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Controlled Human Malarial Infection by Intravenous Injection of Plasmodium Falciparum Sporozoites in Non-Immune Adults

Primary Purpose

Malaria

Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
PfSPZ Challenge
Sponsored by
Sanaria Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Malaria focused on measuring Controlled human malaria infection (CHMI), Malaria challenge, Plasmodium falciparum, PfSPZ Challenge

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
  • Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner if required
  • Women only: Must agree to practice continuous effective contraception for the duration of the study (a method which results in a low failure rate; i.e. less than 1% per year)
  • Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local blood banking eligibility criteria
  • 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
  • A haemoglobin concentration ≥12 g/dl for women and ≥14 g/dl for men

Exclusion Criteria:

  • History of P. falciparum malaria
  • History of long term residence (>5 years) in area known to have significant transmission of P. falciparum
  • 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)
  • 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
  • HIV infection
  • Any confirmed or suspected immunosuppressive or immunodeficient state, 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 to the use of the first-line anti-malarial medications: Atovaquone/Proguanil, Artemether/Lumefantrine, and Chloroquine
  • History of cancer (except 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 60g (men) or 40g (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)
  • Falling in moderate risk or higher categories for fatal or non-fatal cardiovascular event within 5 years (>10%) determined by non-invasive criteria for cardiac risk
  • 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 of left bundle branch block, advanced A-V heart block (secondary or tertiary)
  • A QT/QTc interval >450 ms
  • 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

  • Eberhard Karls University of Tübingen, Germany

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

50 PfSPZ IV

200 PfSPZ IV

800 PfSPZ IV

3200 PfSPZ IV

2500 PfSPZ ID

Arm Description

PfSPZ Challenge

PfSPZ Challenge

PfSPZ Challenge

PfSPZ Challenge

PfSPZ Challenge

Outcomes

Primary Outcome Measures

The infectivity of the administration regimens will be assessed by thick film microscopy and PCR for P. falciparum DNA.
Parasitology and parasite molecular biology tests: These tests are used to determine malaria parasites (thick blood smear and PCR). Both tests are performed at screening and then approximately every 12 hours during the period of intense observation from day 5 until day 21 or until treatment. Thereafter, these tests are performed during safety follow-ups at Days 28, 84, and 168. Turn over time for thick blood smear microscopy is < 2 hours to ensure timely treatment in case of a positive result. PCR results are available only after study completion.

Secondary Outcome Measures

The time from parasite inoculation to first detection of blood stage parasitemia will be assessed by thick blood film microscopy.
The safety of PfSPZ Challenge administered ID or IV and the resultant P. falciparum infection will be assessed by analysing actively and passively collected data from clinical review of volunteers and laboratory measurements
These tests include full blood picture (complete blood count), liver enzymes and creatinine. All of these will be performed once at screening, Day -1 (day before challenge), Day 21 when no parasitemia occurs until then and day of malaria diagnosis. Lastly, these tests will also be performed during safety follow up at Days 28, 84 and 168.

Full Information

First Posted
June 19, 2012
Last Updated
March 31, 2016
Sponsor
Sanaria Inc.
Collaborators
Institute of Tropical Medicine, University of Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT01624961
Brief Title
Controlled Human Malarial Infection by Intravenous Injection of Plasmodium Falciparum Sporozoites in Non-Immune Adults
Official Title
Controlled Human Malarial Infection by Intravenous 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
June 2012 (undefined)
Primary Completion Date
October 2012 (Actual)
Study Completion Date
February 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanaria Inc.
Collaborators
Institute of Tropical Medicine, University of Tuebingen

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) via intravenous (IV) injection.
Detailed Description
TÜCHMI-001 is a single center, open label, randomized and controlled human pilot study to optimize controlled human malaria infection(CHMI) administered by PfSPZ Challenge. Volunteers will be inoculated with PfSPZ Challenge. Controls will receive the PfSPZ Challenge by ID administration. The remaining volunteers will receive the PfSPZ Challenge by IV administration. 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 PCR 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
Controlled human malaria infection (CHMI), Malaria challenge, Plasmodium falciparum, PfSPZ Challenge

