Safety, Tolerability and Efficacy Against Controlled Human Malaria Infection of PfSPZ-LARC2 Vaccine in Malaria-naïve Adults
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- Sanaria Inc.
- 入组人数
- 58
- 试验地点
- 1
- 主要终点
- Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: infection
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled Phase 1 trial of Plasmodium falciparum (Pf) sporozoite (SPZ) late-arresting replication-competent (LARC) malaria vaccine (PfSPZ-LARC2 Vaccine) administered to healthy, malaria-naive study participants in Germany by direct venous inoculation (DVI) to determine safety, tolerability, and vaccine efficacy (VE) against controlled human malaria infection (CHMI). PfSPZ-LARC2 Vaccine contains a deletion of two genes, the Mei2 and LINUP genes, and undergoes developmental arrest in the late liver stages without releasing merozoites into the blood stream (blood stage parasites).
The primary objective of the study is to assess the safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population.
详细描述
This is a randomized, double-blind, placebo-controlled, single-center Phase 1 clinical trial in two parts, with the performance of Part B conditional on the outcome of Part A.
In Part A, eligible healthy participants (N = 5) will be enrolled as a sentinel group that receives a single dose of 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1 and will be followed for 28 days (to Day 29) to identify any breakthrough infections. If there are no breakthrough infections by Day 29, the main cohort (n = 24) will undergo immunization. Participants in the verum group (n = 18) of the main cohort will also receive 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine or normal saline administered on Days 1, 6 and 29.
Participants in both the sentinel group and main cohort will be followed up for parasitemia and adverse events after immunization. After the first immunization on Day 1 in the sentinel group, qPCR will be performed to monitor for P. falciparum blood stage infections daily from Day 7 (day +6) to Day 21 (day +20) and then every other day to Day 29 (day +28) when terminal treatment begins. Thick blood smears (TBS) to monitor for blood stage parasitemia by microscopy will be made on the days that qPCR is performed and read in real-time. TBS will also be done whenever the physician investigator requests a rapid diagnostic test (for whatever reason).
If blood stage parasitemia is not detected during 28 days of follow-up of the sentinel group, the participants will be treated presumptively under direct observation with a three day regimen of atovaquone-proguanil or artemether-lumefantrine), to assure malaria-free status at the end of their participation in the trial.
As soon as the Day 29 qPCR of the sentinel volunteers is determined to be negative, the 24 participants of the main cohort may receive their first immunization with PfSPZ-LARC2 Vaccine or placebo. Following a first immunization on Day 1, the main cohort will receive a second immunization five days later, on Day 6. The qPCR follow-up for the first immunization begins on the next day (Day 7) and will be performed daily from Day 7 (day +6) to Day 12 (day +11), then every other day to Day 22 (day +21) and then weekly thereafter until four weeks after the third immunization, noting that the chance of breakthrough should be much reduced after the first and second immunizations due to the development of immunity. TBS will be performed concurrently as described above and read in real-time.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Access to the unblinded randomization list will be limited exclusively to the syringe preparation team (Pharmaceutical Operations team) and the independent statistician(s) at the data management vendor. These individuals will be unblinded and will not be involved in evaluation or care of the study participants. A copy of participant treatment assignments will be retained at the site in a secure file by the unblinded Pharmaceutical Operations staff.
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adults (male or non-pregnant female) 18 to 45 years of age.
- •Able and willing to participate for the duration of the study.
- •Able and willing to provide written informed consent.
- •Physical examination and laboratory results without clinically significant findings.
- •Women of childbearing potential must agree to use effective means of birth control (e.g. oral or implanted contraceptives, IUD, female condom, diaphragm with spermicide, cervical cap, abstinence, use of a condom by the sexual partner or sterile sexual partner) during the entire study.
- •Due to the potential for reduced effectiveness of hormonal contraceptives during artemether and/or lumefantrine treatment, participants will be counseled to add an additional barrier method of contraception during treatment.
