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Optimization of Controlled Human Malarial Infection by Injection of P. Falciparum Sporozoites in Non-Immune Adults

Primary Purpose

Malaria

Status

Completed

Phase

Phase 1

Locations

Spain

Study Type

Interventional

Intervention

PfSPZ Challenge

About this trial

This is an interventional diagnostic trial for Malaria focused on measuring Malaria, Plasmodium falciparum

Eligibility Criteria

18 Years - 45 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Healthy adults aged 18 to 45 years
Able and willing (in the Investigator's opinion) to comply with all study requirements
Women only: must agree to practice continuous effective contraception for the duration of the study (such as hormonal contraceptives, condom or intrauterine device (IUD)).
Agreement to refrain from blood donation in Spain during the course of the study and thereafter
Agree not to participate in another study with an investigational product during the course of this study
Written informed consent to undergo CHMI
Reachable (24/7) by mobile phone during the whole study period
Willingness to take a curative anti-malarial regimen
Agreement to stay overnight for observation during the period of intensive follow-up post-challenge if required
Answer all questions on the informed consent quiz correctly
A body mass index < 35

Exclusion Criteria:

History of P. falciparum malaria
Travel to malaria endemic region before the participation in the study with positive P. falciparum serology at screening.
Use of systemic antibiotics with known antimalarial activity within 30 days of study enrolment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin)
Is using and intends to continuing using a medication known to cause drug reactions with chloroquine or Malarone®, such as cimetidine, metoclopramide, antacids or kaolin (antacids and kaolin can be administered at least 4 hours from intake of chloroquine)
Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period
Prior receipt of an investigational malaria vaccine
Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed)
Use of immunoglobulins or blood products within 3 months prior to enrolment
Presence of sickle cell anemia, sickle cell trait, thalassemia or thalassemia trait
Pregnancy, lactation or intention to become pregnant during the study
A history of allergic disease or reactions likely to be exacerbated by malaria
Contraindications or known allergy to the first-line anti-malarial medications: chloroquine, atovaquone/proguanil and artemether/lumefantrine.
History of cancer (except successfully treated and cured basal cell carcinoma of the skin and cervical carcinoma in situ)
History of serious psychiatric condition that may affect participation in the study
Any other serious chronic illness requiring hospital specialist supervision
Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 30g (men) or 20g (women) per day
Suspected or known injecting drug abuse in the 5 years preceding enrolment
Seropositive for hepatitis B surface antigen (HBsAg)
Seropositive for hepatitis C virus (antibodies to HCV)
An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system [42]
Abnormal electrocardiogram on screening: pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block (secondary or tertiary)
Volunteers unable to be closely followed for social, geographic or psychological reasons
Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination
Any other significant disease, disorder or finding which, in the opinion of the Investigator, may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data

Sites / Locations

Centre d'Investigació del Medicament Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
CRESIB, Hospital Clínic-Universitat de Barcelona

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Grp 1-10ul x 2; 2,500 PfSPZ Challenge-Part A

Grp 2-50ul x 2; 2,500 PfSPZ Challenge-Part A

Grp 3-250ul x 2; 2,500 PfSPZ Challenge-Part A

Grp 4-50ul x 2; 25,000 PfSPZ Challenge, Part B

Grp 5-Optimal vol Part A x 2; 25,000 PfSPZ Challenge, Part B

Grp 6-Optimal vol Part A x 2; 125,000* PfSPZ Challenge, Part B

Arm Description

PART A: Group 1 (n=6): 2,500 PfSPZ administered IM in a volume of 10 µL in 2 sites (one injection of 10µL containing 1,250 PfSPZ in each deltoid).

PART A: Group 2 (n=6): 2,500 PfSPZ administered IM in a volume of 50 µL in 2 sites (one injection of 50µL containing 1,250 PfSPZ in each deltoid).

PART A: Group 3 (n=6): 2,500 PfSPZ administered IM in a volume of 250 µL in 2 sites (one injection of 250 µL containing 1,250 PfSPZ in each deltoid).

