Study of Malaria Vaccine RTS,S/AS01E in Plasmodium Falciparum-infected and Uninfected Adults Pre-treated With Anti-malarial Therapy

NCT04661579 | Completed Phase 2 Results

• 2 other identifiers: CVIA 078PACTR202006896481432
• Study Type: interventional
• Target: 620
• Locations: 1 country
• Sites: 1

Brief Summary

The main goal of this study is to assess the efficacy of RTS,S/AS01E, a candidate vaccine against malaria caused by Plasmodium falciparum (P. falciparum), in adults positive for P. falciparum at the start of the study, but treated with anti-malarial medications to clear the parasite before receiving multiple doses of the vaccine. The goal is to overcome the reduced vaccine efficacy (hypo-responsiveness to the vaccine) reported in actively or chronically infected adults.

Conditions

Plasmodium Falciparum

Keywords

RTS,S/AS01E; hypo-immuno-responsiveness; open-label randomized study; Phase 2b; Kenyan adults; anti-malarials; fractional dose RTS,S/AS01E

Outcome Measures

Primary Outcomes (1)

• Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4

  Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive polymerase chain reaction (PCR) (Plasmodium falciparum/ Pan-Plasmodium 18S ribosomal ribonucleic acid (rRNA) laboratory developed test \[LDT\]) that can detect sub-clinical parasitemia at the US Army Medical Research Directorate-Africa (USAMRD-A) / Kenya Medical Research Institute (KEMRI) laboratories in Kisumu, Kenya. A positive PCR result from blood samples collected during the ADI was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.

  The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.

Secondary Outcomes (7)

• Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5

  The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.

• Number of Participants With Serious Adverse Events (SAEs)

  From first dose to end of study, up to 65 weeks.

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

  Within 7 days after each vaccination.

• Number of Participants With Unsolicited Adverse Events

  Within 28 days after each vaccination.

• Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3

  Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination)

Study Arms (5)

Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine

EXPERIMENTAL

Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.

Biological: Malaria Vaccine RTS,S/AS01E; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Drug: Artemether / Lumefantrine; Drug: Primaquine

Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine

EXPERIMENTAL

Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.

Biological: Malaria Vaccine RTS,S/AS01E; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Drug: Artemether / Lumefantrine; Drug: Primaquine

Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine

EXPERIMENTAL

Participants with detectable P. falciparum parasitemia at baseline did not receive any anti-malarial medications to clear parasites. Participants received 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. This group is included only for immunological assessment and not for vaccine efficacy.

Biological: Malaria Vaccine RTS,S/AS01E

Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine

PLACEBO COMPARATOR

Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with dihydroartemisinin-piperaquine (DHA/Pip) plus low dose primaquine (LD PQ) 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of artemether/lumefantrine (A/L) plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.

Biological: Abhayrab rabies vaccine; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Drug: Artemether / Lumefantrine; Drug: Primaquine

Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine

PLACEBO COMPARATOR

Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered. Participants received 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule.

Biological: Abhayrab rabies vaccine; Drug: Dihydroartemisinin-piperaquine (DHA/Pip); Drug: Artemether / Lumefantrine; Drug: Primaquine

Interventions

Malaria Vaccine RTS,S/AS01E BIOLOGICAL

RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization.

Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine; Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine; Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine

Abhayrab rabies vaccine BIOLOGICAL

Abhayrab rabies vaccine, 0.5 mL, contains 2.5 IU rabies antigen.

Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine; Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine

Dihydroartemisinin-piperaquine (DHA/Pip) DRUG

Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.

Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine; Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine; Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine; Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine

Artemether / Lumefantrine DRUG

Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.

Also known as: Coartem®

Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine; Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine; Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine; Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine

Primaquine DRUG

One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.

Group 1: Positive Parasitemia; Anti-malarial treatment + RTS,S/AS01E Vaccine; Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine; Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine; Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed or thumb printed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male or female between 18 and 55 years of age, inclusive
• In good general health as evidenced by medical history and clinical examination before entering the study
• Ability to take oral medication and be willing to adhere to the medication regimen
• For females, she must be of non-childbearing potential or use appropriate measures to prevent pregnancy for 30 days prior to vaccination through 2 months after completion of the vaccine series. Non-childbearing potential means she is surgically sterilized or at least one year post-menopausal. Appropriate measures to prevent pregnancy include abstinence or adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant or Depo-Provera). Clinical trial site staff will assist with provision of acceptable birth control for study entry and will discuss with volunteer at screening visit.

You may not qualify if:

