Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR201901672024347 Date of Approval: 23/01/2019
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title LaCHMI-2 (L2) Repeat direct venous inoculation of Plasmodium falciparum sporozoites, strain NF54 and clone 7G8, in healthy adult volunteers naturally exposed to malaria in Gabon: a randomized open-label study
Official scientific title Repeat direct venous inoculation of Plasmodium falciparum sporozoites, strain NF54 and clone 7G8, in healthy adult volunteers naturally exposed to malaria in Gabon: a randomized open-label study
Brief summary describing the background and objectives of the trial Malaria is the most important parasitic disease worldwide and a major cause of paediatric morbidity and mortality in sub-Saharan Africa. An efficacious vaccine will be essential to control and eliminate malaria as well as to contain drug-resistant parasite strains. However, development thereof is hindered in part by our incomplete understanding of protective immunity against this disease. Controlled human malaria infections (CHMI) are a valuable tool for studying anti-malarial immunity. The development by Sanaria Inc. of viable, aseptic, purified, vialed, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) for direct intravenous inoculation (DVI), has allowed for the first time the conduct of CHMIs in endemic populations (under otherwise resource-poor settings) to study naturally-acquired immunity. Two different products are available: PfSPZ Challenge (NF54) and PfSPZ Challenge (7G8), containing respectively the NF54 strain and 7G8 clone of P. falciparum. At the Centre de Recherches Médicales de Lambaréné (CERMEL) in Gabon, an area of high malaria endemicity, two CHMI studies have previously been performed in lifelong-exposed adults using 3,200 PfSPZ Challenge (NF54), a dose that consistently leads to malaria in naïve individuals. Amongst Gabonese adults, three levels of naturally-acquired anti-parasitic immunity could be distinguished: 1. Protection (no parasitemia, no symptoms, no antimalarial therapy required) 2. Control (parasitemia, no symptoms, no antimalarial therapy required) 3. Malaria (parasitemia, symptoms, antimalarial therapy required) However, it is unclear if the level of naturally-acquired immunity in any given indivual is constant or can be improved. L2 will investigate if repeat CHMI with PfSPZ Challenge (NF54) improves immunity against homologous (PfSPZ Challenge (NF54)) and heterologous (PfSPZ Challenge (7G8)) CHMI. The outcome thereof should help to develop more efficacious immunization regimens against malaria.
Type of trial RCT
Acronym (If the trial has an acronym then please provide) L2
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied Malaria
Purpose of the trial Prevention: Vaccines
Anticipated trial start date 15/03/2019
Actual trial start date 26/07/2019
Anticipated date of last follow up 27/05/2021
Actual Last follow-up date
Anticipated target sample size (number of participants) 56
Actual target sample size (number of participants)
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
BLOODSTAGE DZIF
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Randomised Simple randomization using a randomization table created by a computer software program Sealed opaque envelopes Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group A One dose of 3,200 PfSPZ Challenge (7G8), followed by five consecutive doses of 3,200 PfSPZ Challenge (NF54) Each dose will be administered as a single direct venous inoculation (DVI), with 8 weeks between each consecutive dose. Each of six CHMIs will be initiated by DVI of PfSPZ Challenge (7G8 or NF54, respectively), with 8 weeks between consecutive CHMIs. Volunteers will be assessed upon screening, the day before each DVI and at least 3 times a week (at the clinical trial site, at home or by telephone contact) following each CHMI. Laboratory examinations will be performed using a risk-based blood sampling schedule for parasitological diagnosis (at least 3 times per week until Day 28 after each DVI and at least twice weekly thereafter) until a malaria episode is detected or until the next DVI. Passive surveillance will be maintained throughout the whole trial with a clinical team that is reachable 24/7. Malaria episodes will be treated