PART B: BEGINS AFTER COMPLETION OF PART A Group 4 (n=6) (control group) 25,000 PfSPZ administered IM in a volume of 50 µL in 2 sites (one injection of 50 µL containing 12,500 PfSPZ in each deltoid).

PART B: BEGINS AFTER COMPLETION OF PART A Group 5 (n=6) 25,000 PfSPZ administered IM in the optimum volume determined in Part A in 2 sites (one injection of the optimum volume containing 12,500 PfSPZ in each deltoid). If the optimal volume in Part A is 50µL, then Group 5 will be modified to avoid duplication of regimens between groups 4 and 5. In this case, volunteers in group 5 will be administered a dose of 25,000 PfSPZ administered intradermally in four 10 µL injections. (Every volunteer will receive 4 ID injections of 6,250 PfSPZ in a volume of 10 µL each, with 2 injections in each arm respectively).

PART B: BEGINS AFTER COMPLETION OF PART A Group 6 (n=6) 125,000 PfSPZ administered IM in the optimum volume determined in Part A in 2 sites (one injection of the optimum volume containing 62,500 PfSPZ in each deltoid) if the volume is 50 µL or 250 µL. *If the optimal volume in Part A is 10 µL, then Group 6 will receive 100,000 PfSPZ (2 inoculations of 50,000 PfSPZ) instead of 125,000 PfSPZ.

Outcomes

Primary Outcome Measures

Infectivity of the administration regimens

For each trial stage (A and B) the infectivity of the three administration regimens will be assessed by thick film microscopy and q-PCR for P. falciparum DNA. The time from parasite inoculation to first detection of blood stage parasitemia will be assessed by thick blood film microscopy.

Secondary Outcome Measures

Safety of PfSPZ Challenge

The safety of PfSPZ Challenge and the resultant P. falciparum infection will be assessed by analysing actively and passively collected data from clinical review of volunteers and laboratory measurements.

Full Information

NCT ID

NCT01771848

First Posted

January 8, 2013

Last Updated

March 31, 2016

Sponsor

Sanaria Inc.

Collaborators

Barcelona Centre for International Health Research

1. Study Identification

Unique Protocol Identification Number

NCT01771848

Brief Title

Optimization of Controlled Human Malarial Infection by Injection of P. Falciparum Sporozoites in Non-Immune Adults

Official Title

A Study to Optimize Controlled Human Malarial Infection by Injection of Plasmodium Falciparum Sporozoites in Non-Immune Adults

Study Type

Interventional

2. Study Status

Record Verification Date

March 2016

Overall Recruitment Status

Completed

Study Start Date

December 2012 (undefined)

Primary Completion Date

May 2013 (Actual)

Study Completion Date

July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanaria Inc.

Collaborators

Barcelona Centre for International Health Research

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The study is designed to establish the best dose to safely infect healthy individuals with Plasmodium falciparum sporozoites (PfSPZ) by injection. The goal of this study is to achieve infections in human volunteers with infection rates of 100% and pre-patent periods of less than 12 days.

