPZ-CVac with chloroquine will be assessed only against CHMI with heterologous parasites (Arm 3), as protection against homologous parasites has now been shown in two separate trials. It will thus be possible to compare the efficacy of the two partner drugs against heterologous CHMI. 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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 < 17 or 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03083847


Contacts
Contact: Sara A Healy, M.D. (240) 747-7497 sara.healy@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Principal Investigator: Sara A Healy, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03083847     History of Changes
Other Study ID Numbers: 170067
17-I-0067
First Submitted: March 14, 2017
First Posted: March 20, 2017
Last Update Posted: July 27, 2017
Last Verified: July 17, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Malaria
Parasitemia
Immune
Responses
Sporozoites

Additional relevant MeSH terms:
Malaria
Protozoan Infections
Parasitic Diseases
Chloroquine
Chloroquine diphosphate
Pyrimethamine
Amebicides
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Antimalarials
Antirheumatic Agents
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Filaricides
Antinematodal Agents
Anthelmintics
Folic Acid Antagonists
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action