with artemether-lumefantrine (AL), or alternatively artesunate monotherapy for 5 days. Following DVI with PfSPZ Challenge (NF54), antimalarial treatment will be triggered by parasitaemia in combination with at least one malaria-associated symptom. Following DVI with PfSPZ Challenge (7G8), treatment will be initiated upon first positive thick blood smear or else presumptively on day 21 post DVI. In addition, primaquine (0.25 mg/kg) will be given to clear potential Pf7G8 gametocytes. (Early treatment and primaquine during CHMI with PfSPZ Challenge (7G8) is used to prevent transmission of Pf, clone 7G8 in Africa, since 7G8 originates from Brazil.) All volunteers will be treated presumptively 56 days following the last DVI if this did not already result in treatment for malaria. Passive follow-up will continue until 6 months after last DVI (total follow-up per participant ~16 months). 28 Active-Treatment of Control Group
Experimental Group B Four consecutive doses of of 3,200 PfSPZ Challenge (NF54), followed by one dose of 3,200 PfSPZ Challenge (7G8), followed by one final dose of 3,200 PfSPZ Challenge (NF54) Each dose will be administered as a single direct venous inoculation (DVI), with 8 weeks between each consecutive dose. Each of six CHMIs will be initiated by DVI of PfSPZ Challenge (NF54 or 7G8, respectively), with 8 weeks between consecutive CHMIs. Volunteers will be assessed upon screening, the day before each DVI and at least 3 times a week (at the clinical trial site, at home or by telephone contact) following each CHMI. Laboratory examinations will be performed using a risk-based blood sampling schedule for parasitological diagnosis (at least 3 times per week until Day 28 after each DVI and at least twice weekly thereafter) until a malaria episode is detected or until the next DVI. Passive surveillance will be maintained throughout the whole trial with a clinical team that is reachable 24/7. Malaria episodes will be treated with artemether-lumefantrine (AL), or alternatively artesunate monotherapy for 5 days. Following DVI with PfSPZ Challenge (NF54), antimalarial treatment will be triggered by parasitaemia in combination with at least one malaria-associated symptom. Following DVI with PfSPZ Challenge (7G8), treatment will be initiated upon first positive thick blood smear or else presumptively on day 21 post DVI. In addition, primaquine (0.25 mg/kg) will be given to clear potential Pf7G8 gametocytes. (Early treatment and primaquine during CHMI with PfSPZ Challenge (7G8) is used to prevent transmission of Pf, clone 7G8 in Africa, since 7G8 originates from Brazil.) All volunteers will be treated presumptively 56 days following the last DVI if this did not already result in treatment for malaria. Passive follow-up will continue until 6 months after last DVI (total follow-up per participant ~16 months). 28
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
• 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 (a method which results in a failure rate 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 receive PfSPZ products: o PfSPZ Challenge (NF54) o PfSPZ Challenge (7G8) • Reachable (24/7) by mobile phone from the time of each PfSPZ Challenge inoculation until treatment is successfully completed • Willingness to take antimalarial medication • Agreement to stay overnight for observation at any time during follow-up post-challenge if judged clinically necessary • Answer all questions on the informed consent quiz correctly • Use of antimalarials within past 30 days • Recent use of systemic antibiotics with known antimalarial activity • Receipt of an investigational product within past 30 days, or during the study • Immunization with >3 vaccines within past 4 weeks • HIV infection • Hb <10 g/dL (F) or <12 g/dL (M) • Sickle cell anaemia (e.g. HbSS, HbSC) • Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent, severe infections or chronic (>14 days) immunosuppressant med. within the past 6 months (except inhaled/ topical steroids) • Use of immunoglobulins or blood products within past 3 months • Pregnancy, lactation or intention to become pregnant during the study • Contraindications to artemether-lumefantrine or low-dose primaquine • History of cancer (except basal cell ca. and cervical ca. in situ) • History of serious psychiatric