Detailed Description

This is an single center,open label, escalated and controlled human pilot study to optimize CHMI (controlled human malaria infection) administered by PfSPZ Challenge. The study was designed with an escalated dosing design in order to answer two questions: Does altering the volume of administration, alter infectivity of PfSPZ Challenge administered IM (intramuscular)? By varying the volume of inoculation of the 2,500 dose of PfSPZ administered IM we try to increase infection rates and decrease pre-patent period (Part A). When administered in the optimum volume determined in Part A, does increasing the dose increase the infectivity and decrease the pre-patent period of PfSPZ Challenge? By increasing the dose of PfSPZ we try to decrease the pre-patent period at the higher dose (Part B). Besides increasing the infectivity rate, we aim to reduce the pre-patent period to ~11 days. In Part A of the trial, the volume of inoculation will vary in order to identify the optimal volume needed for a dose of 2,500 PfSPZ to induce the greatest infection rate (defined as highest percentage of infected volunteers and shortest pre-patent period.) The outcome variables of part A are: Number of volunteers infected per group. Pre-patent period by thick blood smear in individuals in each group. Pre-patent period by quantitative PCR (qPCR) in individuals in each group. Parasite density when parasites first detected by thick blood smear and qPCR. Peak parasite density during the first 48 hours after first detection by qPCR. During Part A, an interim analysis will be performed in order to determine the optimal volume of inoculation that will be used during Part B. The variables that will be taken into account for this interim analysis will be: 1) number of volunteers infected per group and 2) pre-patent period by thick blood smear in individuals in each group. Part B will assess the effect of the optimal volume of inoculation determined in part A when administered with different PfSPZ doses, compared to the dose of 25,000 PfSPZ in 50 µL However, i) If the optimal volume in Part A is 10 µL, then Group 6 will receive 100,000 PfSPZ (2 inoculations of 50,000 PfSPZ) instead of 125,000 PfSPZ, as the PfSPZs are vialed at 100,000 PfSPZ in 20 µL. ii) If the optimal volume in Part A is 50µL, then Group 5 will be modified to avoid duplication of regimens between groups 4 and 5. In this case, volunteers in group 5 will be administered a dose of 25,000 PfSPZ administered ID (intradermal) in four 10 µL injections. (Every volunteer will receive 4 ID injections of 6,250 PfSPZ in a volume of 10 µL each, with 2 injections in each arm respectively). The outcome variables in this part of the study are: Number of volunteers infected per group. Pre-patent period by thick blood smear in individuals in each group. Pre-patent period by qPCR in individuals in each group. Parasite density when parasites first detected by qPCR. Peak parasite density during the first 48 hours after first detection by qPCR. Estimated number (±95% confidence interval) of liver stage schizonts per volunteer and mean (±95% confidence interval) for each group. All volunteers recruited will be healthy adults aged between 18 and 45 years. Safety and infectivity data will be collected for each of the regimens and dose-levels. Volunteers and clinical investigators will not be blinded to group allocation, however laboratory investigators processing blood films and samples for qPCR analysis will be blinded to group allocation.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malaria

Keywords

Malaria, Plasmodium falciparum

7. Study Design

Primary Purpose

Diagnostic

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Grp 1-10ul x 2; 2,500 PfSPZ Challenge-Part A

Arm Type

Experimental

Arm Description

PART A: Group 1 (n=6): 2,500 PfSPZ administered IM in a volume of 10 µL in 2 sites (one injection of 10µL containing 1,250 PfSPZ in each deltoid).

Arm Title

Grp 2-50ul x 2; 2,500 PfSPZ Challenge-Part A

Arm Type

Experimental

Arm Description

PART A: Group 2 (n=6): 2,500 PfSPZ administered IM in a volume of 50 µL in 2 sites (one injection of 50µL containing 1,250 PfSPZ in each deltoid).

Arm Title

Grp 3-250ul x 2; 2,500 PfSPZ Challenge-Part A

Arm Type

Experimental

Arm Description

PART A: Group 3 (n=6): 2,500 PfSPZ administered IM in a volume of 250 µL in 2 sites (one injection of 250 µL containing 1,250 PfSPZ in each deltoid).

Arm Title

Grp 4-50ul x 2; 25,000 PfSPZ Challenge, Part B

Arm Type

Experimental

Arm Description

Arm Title

Grp 5-Optimal vol Part A x 2; 25,000 PfSPZ Challenge, Part B

Arm Type

Experimental

Arm Description

Arm Title

Grp 6-Optimal vol Part A x 2; 125,000* PfSPZ Challenge, Part B

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

PfSPZ Challenge

Intervention Description

Aseptic, purified, vialed, cryopreserved fully infectious NF54 P. falciparum sporozoites

Primary Outcome Measure Information:

Title

Infectivity of the administration regimens

Description

Time Frame

Study day 6 to day 90 post challenge

Secondary Outcome Measure Information:

