Dose Escalation PfSPZ-CVac

NCT03083847 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 17006717-I-0067
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

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
• 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.

Conditions

Malaria

Keywords

Malaria; Parasitemia; Immune; Responses; Sporozoites

Outcome Measures

Primary Outcomes (4)

• Number of Participants With P.Falciparum Blood Stage Infection

  Participants with P. falciparum blood stage infection defined as detection of P. falciparum parasites by qPCR (real time NIH qPCR and sensitive retrospective Laboratory of Malaria Immunology \& Vaccinology (LMIV) qPCR) following Sanaria® PfSPZ Challenge (NF54) via direct venous injection (DVI).

  14 days post PfSPZ Challenge injection

• Number of Participants Requiring Treatment With Additional Anti-malarial Medication

  Incidence of a clinical malaria diagnosis occurring after PfSPZ-Cvac challenge requiring treatment with atovaquone/proguanil (Malarone).

  12 days post PfSPZ Challenge injection

• Number of Participants With Local and Systemic Adverse Events (AEs)

  Participants who had one or more episodes of related or/and unrelated adverse events (AEs). An AE is defined as any untoward medical occurrence temporarily associated with the subject's participation in research, whether or not considered related or not. Refer to adverse event table for specific AE.

  7 months

• Number of Participants With Serious Adverse Events (SAEs)

  Participants who had one or more episodes of serious adverse events (SAEs). SAE is defined as a life-threatening reaction or event that results in death.

  7 months

Study Arms (10)

Pilot (1a): 1 injection of 5x10^4 PfSPZ Challenge+pyrimethamine

EXPERIMENTAL

Pilot Phase - 1 injection of 5x10\^4 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection

Drug: Pyrimethamine; Biological: Sanaria PfSPZ Challenge

Pilot (1b):1 injection of 1x10^5 PfSPZ Challenge+pyrimethamine

EXPERIMENTAL

Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection

Drug: Pyrimethamine; Biological: Sanaria PfSPZ Challenge

Pilot (1d):1 injection of 2x10^5 PfSPZ Challenge+pyrimethamine

EXPERIMENTAL

Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 50mg of pyrimethamine dosed on days 2 and 3 after injection

Drug: Pyrimethamine; Biological: Sanaria PfSPZ Challenge

Pilot (5a): 1 injection of 1x10^5 PfSPZ Challenge+chloroquine

EXPERIMENTAL

Pilot Phase - 1 injection of 1x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection

Drug: Chloroquine Phosphate; Biological: Sanaria PfSPZ Challenge

Pilot (5b): 1 injection of 2x10^5 PfSPZ Challenge+chloroquine

EXPERIMENTAL

Pilot Phase - 1 injection of 2x10\^5 sporozoites of PfSPZ Challenge (NF54) with 1000mg of chloroquine (loading dose) 2 days prior to injections and 500mg (maintenance dose) 5 days post injection

Drug: Chloroquine Phosphate; Biological: Sanaria PfSPZ Challenge

Main (2a):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+NF54

EXPERIMENTAL

Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + homologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (NF54) at 12 weeks after third injection

Drug: Pyrimethamine; Biological: Sanaria PfSPZ Challenge

Main (2b):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+7G8

EXPERIMENTAL

Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + pyrimethamine on days 2 and 3 post injection + heterologous CHMI with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection

Drug: Pyrimethamine; Biological: Sanaria PfSPZ Challenge

Main (3):3 doses of 2x10^5 PfSPZ Challenge+chloroquine+7G8

EXPERIMENTAL

Main Phase - 3 monthly doses of 2x10\^5 sporozoites of PfSPZ Challenge + weekly chloroquine (1000mg given 2 days prior to injections and 500mg given 5 days post injection and weekly thereafter until 5 days post third injection) + heterologous controlled human malaria infection (CHMI) with 3.2x10\^3 PfSPZ Challenge (7G8) at 12 weeks after third injection

Drug: Chloroquine Phosphate; Biological: Sanaria PfSPZ Challenge

Main Phase (4a) - Infectivity Control: NF54 (homologous) CHMI

EXPERIMENTAL

Main Phase - Infectivity Control with one dose of 3.2x10\^3 sporozoites of PfSPZ Challenge (NF54) (homologous) controlled human malaria infection (CHMI)

Biological: Sanaria PfSPZ Challenge

Main Phase (4b) - Infectivity Control: 7G8 (heterologous) CHMI

EXPERIMENTAL

Main Phase - Infectivity Control with 3.2x10\^3 sporozoites of PfSPZ Challenge 7G8 (heterologous) controlled human malaria infection (CHMI)

Biological: Sanaria PfSPZ Challenge

Interventions

Chloroquine Phosphate DRUG

Chloroquine has been widely used for treatment and prophylaxis of malaria since 1946 (Most, London et al. 1984). It was the treatment of choice for uncomplicated malaria for decades because it was safe, well tolerated, affordable and highly effective for the treatment of malaria. However, increasing spread of chloroquine- resistant Pf over the last two decades has severely limited its use (Wellems 2002). Chloroquine phosphate is U.S Food and Drug Administration (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.

