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Trial registered on ANZCTR


Registration number
ACTRN12607000552482
Ethics application status
Approved
Date submitted
12/10/2007
Date registered
26/10/2007
Date last updated
29/06/2012
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 randomised, double blinded within dose, controlled, dose- escalation, safety and immunogenicity study of a blood-stage vaccine (MSP2-C1/ISA 720) against Plasmodium falciparum MSP2 in healthy volunteers
Scientific title
Safety and tolerability trial of a randomised, placebo-controlled MSP2-C1/ISA720 malaria vaccine in healthy volunteers
Universal Trial Number (UTN)
Trial acronym
QP07C08
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malaria 2446 0
Condition category
Condition code
Infection 2550 2550 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The MSP2-C1/ ISA720 malaria vaccine is supplied as a milky white emulsion in single dose vials. Each 5 mL vial contains 0.8 mL, of which 0.5 mL is the intended volume to be injected. 0.5 mL of vaccine contains the equivalent of 0.15 ml of buffer containing antigen emulsified in Montanide® ISA720. The MSP2-C1/ ISA720 vaccine and ISA720 Control conforms to established requirements for sterility, safety and identity. The MSP2-C1/ISA720 malaria vaccine will be injected intramascularly into the 3 subgroups of participants within the intervention group. The vaccine will be provided in multiple doses, as three immunizations, twelve weeks apart. The first subgroup will receive 10 micrograms in each injection, the second subgroup will receive 40 micrograms in each injection, and the third subgroup will receive 80 micrograms in each injection.
Intervention code [1] 2176 0
Prevention
Comparator / control treatment
Buffered ISA 720 adjuvant is the "placebo" and this is given in three doses, 12 weeks apart, in 0.5 ml volume, intramuscularly into the 3 subgroups of participants in the control group. The first subgroup will receive 10 micrograms in each injection, the second subgroup will receive 40 micrograms in each injection, and the third subgroup will receive 80 micrograms in each injection.
Control group
Placebo

Outcomes
Primary outcome [1] 3456 0
Safety and tolerability
Timepoint [1] 3456 0
Safety and tolerability of 3 vaccinations assessed from baseline by diary cards, telephone calls at days 0, 1, 21, 85, 105, 169 and 189 and by clinical evaluations at days 3,7,14,28,56,84,87,91,98,112,140, 168, 171, 175, 182, 196 and 336
Secondary outcome [1] 5760 0
Humoral and cellular immune
Timepoint [1] 5760 0
Humoral and cellular immune response assessed by blood analysis at baseline out to days 0, 28, 84, 112, 168, 196 and 336

Eligibility
Key inclusion criteria
Healthy, withhold donating blood.
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Malaria disease or exposure, intercurrent disease, recent illness, treatment with corticosteroids, anti-coagulant, anti-inflammatory or immunomodulator drugs, history severe allergic reaction or anaphylaxis, live vaccination within 4 weeks or dead vaccination within 2 weeks or participation in a clinical trial in the 4 weeks prior

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Eligible patients assigned to cohorts and randomised and blinded within cohorts.
Blinded treatment provided by identical and blinded syringes prepared by unblinded pharmacist according to randomisation schedule provided by study statistician. The statistician is off-site.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation schedule provided by study statistician. Randomisation is based on a permuted block process, with the random numbers being generated by an application of the "Mersenne-Twister" algorithm from Matsumoto and Nishimura (1998). It involves a twisted General Functional System Requirement (GFSR) with period /2^19937 - 1/ and equidistribution in 623 consecutive dimensions (over the whole period). The "seed" is a 624-dimensional set of 32-bit integers plus a current position in that set.

Reference: Matsumoto, M. and Nishimura, T. (1998) Mersenne Twister: A 623-dimensionally equidistributed uniform pseudo-random number generator, Association for Computing Machinery (ACM) Transactions on Modeling and Computer Simulation, 8, 3–30.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Dose-escalating
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/10/2007
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
45
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 275 0
4006

Funding & Sponsors
Funding source category [1] 2696 0
Other Collaborative groups
Name [1] 2696 0
The PATH Malaria Vaccine Initiative
Country [1] 2696 0
United States of America
Primary sponsor type
Other
Name
The Queensland Institute of Medical Research
Address
300 Herston Rd, Herston, Queensland, 4006
Country
Australia
Secondary sponsor category [1] 2441 0
Other Collaborative groups
Name [1] 2441 0
The PATH Malaria Vaccine Initiative
Address [1] 2441 0
7500 Old Georgetown Rd, 12th Floor, Bethesda, MD, 20814 - 6133
Country [1] 2441 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 4618 0
The Queensland Institute of Medical Research Human Research Ethics Committee
Ethics committee address [1] 4618 0
The Queensland Institute of Medical Research, Post Office Royal Brisbane, Q 4029
Ethics committee country [1] 4618 0
Australia
Date submitted for ethics approval [1] 4618 0
Approval date [1] 4618 0
10/10/2007
Ethics approval number [1] 4618 0