Title

Safety of PfSPZ Challenge

Description

Time Frame

All study visits until day 90 post challenge

Other Pre-specified Outcome Measures:

Title

Parasite multiplication rates using qPCR for P. falciparum DNA

Description

The dynamics of P. falciparum parasite growth following administration of PfSPZ Challenge is assessed by analyzing parasite multiplication rates using qPCR for P. falciparum DNA. Measurements will be used to model parasite kinetics and to estimate the number of infected liver cells. A mathematical model will also be built to describe infection dynamics, parasite distribution, circulation time and parasite turn-over

Time Frame

Samples taken at pre-determined timepoints upto 8 months

Title

Cellular and humoral immune responses against parasites

Description

Cellular and humoral immune responses against parasites are assessed by transcriptional RNA analysis, multiparameter flow cytometry, ELIspot, luminex assays, protein arrays, IFA, and ELISA.

Time Frame

Samples taken at pre-determined timepoints upto 8 months

Title

Stage specific expression patterns of parasite genes

Description

Stage specific expression patterns of parasite genes is assessed by RNA quantification using reverse transcriptase PCR (rtPCR) and transcriptional profiling on microarray and sequencing platforms,specifically, the presence of mRNA transcripts specific of gametocytes, the pattern of variant gene transcription and adhesion, and the expression of merozoite invasion genes/proteins.

Time Frame

Samples taken at pre-determined timepoints upto 8 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Healthy adults aged 18 to 45 years Able and willing (in the Investigator's opinion) to comply with all study requirements Women only: must agree to practice continuous effective contraception for the duration of the study (such as hormonal contraceptives, condom or intrauterine device (IUD)). Agreement to refrain from blood donation in Spain during the course of the study and thereafter Agree not to participate in another study with an investigational product during the course of this study Written informed consent to undergo CHMI Reachable (24/7) by mobile phone during the whole study period Willingness to take a curative anti-malarial regimen Agreement to stay overnight for observation during the period of intensive follow-up post-challenge if required Answer all questions on the informed consent quiz correctly A body mass index < 35 Exclusion Criteria: History of P. falciparum malaria Travel to malaria endemic region before the participation in the study with positive P. falciparum serology at screening. Use of systemic antibiotics with known antimalarial activity within 30 days of study enrolment (e.g. trimethoprim-sulfamethoxazole, doxycycline, tetracycline, clindamycin, erythromycin, fluoroquinolones, or azithromycin) Is using and intends to continuing using a medication known to cause drug reactions with chloroquine or Malarone®, such as cimetidine, metoclopramide, antacids or kaolin (antacids and kaolin can be administered at least 4 hours from intake of chloroquine) Receipt of an investigational product in the 30 days preceding enrolment, or planned receipt during the study period Prior receipt of an investigational malaria vaccine Any confirmed or suspected immunosuppressive or immunodeficient state, including HIV infection, asplenia, recurrent, severe infections and chronic (more than 14 days) immunosuppressant medication within the past 6 months (inhaled and topical steroids are allowed) Use of immunoglobulins or blood products within 3 months prior to enrolment Presence of sickle cell anemia, sickle cell trait, thalassemia or thalassemia trait Pregnancy, lactation or intention to become pregnant during the study A history of allergic disease or reactions likely to be exacerbated by malaria Contraindications or known allergy to the first-line anti-malarial medications: chloroquine, atovaquone/proguanil and artemether/lumefantrine. History of cancer (except successfully treated and cured basal cell carcinoma of the skin and cervical carcinoma in situ) History of serious psychiatric condition that may affect participation in the study Any other serious chronic illness requiring hospital specialist supervision Suspected or known current alcohol abuse as defined by an alcohol intake of greater than 30g (men) or 20g (women) per day Suspected or known injecting drug abuse in the 5 years preceding enrolment Seropositive for hepatitis B surface antigen (HBsAg) Seropositive for hepatitis C virus (antibodies to HCV) An estimated, ten year risk of fatal cardiovascular disease of ≥5%, as estimated by the Systematic Coronary Risk Evaluation (SCORE) system [42] Abnormal electrocardiogram on screening: pathologic Q wave and significant ST-T wave changes, left ventricular hypertrophy, non-sinus rhythm except isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block (secondary or tertiary) Volunteers unable to be closely followed for social, geographic or psychological reasons Any clinically significant abnormal finding on biochemistry or haematology blood tests, urinalysis or clinical examination Any other significant disease, disorder or finding which, in the opinion of the Investigator, may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pedro L Alonso, MD, Ph.D.

