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Safety and Immunogenicity of the Malaria Vaccine, R21/MatrixM, in Healthy Thai Adults (R21/Matrix-M)

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.
 
ClinicalTrials.gov Identifier: NCT05252845
Recruitment Status : Not yet recruiting
First Posted : February 23, 2022
Last Update Posted : February 23, 2022
Sponsor:
Information provided by (Responsible Party):
University of Oxford

Brief Summary:

Malaria remains one of the leading causes of morbidity and mortality worldwide. Plasmodium falciparum is a complex pathogen with numerous immune evasion mechanisms which has added layers of complexity to the development of safe and protective vaccines. There remains an urgent need to identify and develop more protective and more affordable vaccine candidates that could achieve the World Health Organization (WHO) goal of 75% efficacy against clinical malaria.

R21 is a novel pre-erythrocytic candidate malaria vaccine. R21 includes Hepatitis B surface antigen (HBsAg) fused to the C-terminus and central repeats of the circumsporozoite protein of P. falciparum (CSP), which self-assemble into virus-like particles in yeast. R21 lacks the excess HBsAg found and comprises only fusion protein moieties.

R21/MatrixM (MM) had a favourable safety profile and was well tolerated. The majority of adverse events were mild, with the most common event being fever. None of the serious adverse events were attributed to the vaccine. At one year, vaccine efficacy remained high, at 77%. Participants vaccinated with R21/MM showed high titres of malaria-specific anti- Asn-Ala-Asn-Pro (NANP) antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres after the primary series of vaccinations after a fourth dose administered one year later.

Currently, there are no safety and immunogenicity data for the use of R21/MatrixM in Asian populations. This trial will generate the required data for the use of this vaccine in Asia. For integration with the current targeted malaria elimination (TME) activities, which provide mass drug administrations at months M0, M1, and M2, it would be most efficient and practical to provide the vaccine at the same intervals.

In summary: The investigators propose to conduct a safety and immunogenicity trial of R21/MatrixM in Thai adults. The major aims of this study are to 1) assess the safety and immunogenicity of R21/MatrixM in Thai adults 2) confirm that the co-administration of antimalarial drugs with the malaria vaccine R21/MatrixM does not reduce the immunogenicity of the vaccine and 3) assess the absorption and pharmacokinetics of antimalarial drugs piperaquine, and a single low dose of primaquine (SLDPQ) when co-administered with R21/MatrixM.

This is a randomized, open label, single centre, Phase 2 study. 120 healthy non-pregnant Thai adults, aged 18-55 years, inclusive, will be recruited.

Each participant will be randomized into one of the following study arms in a ratio of 5:5:2, as follows:

  1. R21/MatrixM + Dihydroartimisinin (DHA)-Piperaquine (PIP)+ primaquine (PQ) (Group 1, n=50) will receive R21/MatrixM + 3 doses DHA-PIP+PQ at Month 0, Month 1 and Month 2
  2. R21/MatrixM only (Group 2, n=50) will receive R21/MatrixM standard dose at Month 0, Month 1 and Month 2
  3. DHA-PIP+PQ only (Group 3, n=20) will receive 3 doses DHA-PIP+PQ at Month 0, Month 1 and Month 2

Condition or disease Intervention/treatment Phase
Malaria,Falciparum Biological: R21/Matrix-M vaccination Drug: DHA-PIP Drug: PQ Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Randomized, Open Label, Single Centre, Phase 2 Trial of the Malaria Vaccine, R21/Matrix-M, to Assess Safety and Immunogenicity of the Vaccine in Thai Adults
Estimated Study Start Date : July 2022
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Malaria Vaccines

Arm Intervention/treatment
Experimental: R21/Matrix-M + DHA-PIP+PQ
The R21/Matrix-M vaccine (IM injection) + co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine
Biological: R21/Matrix-M vaccination
R21/Matrix-M is the standard formulation of the vaccine (Once prepared, a standard dose of R21/Matrix-M contains approximately 5 µg of R21 antigen, in 0.5 mL of liquid adjuvant containing 50 µg MatrixM). The reconstituted vaccine will be administered by slow IM injection on Day 0 at Study Months 0, 1 and 2.

