Clinical trial NCT03162614: Efficacy, Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine Evaluating Different Dose Schedules in a Sporozoite Challenge Model in Healthy Malaria-naïve Adults
Official title: Efficacy, Immunogenicity and Safety Study of GSK Biologicals' Candidate Malaria Vaccine (SB257049) Evaluating Various Dose Schedules in a Sporozoite Challenge Model in Healthy Malaria-naïve Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Malaria
Keywords: healthy volunteers
Malaria
malaria vaccine
controlled human challenge
RTS,S/AS01
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: The PATH Malaria Vaccine Initiative (MVI)
First posted: 2017-05-22
Enrollment: 154
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study is designed to evaluate efficacy, immunogenicity and safety of various dose schedules of GSK Biologicals' candidate malaria vaccines RTS,S/AS01B (adult formulation) and RTS,S/AS01E (pediatric formulation) in healthy malaria-naïve subjects aged 18-55 years. The purpose of this study is to investigate whether changes in dosing schedule are associated with increased or equivalent protection, and to evaluate the immune mechanisms associated with vaccine efficacy under varying dosing schedules.

Detailed description: Protocol Amendment 1 incorporated: additional blood sampling for assessment of parasitemia (polymerase chain reaction \[PCR\] testing); clarification that blood samples for both peripheral blood mononuclear cells (PBMC) and plasma will be collected for repository storage; revision of volume of whole blood samples to be taken for parasitemia assessment; clarification that urine pregnancy tests will be conducted for all females and not just those of childbearing potential; deletion of visit at Day 1 post day of challenge; clarification that RNA sequencing and not deep sequencing will be performed in this study.

Note that as a result of internal change in data standards terminology, the study data collected was converted to cDISC and the statistical analysis plan was amended accordingly. "Day 0" in the study design was replaced by "Day 1"; consequently, "Day n" was replaced by "Day n+1". Thus, the timeframes (Day 0, Day n) of Outcome Measures described in this study record are different to that denoted in the full protocol document posted.

Eligibility criteria: Inclusion Criteria:

* Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
* Written informed consent obtained from the subject prior to performing of any study specific procedure.
* A male or female between, and including, 18 and 55 years of age at the time of enrolment.
* Healthy subjects as established by medical history and clinical examination before entering into the study.
* Available to participate for the duration of the study.
* Female subjects of non-childbearing potential may be enrolled in the study.

  - Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause.
* Female subjects of childbearing potential may be enrolled in the study, if the subject:

  * has practiced adequate contraception for 30 days prior to vaccination, and
  * has a negative pregnancy test at enrolment, and
  * has agreed to continue adequate contraception during the entire treatment period and for two months after completion of the vaccination series and/or malaria challenge.

Exclusion Criteria:

* Use of any investigational or non-registered product (drug or vaccine) other than the study vaccines during the period starting 30 days before the first dose of study vaccines (Day -29 to Day 0), or planned use during the study period.
* Any medical condition that in the judgment of the investigator would make intramuscular injection unsafe.
* Chronic administration of immunosuppressants or other immune-modifying drugs during the period starting six months prior to the first vaccine dose. For corticosteroids, this will mean prednisone ≥ 20 mg/day, or equivalent. Inhaled and topical steroids are allowed.
* Administration of long-acting immune-modifying drugs at any time during the study period.
* Chronic use of antibiotics with antimalarial effects.
* Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting seven days before the first dose.
* Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational vaccine/product.
* Seropositive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV).
* Documented HIV-positive subject.
* Previous vaccination against malaria.
* History of malaria chemoprophylaxis within 60 days prior to vaccination.
* Any history of malaria (for the vaccine groups).
* Planned travel to malaria endemic areas during the study period.
* History of splenectomy.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
* Family history of congenital or hereditary immunodeficiency.
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccine.
* History of anaphylaxis post-vaccination.
* Hypersensitivity to latex.
* History of any reaction or hypersensitivity likely to be exacerbated by chloroquine.
* History of psoriasis and porphyria, which may be exacerbated after chloroquine treatment.
* Current use of medications known to cause drug reactions to chloroquine.
* History of severe reactions to mosquito bites.
* Major congenital defects.
* Serious chronic illness.
* History of any neurological disorders or seizures.
* Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 37.5°C/99.5°F for oral, axillary or tympanic route, or ≥ 38.0°C/100.4°F for rectal route.

  - Subjects with a minor illness without fever may be enrolled at the discretion of the investigator.
* Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests.
* Any abnormal baseline laboratory screening tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, hemoglobin, platelet count, total white blood cells (WBC), out of normal range as defined in the protocol.
* Evidence of increased cardiovascular disease risk, "moderate" or "high", according to the National health and nutrition examination survey I criteria.
* Hepatomegaly, right upper quadrant abdominal pain or tenderness.
* Personal history of autoimmune disease.
* Administration of immunoglobulins and/or any blood products during the period starting three months before the first dose of study vaccine or planned administration during the study period.
* Pregnant or lactating female.
* History of chronic alcohol consumption and/or drug abuse.
* Female planning to become pregnant or planning to discontinue contraceptive precautions.
* History of blood donation within 56 days preceding enrolment.
* Any other significant finding that in the opinion of the investigator would increase the risk of having an adverse outcome from participating in this study.