Organizational Affiliation

Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre d'Investigació del Medicament Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

City

Barcelona

ZIP/Postal Code

08025

Country

Spain

Facility Name

CRESIB, Hospital Clínic-Universitat de Barcelona

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

25889522

Citation

Mordmuller B, Supan C, Sim KL, Gomez-Perez GP, Ospina Salazar CL, Held J, Bolte S, Esen M, Tschan S, Joanny F, Lamsfus Calle C, Lohr SJ, Lalremruata A, Gunasekera A, James ER, Billingsley PF, Richman A, Chakravarty S, Legarda A, Munoz J, Antonijoan RM, Ballester MR, Hoffman SL, Alonso PL, Kremsner PG. Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J. 2015 Mar 18;14:117. doi: 10.1186/s12936-015-0628-0.

Results Reference

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Citation

Shekalaghe S, Rutaihwa M, Billingsley PF, Chemba M, Daubenberger CA, James ER, Mpina M, Ali Juma O, Schindler T, Huber E, Gunasekera A, Manoj A, Simon B, Saverino E, Church LWP, Hermsen CC, Sauerwein RW, Plowe C, Venkatesan M, Sasi P, Lweno O, Mutani P, Hamad A, Mohammed A, Urassa A, Mzee T, Padilla D, Ruben A, Sim BKL, Tanner M, Abdulla S, Hoffman SL. Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2014 Sep;91(3):471-480. doi: 10.4269/ajtmh.14-0119. Epub 2014 Jul 28.

Results Reference

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PubMed Identifier

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Citation

Roestenberg M, Bijker EM, Sim BKL, Billingsley PF, James ER, Bastiaens GJH, Teirlinck AC, Scholzen A, Teelen K, Arens T, van der Ven AJAM, Gunasekera A, Chakravarty S, Velmurugan S, Hermsen CC, Sauerwein RW, Hoffman SL. Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 2013 Jan;88(1):5-13. doi: 10.4269/ajtmh.2012.12-0613. Epub 2012 Nov 13.

Results Reference

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PubMed Identifier

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Citation

Sheehy SH, Spencer AJ, Douglas AD, Sim BK, Longley RJ, Edwards NJ, Poulton ID, Kimani D, Williams AR, Anagnostou NA, Roberts R, Kerridge S, Voysey M, James ER, Billingsley PF, Gunasekera A, Lawrie AM, Hoffman SL, Hill AV. Optimising Controlled Human Malaria Infection Studies Using Cryopreserved P. falciparum Parasites Administered by Needle and Syringe. PLoS One. 2013 Jun 18;8(6):e65960. doi: 10.1371/journal.pone.0065960. Print 2013.

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Citation

Gomez-Perez GP, Legarda A, Munoz J, Sim BK, Ballester MR, Dobano C, Moncunill G, Campo JJ, Cistero P, Jimenez A, Barrios D, Mordmuller B, Pardos J, Navarro M, Zita CJ, Nhamuave CA, Garcia-Basteiro AL, Sanz A, Aldea M, Manoj A, Gunasekera A, Billingsley PF, Aponte JJ, James ER, Guinovart C, Antonijoan RM, Kremsner PG, Hoffman SL, Alonso PL. Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naive volunteers: effect of injection volume and dose on infectivity rates. Malar J. 2015 Aug 7;14:306. doi: 10.1186/s12936-015-0817-x.

Results Reference

result

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Optimization of Controlled Human Malarial Infection by Injection of P. Falciparum Sporozoites in Non-Immune Adults

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