Main (3):3 doses of 2x10^5 PfSPZ Challenge+chloroquine+7G8; Pilot (5a): 1 injection of 1x10^5 PfSPZ Challenge+chloroquine; Pilot (5b): 1 injection of 2x10^5 PfSPZ Challenge+chloroquine

Pyrimethamine DRUG

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. January2014)

Main (2a):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+NF54; Main (2b):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+7G8; Pilot (1a): 1 injection of 5x10^4 PfSPZ Challenge+pyrimethamine; Pilot (1b):1 injection of 1x10^5 PfSPZ Challenge+pyrimethamine; Pilot (1d):1 injection of 2x10^5 PfSPZ Challenge+pyrimethamine

Sanaria PfSPZ Challenge BIOLOGICAL

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.

Main (2a):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+NF54; Main (2b):3 doses of 2x10^5 PfSPZ Challenge+pyrimethamine+7G8; Main (3):3 doses of 2x10^5 PfSPZ Challenge+chloroquine+7G8; Main Phase (4a) - Infectivity Control: NF54 (homologous) CHMI; Main Phase (4b) - Infectivity Control: 7G8 (heterologous) CHMI; Pilot (1a): 1 injection of 5x10^4 PfSPZ Challenge+pyrimethamine; Pilot (1b):1 injection of 1x10^5 PfSPZ Challenge+pyrimethamine; Pilot (1d):1 injection of 2x10^5 PfSPZ Challenge+pyrimethamine; Pilot (5a): 1 injection of 1x10^5 PfSPZ Challenge+chloroquine; Pilot (5b): 1 injection of 2x10^5 PfSPZ Challenge+chloroquine

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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 (Endemic areas are defined per the CDC website. Factors such as but not limited to use of antimalaria prophylaxis during travel, length of stay, activities during the travel, history of illnesses within 30 days of travel will be considered to determine the likelihood that the subject was exposed to malaria)
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Sanaria Inc.: collaborator

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Bijker EM, Borrmann S, Kappe SH, Mordmuller B, Sack BK, Khan SM. Novel approaches to whole sporozoite vaccination against malaria. Vaccine. 2015 Dec 22;33(52):7462-8. doi: 10.1016/j.vaccine.2015.09.095. Epub 2015 Oct 23.

  PMID: 26469716 BACKGROUND

• Mordmuller B, Supan C, Sim KL, Gomez-Perez GP, Ospina Salazar CL, Held J, Bolte S, Esen M, Tschan S, Joanny F, Lamsfus Calle C, Lohr SJ, Lalremruata A, Gunasekera A, James ER, Billingsley PF, Richman A, Chakravarty S, Legarda A, Munoz J, Antonijoan RM, Ballester MR, Hoffman SL, Alonso PL, Kremsner PG. Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J. 2015 Mar 18;14:117. doi: 10.1186/s12936-015-0628-0.

  PMID: 25889522 BACKGROUND

• Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, van de Vegte-Bolmer M, van Schaijk B, Teelen K, Arens T, Spaarman L, de Mast Q, Roeffen W, Snounou G, Renia L, van der Ven A, Hermsen CC, Sauerwein R. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009 Jul 30;361(5):468-77. doi: 10.1056/NEJMoa0805832.

  PMID: 19641203 BACKGROUND

• Mwakingwe-Omari A, Healy SA, Lane J, Cook DM, Kalhori S, Wyatt C, Kolluri A, Marte-Salcedo O, Imeru A, Nason M, Ding LK, Decederfelt H, Duan J, Neal J, Raiten J, Lee G, Hume JCC, Jeon JE, Ikpeama I, Kc N, Chakravarty S, Murshedkar T, Church LWP, Manoj A, Gunasekera A, Anderson C, Murphy SC, March S, Bhatia SN, James ER, Billingsley PF, Sim BKL, Richie TL, Zaidi I, Hoffman SL, Duffy PE. Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity. Nature. 2021 Jul;595(7866):289-294. doi: 10.1038/s41586-021-03684-z. Epub 2021 Jun 30.

  PMID: 34194041 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Malaria; Parasitemia

Interventions

chloroquine diphosphate; Pyrimethamine

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Patrick Duffy
• Organization: National Institute of Allergy and Infectious Diseases

Patrick.Duffy@nih.gov

(301) 761-5089

Study Officials

• Patrick E Duffy, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 14, 2017
• First Posted: March 20, 2017
• Study Start: June 5, 2017
• Primary Completion: June 26, 2019
• Study Completion: June 26, 2019
• Last Updated: June 1, 2021
• Results First Posted: July 24, 2020

Record last verified: 2019-12-09

Locations

US (1)