- •Women with a history of surgical or chemical sterilization (e.g. tubal ligation, hysterectomy, other) must provide written documentation of the procedure from a health care provider.
- •Agree not to travel to a malaria endemic region during the course of the trial.
排除标准
- •Unable to provide informed consent including inability to pass the test of understanding.
- •Receipt of a malaria vaccine in a prior clinical trial.
- •History of a splenectomy or sickle cell disease.
- •History of a neurologic disorder (including non-febrile seizures or complex febrile seizures) or formal history of migraine headache.
- •Current use of systemic immunosuppressant pharmacotherapy.
- •Receipt of a live vaccine within 4 weeks of first immunization or of 3 or more non-live vaccines within 2 weeks of first immunization.
- •Women who are breast-feeding, pregnant or planning to become pregnant during the study period.
- •Known allergy or hypersensitivity reaction (e.g., anaphylaxis, erythema multiforme or Stevens-Johnson syndrome, angioedema, vasculitis) to atovaquone-proguanil (Malarone®), artemether-lumefantrine (Coartem®), any components of these formulations, or any component of the investigational products.
- •History of anaphylaxis or other life-threatening reaction to a vaccine.
- •Participation in any study involving investigational vaccine or drug within 4 weeks prior to enrollment that in the estimation of the site PI might adversely affect the individual's safety or the quality of data to be collected.
- •Evidence of increased cardiovascular disease risk; defined as >10% five-year risk by non-laboratory method (Gaziano, 2008) [80].
- •Plan to participate in another investigational vaccine/drug research during the study.
- •Plan for major surgery between enrollment until 28 days post-CHMI.
- •Use or planned use of any drug with anti-malarial activity that would precede or coincide with malaria challenge or vaccination.
- •Anticipated use of medications known to cause drug reactions with atovaquone-proguanil or artemether-lumefantrine such as tetracycline, rifampin, rifabutin, cimetidine, metoclopramide, antacids, anti-coagulants such as coumarin, indinavir, and kaolin.
- •Anticipated use of medications known to:
- •Be substrates, inhibitors or strong inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, and/or St. John's wort) [strong inducers of CYP3A4 when taken concomitantly with artemether and/or lumefantrine can result in decreased concentration(s) and loss of antimalarial efficacy].
- •Be metabolized by the cytochrome enzyme CYP2D6 (e.g., primaquine, tafenoquine, flecainide, imipramine, amitriptyline, clomipramine).
- •Have a mixed effect on CYP3A4 (e.g., antiretrovirals).
- •Prolong the QT interval (e.g., quinine, quinidine, halofantrine, mefloquine, procainamide, disopyramideamiodarone, sotalol, pimozide, ziprasidone, tetracycline, doxycline, fluoroquinolone, imidazole, and triazole antifungal agents). Note: in the case of halofantrine, this drug may not be used within a month of artemether/lumefantrine due to its very significant effect on QT interval.
- •Positive HIV, HBsAg or HCV serology.
- •An abnormal electrocardiogram, defined as one showing pathologic Q waves and significant ST-T wave changes; left ventricular hypertrophy; any non-sinus rhythm including isolated premature ventricular contractions, but excluding isolated premature atrial contractions; right or left bundle branch block; or advanced (secondary or tertiary) A-V heart block; or other clinically significant abnormalities on the electrocardiogram.
- •History of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
- •Family history (grandparents, parents or siblings) of congenital prolongation of the QT interval or sudden death.
- •History of disturbances of the electrolyte balance (e.g., hypokalemia or hypomagnesemia).
- •History of severe renal impairment (creatinine clearance <30 mL/min) (risk of pancytopenia in patients with severe renal impairment treated with proguanil).
- •History of chronic liver disease.
- •Any clinically significant deviation from the normal range in biochemistry or hematology tests measured at screening and not resolving.