Drug: DHA-PIP
Dihydroartemisinin/piperaquine tablets for adult patients each contain 40 mg dihydroartemisinin and 320 mg piperaquine with a therapeutic dose range between 2-10 mg/kg/day dihydroartemisinin and 16-26 mg/kg/dose piperaquine. Participants will receive three rounds of antimalarial drugs - each round starting on the day of vaccination (Day 0) at Study Months 0, 1 and 2. Each round consists of three daily doses of co-formulated dihydroartemisinin/piperaquine on Day 0, 1, and 2.

Drug: PQ
Each participant will receive a single low dose primaquine on the day of vaccination (Day 0) at Month 0, Month 1, and Month 2. One single low dose primaquine of approximately 0.25 mg/kg will be administered.

Experimental: R21/Matrix-M only
The R21/Matrix-M vaccine (IM injection) only
Biological: R21/Matrix-M vaccination
R21/Matrix-M is the standard formulation of the vaccine (Once prepared, a standard dose of R21/Matrix-M contains approximately 5 µg of R21 antigen, in 0.5 mL of liquid adjuvant containing 50 µg MatrixM). The reconstituted vaccine will be administered by slow IM injection on Day 0 at Study Months 0, 1 and 2.

Active Comparator: DHA-PIP+PQ only
Co-formulated Dihydroartemisinin/Piperaquine tablets + one single low dose of Primaquine
Drug: DHA-PIP
Dihydroartemisinin/piperaquine tablets for adult patients each contain 40 mg dihydroartemisinin and 320 mg piperaquine with a therapeutic dose range between 2-10 mg/kg/day dihydroartemisinin and 16-26 mg/kg/dose piperaquine. Participants will receive three rounds of antimalarial drugs - each round starting on the day of vaccination (Day 0) at Study Months 0, 1 and 2. Each round consists of three daily doses of co-formulated dihydroartemisinin/piperaquine on Day 0, 1, and 2.

Drug: PQ
Each participant will receive a single low dose primaquine on the day of vaccination (Day 0) at Month 0, Month 1, and Month 2. One single low dose primaquine of approximately 0.25 mg/kg will be administered.




Primary Outcome Measures :
  1. Occurrence of adverse events (AEs), according to the Medical Dictionary for Regulatory Activities (MedRA) classification. [ Time Frame: From the date of the first vaccination to 29 days after the last vaccination ]
  2. Occurrence of serious adverse events (SAEs), according to the MedRA classification. [ Time Frame: During the whole study period, i.e. during a 6-month follow-up period from the receipt of first vaccination ]

Secondary Outcome Measures :
  1. For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody)circumsporozoite (anti-circumsporoziote antibody) [ Time Frame: One month after the first dose (at Study Month 1) ]
  2. For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody) [ Time Frame: One month after the second dose (at Study Month 2) ]
  3. For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody) [ Time Frame: One month after the third dose (at Study Month 3) ]
  4. For Arms 1 and 2, the concentration of antibodies against Plasmodium falciparum circumsporozoite (anti-NANP total IgG antibody) [ Time Frame: Six months after the first dose (at Study Month 6) ]
  5. Exploratory immunology endpoints including but not limited to cellular immunity [ Time Frame: One month after the first dose (at Study Month 1) ]
  6. Exploratory immunology endpoints including but not limited to cellular immunity [ Time Frame: One month after the second dose (at Study Month 2) ]
  7. Exploratory immunology endpoints including but not limited to cellular immunity [ Time Frame: One month after the third dose (at Study Month 3) ]
  8. Exploratory immunology endpoints including but not limited to cellular immunity [ Time Frame: Six months after the first dose (at Study Month 6) ]
  9. For Arms 1 and 3, piperaquine levels following the administration of the antimalarials with or without vaccine [ Time Frame: On day 0, 1, 2, and 7 of study month 0, 1, and 2 ]


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.