Primary outcomes:
measure: Number of Subjects With at Least One Occurrence of Plasmodium Falciparum (P. Falciparum) Parasitemia for Each Vaccination Schedule Versus Infectivity Controls
timeFrame: Following sporozoite challenge starting 3 months after the last vaccine dose (Day 287) for up to 28 days post-challenge (Day 315).
Secondary outcomes:
measure: Time to Onset of P. Falciparum Parasitemia After Sporozoite Challenge for Each Vaccination Schedule
timeFrame: Following sporozoite challenge starting 3 months after the last vaccine dose (at Day 287) for up to 28 days post-challenge (at Day 315).
measure: Anti-Circumsporozoite (Anti-CS) Repeat Region Antibody Concentrations
timeFrame: At Day 1, Day 59, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx Groups. At Day 1, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from Adu1Fx Group
measure: Anti-Hepatitis B (Anti-HBs) Immunoglobulin G (IgG) Antibody Concentrations
timeFrame: At Day 1, Day 59, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from AduFx, 2PedFx, PedFx, and Adu2Fx Groups. At Day 1, Day 197, Day 227, Day 287, Day 315, and Day 377 for subjects from Adu1Fx Group
measure: Number of Subjects With Any Solicited Local Symptoms
timeFrame: Within the 7-day period (Days 1-7) after dose 1, dose 2 (except for Adu1Fx Group) and dose 3.
measure: Number of Subjects With Any Solicited General Symptoms
timeFrame: Within the 7-day period (Days 1-7) after dose 1, dose 2 (except for Adu1Fx Group) and dose 3.
measure: Number of Subjects With Any Unsolicited Adverse Events (AEs) After Any Vaccination
timeFrame: Within the 30-day period (Days 1-30), after any vaccination (across doses)
measure: Number of Subjects With Any Unsolicited AEs After Challenge
timeFrame: Within the 30-day (Days 1-30) period post-challenge
measure: Number of Subjects With Any, Fatal or Related Serious Adverse Events (SAEs) After Each Vaccination
timeFrame: Within the 30-day period (Days 1-30) after any vaccination (across doses)
measure: Number of Subjects With Any, Fatal or Related SAEs During the Whole Study Period
timeFrame: From Day 1 up to study conclusion (Day 377)
measure: Number of Subjects With Any AE and SAE Leading to Withdrawal From Further Vaccination
timeFrame: From Day 1 up to study conclusion (Day 377)
measure: Number of Subjects With Potential Immune Mediated Diseases (pIMDs)
timeFrame: From Day 1 up to study conclusion (Day 377)
measure: Number of Subjects With Meningitis
timeFrame: From Day 1 up to study conclusion (Day 377)
measure: Number of Subjects With Abnormal Laboratory Values Gradings
timeFrame: At Visit 1 Screening (Day -89 to Day 1), Day 36, Day 59, Day 204, Day 227, between Day 292 & Day 313, and Day 315 for each vaccinated subject.For Infectivity Control subjects at Visit 1b Screening (Day 231 to Day 287),between Day 292 & Day 313,and Day 315
measure: Number of Subjects With Any, Fatal or Related SAE, After Challenge
timeFrame: From day of challenge (Day 287) to the end of the challenge phase (Day 315)
Other outcomes:
Locations:
city: Silver Spring
country: United States
facility: GSK Investigational Site
state: Maryland
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: James E. Moon, Christian Ockenhouse, Jason A. Regules, Johan Vekemans, Cynthia Lee, Ilin Chuang, Magali Traskine, Erik Jongert, Karen Ivinson, Danielle Morelle, Jack L. Komisar, Marc Lievens, Martha Sedegah, Lindsey Garver, April K. Sikaffy, Norman C. Waters, William Ripley Ballou, Opokua Ofori-Anyinam for the RTS,S Malaria Vaccine Working Group. CLI_092_A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naïve Adults. J Infect Dis. 2020 Jul 20;jiaa421. doi: 10.1093/infdis/jiaa421. Online ahead of print.
citation: Moon JE, Ockenhouse C, Regules JA, Vekemans J, Lee C, Chuang I, Traskine M, Jongert E, Ivinson K, Morelle D, Komisar JL, Lievens M, Sedegah M, Garver LS, Sikaffy AK, Waters NC, Ballou WR, Ofori-Anyinam O; RTS,S Malaria Vaccine Working Group. A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naive Adults. J Infect Dis. 2020 Oct 13;222(10):1681-1691. doi: 10.1093/infdis/jiaa421.