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
50 PfSPZ IV
Arm Type
Experimental
Arm Description
PfSPZ Challenge
Arm Title
200 PfSPZ IV
Arm Type
Experimental
Arm Description
PfSPZ Challenge
Arm Title
800 PfSPZ IV
Arm Type
Experimental
Arm Description
PfSPZ Challenge
Arm Title
3200 PfSPZ IV
Arm Type
Experimental
Arm Description
PfSPZ Challenge
Arm Title
2500 PfSPZ ID
Arm Type
Experimental
Arm Description
PfSPZ Challenge
Intervention Type
Biological
Intervention Name(s)
PfSPZ Challenge
Other Intervention Name(s)
Aseptic, cryopreserved P. falciparum sporozoites
Intervention Description
PfSPZ Challenge are aseptic, cryopreserved P. falciparum sporozoites.
Primary Outcome Measure Information:
Title
The infectivity of the administration regimens will be assessed by thick film microscopy and PCR for P. falciparum DNA.
Description
Parasitology and parasite molecular biology tests: These tests are used to determine malaria parasites (thick blood smear and PCR). Both tests are performed at screening and then approximately every 12 hours during the period of intense observation from day 5 until day 21 or until treatment. Thereafter, these tests are performed during safety follow-ups at Days 28, 84, and 168. Turn over time for thick blood smear microscopy is < 2 hours to ensure timely treatment in case of a positive result. PCR results are available only after study completion.
Time Frame
Day 5 until day 21 or until treatment
Secondary Outcome Measure Information:
Title
The time from parasite inoculation to first detection of blood stage parasitemia will be assessed by thick blood film microscopy.
Time Frame
Day 5 until day 21 or until treatment
Title
The safety of PfSPZ Challenge administered ID or IV and the resultant P. falciparum infection will be assessed by analysing actively and passively collected data from clinical review of volunteers and laboratory measurements
Description
These tests include full blood picture (complete blood count), liver enzymes and creatinine. All of these will be performed once at screening, Day -1 (day before challenge), Day 21 when no parasitemia occurs until then and day of malaria diagnosis. Lastly, these tests will also be performed during safety follow up at Days 28, 84 and 168.
Time Frame
Screening to Day 168

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
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 Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner if required Women only: Must agree to practice continuous effective contraception for the duration of the study (a method which results in a low failure rate; i.e. less than 1% per year) Agreement to refrain from blood donation during the course of the study and after the end of their involvement in the study according to the local blood banking eligibility criteria 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 A haemoglobin concentration ≥12 g/dl for women and ≥14 g/dl for men Exclusion Criteria: History of P. falciparum malaria History of long term residence (>5 years) in area known to have significant transmission of P. falciparum 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) 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 HIV infection Any confirmed or suspected immunosuppressive or immunodeficient state, 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 to the use of the first-line anti-malarial medications: Atovaquone/Proguanil, Artemether/Lumefantrine, and Chloroquine History of cancer (except 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 60g (men) or 40g (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) Falling in moderate risk or higher categories for fatal or non-fatal cardiovascular event within 5 years (>10%) determined by non-invasive criteria for cardiac risk 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 of left bundle branch block, advanced A-V heart block (secondary or tertiary) A QT/QTc interval >450 ms 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
Benjamin G Mordmüller, MD
Organizational Affiliation
Eberhard Karls University of Tübingen, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Eberhard Karls University of Tübingen, Germany
City
Tübingen
ZIP/Postal Code
D-72074
Country
Germany

12. IPD Sharing Statement

Citations:
PubMed Identifier
26245196
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
background
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
result
Links:
URL
http://www.malariajournal.com/content/14/1/117
Description
Publication of trials results

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Controlled Human Malarial Infection by Intravenous Injection of Plasmodium Falciparum Sporozoites in Non-Immune Adults

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