- •Any medical, psychiatric, social, behavioral or occupational condition or situation (including active alcohol or drug abuse) that, in the judgment of the site PI, impairs the participant's ability to give informed consent, increases the risk to the participant of participation in the study, affects the ability of the participant to participate fully in the study, or might negatively impact the quality, consistency, integrity or interpretation of data derived from their participation in the study. This includes persons in emergency situations such as refugees.
研究组 & 干预措施
Part B Main Cohort Normal Saline control group
The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: Normal Saline (Placebo) (Other)
Part B Main Cohort Normal Saline control group
The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: PfSPZ Challenge (NF54) (Biological)
Part B Main Cohort PfSPZ-LARC2 verum group
If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 4x10^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 4x10^5 PfSPZ of PfSPZ-LARC2 Vaccine administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: PfSPZ Challenge (NF54) (Biological)
Part A Sentinel Group PfSPZ-LARC2
A sentinel group of 5 volunteers in part A that receives a single dose of 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1, will be followed for 28 days (to Day 29) to identify any breakthrough infections.
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Part A Main Cohort PfSPZ-LARC2 verum group
If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Part A Main Cohort PfSPZ-LARC2 verum group
If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 2x10^5 PfSPZ of PfSPZ-LARC2 Vaccine administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: PfSPZ Challenge (NF54) (Biological)
Part A Main Cohort Normal Saline control group
The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
Edit
干预措施: Normal Saline (Placebo) (Other)
Part A Main Cohort Normal Saline control group
The blinded control group (n = 6) of the main cohort will receive normal saline as placebo, also by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen of normal saline administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
Edit
干预措施: PfSPZ Challenge (NF54) (Biological)
Part B Sentinel Group PfSPZ-LARC2
If any vaccinee in Part A develops Pf parasitemia following CHMI, and if the safety monitoring committee (SMC) has recommended that the study should continue, the study will proceed to Part B in which the dose of PfSPZ-LARC2 Vaccine will be doubled to 4x10^5 PfSPZ. A sentinel group of 5 volunteers in part B that receives a single dose of 4x10^5 PfSPZ of PfSPZ-LARC2 Vaccine by direct venous inoculation (DVI) on Day 1, will be followed for 28 days (to Day 29) to identify any breakthrough infections.
干预措施: PfSPZ-LARC2 Vaccine (Biological)
Part B Main Cohort PfSPZ-LARC2 verum group
If there are no breakthrough infections by Day 29 in the sentinel, the verum group in the main cohort (n = 18) will undergo immunization. Participants will receive 4x10^5 PfSPZ of PfSPZ-LARC2 Vaccine per immunization dose by DVI. All of the participants in the main cohort will progress through a 3-dose immunization regimen with 4x10^5 PfSPZ of PfSPZ-LARC2 Vaccine administered on Days 1, 6 and 29. Twelve weeks after the third immunization dose, the main cohort participants will undergo homologous CHMI using DVI of 3.2x10^3 PfSPZ of PfSPZ Challenge (NF54).
干预措施: PfSPZ-LARC2 Vaccine (Biological)
结局指标
主要结局
Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: infection
时间窗: 28 days after immunization
Number of trial participants with blood stage infection during the first 28 days after immunization.
Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: related AEs
时间窗: 7 days after injection of PfSPZ-LARC2 Vaccine
Incidence of at least possibly related grade 3 solicited adverse events (AE) and grade 3 abnormal laboratory values occurring in the 7 days after injection of PfSPZ-LARC2 Vaccine .
Safety and tolerability of administration of PfSPZ-LARC2 Vaccine, with special attention to the adequacy of attenuation, in the intention-to-treat (ITT) population: related SAEs
时间窗: Time of first immunization to the end of the study
Incidence of related serious adverse events (SAEs)
次要结局
- Vaccine Efficacy (VE) (1 minus the risk ratio) against homologous CHMI with PfSPZ Challeng(NF54) conducted 12 weeks after 3rd immunization in the modified ITT (mITT) population(21 days following CHMI)
- Humoral immune responses to PfCSP and their relationship to VE.(The day before immunization until 21 days post CHMI)