Summary
Brief summary
The goal of this Phase 1 vaccine trial is to demonstrate safety and immunogenicity of MSP2-C1/ISA720 malaria vaccine in healthy adult human volunteers. The World Health Organisation reported in 2005 that malaria kills more than 1 million people annually and that approximately 3.2 million people living in 107 countries or territories are at risk of infection [1]. Most of the malaria mortality occurs in sub Saharan Africa and in children under 5 years of age. Of the four species of malaria parasite that infect humans, Plasmodium falciparum is responsible for the majority of these deaths. Mounting drug resistance of the malaria parasite, as well as widespread resistance of mosquitoes to insecticides, make these control strategies increasingly unrealistic. A vaccine that would reduce both mortality and morbidity secondary to P. falciparum infection would be a valuable resource in the fight against this disease.
Trial website
www.qpharm.com.au/volunteer-advertisments.htm
Trial related presentations / publications
WHO and UNICEF World Malaria Report 2005.

Smythe JA, Coppel RL, Brown GV, et al. (1988). Identification of two integral membrane proteins of Plasmodium falciparum. Proc Natl Acad Sci. USA 85: 5195-5199.

Gerold P, Schofield L, Blackman MJ, et al. (1996) Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum.

Cowman AF, Baldi DL, Healer J, et al. (2000) Functional analysis of proteins involved in Plasmodium falciparum merozoite invasion of red blood cells. FEBS Lett 476: 84-88.

Dubbeld MA, Kocken CH, Thomas AW. (1998) Merozoite surface protein 2 of Plasmodium reichenowi is a unique mosaic of Plasmodium falciparum allelic forms and species-specific elements. Mol Biochem Parasitol 92: 187-92.

Smythe JA, Coppel RL, Day KP. et al. (1991) Structural diversity in the Plasmodium falciparum merozoite surface antigen 2. Proc Natl Acad Sci USA 88: 1751-1755.

Fenton B, Clark JT, Khan CM, et al. (1991) Structural and antigenic polymorphism of the 35- to 48-kilodalton merozoite surface antigen (MSA-2) of the malaria parasite Plasmodium falciparum. Mol Cell Biol. 11: 963-71.

Al-Yaman F, Genton B, Anders RF, et al. (1994) Relationship between humoral response to Plasmodium falciparum merozoite surface antigen-2 and malaria morbidity in a highly endemic area of Papua New Guinea. Am J Trop Med Hyg 51: 593-602.

Taylor RR, Smith DB, Robinson VJ, et al. (1995) Human antibody response to Plasmodium falciparum merozoite surface protein 2 is serogroup specific and predominantly of the immunoglobulin G3 subclass. Infect Immun 11: 4382-8.

Lawrence N, Stowers A, Mann V, et al. (2000) Recombinant chimeric proteins generated from conserved regions of Plasmodium falciparum merozoite surface protein 2 generate antiparasite humoral responses in mice. Parasite Immunol 22: 211-221.

Taylor RR, Allen SJ, Greenwood BM, Riley EM. (1998) IgG3 antibodies to Plasmodium falciparum merozoite surface protein 2 (MSP2): increasing prevalence with age and association with clinical immunity to malaria. Am J Trop Med Hyg 58: 406-413.

Metzger WG, Okenu DM, Cavanagh DR, et al. (2003) Serum IgG3 to the Plasmodium falciparum merozoite surface protein 2 is strongly associated with a reduced prospective risk of malaria. Parasite Immunol 25: 307-312.

Polley SD, Conway DJ, Cavanagh DR, et al. (2006) High levels of serum antibodies to merozoite surface protein 2 of Plasmodium falciparum are associated with reduced risk of clinical malaria in coastal Kenya. Vaccine 24: 4233-4246.

Eisen DP, Saul A, Fryauff DJ, Reeder JC, Coppel RL. (2002) Alterations in Plasmodium falciparum genotypes during sequential infections suggest the presence of strain specific immunity. Am J Trop Med Hyg 67: 8-16.

Epping RJ, Goldstone SD, Ingram LT, et al. (1988) An epitope recognised by inhibitory monoclonal antibodies that react with a 51 kilodalton merozoite surface antigen in Plasmodium falciparum. Mol. Biochem. Parasitol. 1988, 28:1-10.

Clark JT, Donachie S, Anand R. et al. (1989) 46-53 kilodalton glycoprotein from the surface of Plasmodium falciparum merozoites Mol. Biochem. Parasitol. 1989, 32:15-24.

Miettinen-Baumann A, Strych W, McBride J, Heidrich HG, et al. (1988) A 46,000 dalton Plasmodium falciparum merozoite surface glycoprotein not related to the 185,000-195,000 dalton schizont precursor molecule: isolation and characterization. Parasitol. Res. 1988, 74:317-323.

Druilhe P, Bouharoun-Tayoun H. (2002) Antibody-dependent cellular inhibition assay. Methods Mol Med 72: 529-34.

Miles A, McClellan H, Rausch K, et al. (2005) Montanide ISA720 vaccines: quality control of emulsions, stability of formulated antigens, and comparative immunogenicity of vaccine formulations. Vaccine 23: 2530-39.