• Planned administration/administration of a vaccine not foreseen by the study protocol from within 30 days before the first dose of study vaccine until 30 days after the last dose of study vaccine.†
• Any prior receipt of any rabies vaccine or experimental malaria vaccine.
• Confirmed or suspected significant immunosuppressive or immunodeficient condition as determined by the investigator, including clinical stage 3 or 4 human immunodeficiency virus (HIV) infection.
• A family history of congenital or hereditary immunodeficiency.
• History of allergic reactions, significant immunoglobulin E (IgE)-mediated events or anaphylaxis to previous immunizations.
• History of any neurologic disorders.
• Acute disease (defined as the presence of a moderate or severe illness with or without fever), including acute malaria, at the time of enrolment. All vaccines can be administered to persons with a minor illness, such as diarrhea or mild upper respiratory infection without fever, i.e. Oral temperature \< 37.5°C\*. Individuals excluded with acute disease, including acute malaria, can become eligible again after complete recovery of the illness, including appropriate treatment as applicable, and can be rescreened at a later date. \*Temperature readings may be taken by site staff either using either oral, axillary, or infrared thermal thermometers during clinic or field visits, while subjects enrolled in the reactogenicity cohort will be supplied with oral thermometers for the purposes of recording their own temperature measurements in the memory aid over 7 days after each vaccination.
• Acute or chronic, clinically significant pulmonary, cardiovascular (including cardiac arrythmias) , hepatic or renal functional abnormality, as determined by medical history, physical examination or laboratory screening tests.
• History of homozygous sickle cell disease (Hgb SS).
• Any clinically significant laboratory abnormalities as determined by the investigator on screening labs.
• History of splenectomy.
• Administration of immunoglobulins, blood transfusions or other blood products within the three months preceding the first dose of study vaccine or planned administration during the study period.
• Pregnant (i.e. a positive pregnancy test) or lactating female during immunization phase of the study (refer to section 2.3 for rationale). If a woman becomes pregnant after all vaccinations are complete, she will not be excluded from the remainder of the study.
• Female planning to become pregnant or planning to discontinue contraceptive precautions during the vaccination phase.
• History of chronic alcohol consumption and/or drug abuse.

Sponsors & Collaborators

• PATH: lead
• Walter Reed Army Institute of Research (WRAIR): collaborator
• GlaxoSmithKline: collaborator
• Kenya Medical Research Institute: collaborator
• FHI Clinical SA Proprietary Limited: collaborator
• DF/Net: collaborator

Study Sites (1)

Lucas O Tina

Kisumu, Kisumu County, 40100, Kenya

Location

Related Publications (17)

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• RTS,S Clinical Trials Partnership; Agnandji ST, Lell B, Fernandes JF, Abossolo BP, Methogo BG, Kabwende AL, Adegnika AA, Mordmuller B, Issifou S, Kremsner PG, Sacarlal J, Aide P, Lanaspa M, Aponte JJ, Machevo S, Acacio S, Bulo H, Sigauque B, Macete E, Alonso P, Abdulla S, Salim N, Minja R, Mpina M, Ahmed S, Ali AM, Mtoro AT, Hamad AS, Mutani P, Tanner M, Tinto H, D'Alessandro U, Sorgho H, Valea I, Bihoun B, Guiraud I, Kabore B, Sombie O, Guiguemde RT, Ouedraogo JB, Hamel MJ, Kariuki S, Oneko M, Odero C, Otieno K, Awino N, McMorrow M, Muturi-Kioi V, Laserson KF, Slutsker L, Otieno W, Otieno L, Otsyula N, Gondi S, Otieno A, Owira V, Oguk E, Odongo G, Woods JB, Ogutu B, Njuguna P, Chilengi R, Akoo P, Kerubo C, Maingi C, Lang T, Olotu A, Bejon P, Marsh K, Mwambingu G, Owusu-Agyei S, Asante KP, Osei-Kwakye K, Boahen O, Dosoo D, Asante I, Adjei G, Kwara E, Chandramohan D, Greenwood B, Lusingu J, Gesase S, Malabeja A, Abdul O, Mahende C, Liheluka E, Malle L, Lemnge M, Theander TG, Drakeley C, Ansong D, Agbenyega T, Adjei S, Boateng HO, Rettig T, Bawa J, Sylverken J, Sambian D, Sarfo A, Agyekum A, Martinson F, Hoffman I, Mvalo T, Kamthunzi P, Nkomo R, Tembo T, Tegha G, Tsidya M, Kilembe J, Chawinga C, Ballou WR, Cohen J, Guerra Y, Jongert E, Lapierre D, Leach A, Lievens M, Ofori-Anyinam O, Olivier A, Vekemans J, Carter T, Kaslow D, Leboulleux D, Loucq C, Radford A, Savarese B, Schellenberg D, Sillman M, Vansadia P. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med. 2012 Dec 13;367(24):2284-95. doi: 10.1056/NEJMoa1208394. Epub 2012 Nov 9.

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• RTS,S Clinical Trials Partnership. Efficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014 Jul 29;11(7):e1001685. doi: 10.1371/journal.pmed.1001685. eCollection 2014 Jul.

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MeSH Terms

Conditions

Malaria, Falciparum

Interventions

RTS malaria vaccine; Artemether, Lumefantrine Drug Combination; Primaquine

Condition Hierarchy (Ancestors)

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Artemether; Artemisinins; Reactive Oxygen Species; Free Radicals; Inorganic Chemicals; Organic Chemicals; Lumefantrine; Fluorenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sesquiterpenes; Terpenes; Polycyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Christian F. Ockenhouse, MD, PhD
• Organization: PATH

cockenhouse@path.org

1 (206) 285-3500

Study Officials

• Lucas O Tina, MD, MTM&H

  Kombewa Clinical Research Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Three groups (Groups 1, 2, and 3) will be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th fractional dose. Two groups (Groups 4 and 5) will be administered a comparator vaccine on a 0, 1, 7 month schedule.

Study Record Dates

• First Submitted: October 26, 2020
• First Posted: December 10, 2020
• Study Start: November 6, 2020
• Primary Completion: June 22, 2022
• Study Completion: August 17, 2022
• Last Updated: July 19, 2024
• Results First Posted: July 19, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

KE (1)