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

The participant is eligible to enter the study if all of the following apply:

  1. Participant is a healthy adult, aged 18 to 55 years (inclusive), of Thai origin.
  2. Participant is willing and able to give informed consent to participate in the trial
  3. Able, in the investigator's opinion, and willing to comply with the study requirements and follow-up.
  4. Women of childbearing potential: must agree to practice continuous, effective contraception for the duration of the trial, and have a negative pregnancy test before each vaccination. (Costs for contraceptives will be reimbursed by the trial.)

Exclusion criteria

The following criteria should be checked at the time of study entry. If ANY exclusion criterion applies, the subject must not be included in the study:

  1. Pregnancy or breastfeeding, or planned pregnancy during the course of the study.
  2. Presence of any medical condition (physical or mental) which, may place the participant at undue risk or interfere with the results of the study*. Including: serious cardiac, renal, hepatic or neurological disease, severe malnutrition
  3. Any confirmed or suspected immunosuppressive or immunodeficient condition. Including: history of splenectomy, human immunodeficiency virus (HIV) infection
  4. Chronic administration (>14 days in total) of immunosuppressants or other immune-modifying drugs within six months of enrollment. Including: oral corticosteroids equivalent to prednisone > 20 mg/day (a)
  5. History of an autoimmune disease
  6. Hepatitis B surface antigen (HBsAg) detected in serum.
  7. Screening electrocardiogram (ECG) demonstrating a QTc interval ≥ 450 ms
  8. Seropositivity for hepatitis C virus (antibodies to HCV) at screening (b)
  9. Finding on safety laboratory values as defined below:

    • AST > 2 x upper normal limit
    • ALT > 2 x upper normal limit
    • Anaemia (Hb < 10 g/dL),
    • Platelets < 100,000
    • Total bilirubin > 2 x upper normal limit
  10. Abnormalities of examination or investigations at screening. Including: hepatomegaly, right upper quadrant abdominal pain or tenderness, abnormal blood tests (as defined in the protocol which are not listed above)
  11. Positive malaria parasitaemia at screening or baseline (Month 0, Day 0).
  12. Receipt or planned receipt of an investigational medical product or participation in an interventional clinical trial during the study period
  13. Contraindications to the use of artemisinins, piperaquine or primaquine*. Including: use of medications with known potential interactions, prior allergic reactions to one or more components of the drug regimen.
  14. History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (e.g. egg products)
  15. History of clinically significant contact dermatitis.
  16. Contraindication to intramuscular (IM) injection*
  17. Administration of a vaccine not included in the study protocol within 30 days of a study vaccine (c).
  18. History of anaphylaxis post-vaccination.
  19. 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.

    • subject to the investigator's judgement

Exceptions:

a Inhaled and topical steroids. b Participation in hepatitis C vaccine study with confirmed negative HCV antibodies prior to participation in that study, and negative HCV RNA PCR at screening for this study c The following vaccinations may be administered more than 7 days before or after a study vaccination: polio, diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Bacillus Calmette-Guérin (BCG vaccine), measles, influenza, pneumococcal disease, COVID-19 or yellow fever


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): NCT05252845


Contacts
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Contact: Lorenz von Seidlein, MD +66 9 2648 6322 Lorenz@tropmedres.ac

Locations
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Thailand
Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University
Bangkok, Thailand, 10400
Contact: Podjanee Jittamala, MD       podjanee@tropmedres.ac   
Contact: Borimas Hanboonkunuprakarn, MD       Borimas@tropmedres.ac   
Sponsors and Collaborators
University of Oxford
Investigators
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Principal Investigator: Lorenz von Seidlein, MD Mahidol Oxford Tropical Medicine Research Unit
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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT05252845    
Other Study ID Numbers: MAL22001
MR/T006161/1 ( Other Grant/Funding Number: Medical Research Council [MRC] )
First Posted: February 23, 2022    Key Record Dates
Last Update Posted: February 23, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Oxford:
Malaria vaccine
Immunogenicity of the malaria vaccine
Immunologic response to malaria vaccine
Additional relevant MeSH terms:
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Malaria
Malaria, Falciparum
Protozoan Infections
Parasitic Diseases
Infections
Vector Borne Diseases