Sturchler D, Berger R, Rudin C, et al. (1995) Safety, immunogenicity, and pilot efficacy of Plasmodium falciparum sporozoite and asexual blood-stage combination vaccine in Swiss adults. Am J Trop Med Hyg 53: 423-31.

Saul A, Lawrence G, Smillie A, et al. (1999) Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant. Vaccine 17: 3145-59.

Lawrence G, Cheng QQ, Reed C, et al. (2000) Effect of vaccination with 3 recombinant asexual-stage malaria antigens on initial growth rates of Plasmodium falciparum in non-immune volunteers. Vaccine 18: 1925-31.

Cheng Q, Lawrence G, Reed C, et al. (1997) Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines. Am J Trop Med Hyg 57: 495-500.

Genton B, Al-Yaman F, Anders R, et al. (2000) Safety and immunogenicity of a three-component blood-stage malaria vaccine in adults living in an endemic area of Papua New Guinea. Vaccine 18: 2504-11.

Genton B, Betuela I, Felger I, Al-Yaman F, et al. (2002) A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis 185: 820-7.

Genton B, Al-Yaman F, Betuela I, et al. (2003) Safety and immunogenicity of a three-component blood-stage malaria vaccine (MSP1, MSP2, RESA) against Plasmodium falciparum in Papua New Guinean children. Vaccine 22: 30-41.
Lopez JA, Weilenman C, Audran R, et al. (2001) A synthetic malaria vaccine elicits a potent CD8+ and CD4+ T lymphocyte immune response in humans. Implication for vaccination strategies. Eur J Immunol 31: 1989-98.

Saul A, Lawrence G, Allworth A, et al. (2005) A human phase 1 vaccine clinical trial of the Plasmodium falciparum malaria vaccine candidate apical membrane antigen 1 in Montanide ISA720 adjuvant. Vaccine 23: 3076-83.

Hermsen CC, Verhage DF, Telgt DS, et al. (2007) Glutamate-rich protein (GLURP) induces antibodies that inhibit in vitro growth of Plasmodium falciparum in a phase 1 malaria vaccine trial. Vaccine 25: 2930-40.

Audran R, Cachat M, Lurati F, et al. (2005) Phase I malaria vaccine trial with a long synthetic peptide derived from the merozoite surface protein 3 antigen. Infect Immun 73: 8017-26.

Oliveira GA, Wetzel K, Calvo-Calle JM, et al. (2005) Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial. Infect Immun 73: 3587-97

Walther M, Dunachie S, Keating S, et al. (2005) Safety, immunogenicity and efficacy of a pre-erythrocytic malaria candidate vaccine, ICC-1132 formulated in Seppic ISA 720. Vaccine 23: 857-64.
Toledo H, Baly A, Castro O, et al. (2001) A phase I clinical trial of a multi-epitope polypeptide TAB9 combined with Montanide ISA720 adjuvant in non-HIV-1 infected human volunteers. Vaccine 19: 4328-36.

Engers H, Kieny MP, Malhotra P, Pink JR. (2003) Third meeting on Novel Adjuvants Currently in or Close to Clinical Testing World Health Organization--Organisation Mondiale de la Sante, Fondation Merieux, Annecy, France, 7-9 January 2002. Vaccine 21:3503-24.

Cody CL, Baraff LJ, Cherry JD, Marcy SM & Manclark CR. (1981) Nature and rates of adverse reactions associated with DTP and DT immunizations in infants and children. Pediatrics 68:650-660.

Persson KEM, Lee CT, Marsh K and Beeson JG. (2006) The development and optimization of high throughput methods to measure Plasmodium falciparum growth inhibitory antibodies. J. Clin. Microbiol. 44:1665-73)

Holm S. A simple sequentially rejective multiple test procedure. (1979) Scandinavian Journal of Statistics, 6:65–70.
Patterson H and Thompson R. (1971) Recovery of inter-block information when block sizes are unequal. Biometrika, 58:545–54.
Public notes

Contacts
Principal investigator
Name 28108 0
Address 28108 0
Country 28108 0
Phone 28108 0
Fax 28108 0
Email 28108 0
Contact person for public queries
Name 11265 0
Dr Suzanne Elliott
Address 11265 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 11265 0
Australia
Phone 11265 0
61 7 3845 3636
Fax 11265 0
61 7 3845 3637
Email 11265 0
[email protected]
Contact person for scientific queries
Name 2193 0
Dr Suzanne Elliott
Address 2193 0
Q-Pharm Pty Ltd
QIMR
Clive Berghofer Cancer Research Centre
Level D
300 Herston Rd
Herston QLD 4006
Country 2193 0
Australia
Phone 2193 0
61 7 3845 3636
Fax 2193 0
61 7 3845 3637
Email 2193 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
Dimensions AIBlood stage vaccines for Plasmodium falciparum2010https://doi.org/10.4161/hv.6.8.11446
EmbaseHuman Immunization with a Polymorphic Malaria Vaccine Candidate Induced Antibodies to Conserved Epitopes That Promote Functional Antibodies to Multiple Parasite Strains.2018https://dx.doi.org/10.1093/infdis/jiy170
N.B. These documents automatically identified may not have been verified by the study sponsor.