condition • Any other serious chronic illness requiring hospital specialist supervision • Suspected or known current alcohol abuse (>60g (M) or >40g (F) per day) • Suspected or known injecting drug abuse in past 5 years • HBsAg-positivity • Anti-HCV positivity • Moderate or higher (>10%) risk of fatal or non-fatal cardiovascular event within 5 years determined by non-invasive criteria • BMI >35 kg/m2 • Abnormal ECG on screening: pathologic Q wave, significant ST-T wave changes, LVH, clinically significant arrhythmias, LBBB, secondary or tertiary A-V heart block or a QT/QTcB interval >450 ms • Volunteers unable to be closely followed for social, geographic or psychological reasons • Any clinically significant abnormal finding on biochemistry, hematology, urine analysis or clinical examination • History of seizure (except uncomplicated febrile convulsion in childhood) • Any other significant disease, disorder or finding which, in the opinion of the investigator, may significantly increase the volunteer’s risk of participation, or ability to participate, in the study or impair interpretation of the study data Adult: 19 Year-44 Year 18 Year(s) 45 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 15/12/2018 Comite National d Ethique pour la Recherche
Ethics Committee Address
Street address City Postal code Country
Libreville Libreville 2217 Gabon
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Change in clinical and parasitological characteristics between each of five repeated controlled human malaria infections (CHMI) by direct venous inoculation (DVI) of PfSPZ Challenge (NF54) using the ordered categories: 1. Protection (no parasitemia, no symptoms) 2. Control (parasitemia, no symptoms) 3. Malaria (positive thick blood smear and symptoms) Until 56 days after each DVI
Primary Outcome Number or occurrence of at least possibly related Grade 3 AEs and SAEs from time of first administration of PfSPZ Challenge to the end of the follow-up period Until the end of follow-up, i.e. 6 months after final DVI
Secondary Outcome Proportion of volunteers with parasitemia following first CHMI with PfSPZ Challenge (NF54) and PfSPZ Challenge (7G8), respectively Until 56 days after each first DVI
Secondary Outcome Difference in proportion of volunteers with parasitemia receiving PfSPZ Challenge (7G8) before PfSPZ Challenge (NF54) to volunteers with parasitemia receiving PfSPZ Challenge (7G8) following repeated PfSPZ Challenge (NF54) Until 21 days after each respective PfSPZ Challenge 7G8 DVI
Secondary Outcome Change in clinical and parasitological characteristics of volunteers receiving PfSPZ Challenge (NF54) immediately before and after receiving PfSPZ Challenge (7G8) Until 56 days after each respective PfSPZ Challenge NF54 DVI
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Centre de Recherches Medicales de Lambarene Hopital Albert Schweitzer Lambarene 0242 Gabon
FUNDING SOURCES
Name of source Street address City Postal code Country
Deutsches Zentrum fur Infektionsforschung e.V. Inhoffenstrasse 7 Braunschweig 38124 Germany
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Centre de Recherches Medicale de Lambarene Hopital Albert Schweitzer Lambarene 0242 Gabon Research Institute
COLLABORATORS
Name Street address City Postal code Country
Institut fur Tropenmedizin of University Clinic Tuebingen Wilhelmstrasse 27 Tuebingen 72074 Germany
Sanaria Inc. 9800 Medical Center Drive, Suite A209 Rockville 20850 United States of America
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Matthew McCall matthew.mccall@cermel.org +24106942023 Centre de Recherche Medicales de Lambarene
City Postal code Country Position/Affiliation
Lambarene 0242 Gabon clinical microbiologist and group leader
Role Name Email Phone Street address
Public Enquiries Bertrand Lell bertrand.lell@cermel.org +24107877557 Centre de Recherche Medicales de Lambarene
City Postal code Country Position/Affiliation
Lambarene 0242 Gabon Co director
Role Name Email Phone Street address
Scientific Enquiries Benjamin Mordmuller benjamin.mordmueller@uni-tuebingen.de +4970712982366 Wilhemlstrasse 27
City Postal code Country Position/Affiliation
Tuebingen 72074 Germany Co director
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
No
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information