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.: PACTR202008822861957 Date of Approval: 28/08/2020
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public title Safety and Pharmacokinetics of the Combination Broadly Neutralizing Antibodies, 3BNC117-LS-J and 10-1074-LS-J, in Healthy American and African Adults Lay Title: IAVI C100
Official scientific title Safety and Pharmacokinetics of the Combination Broadly Neutralizing Antibodies, 3BNC117-LS-J and 10-1074-LS-J, in Healthy American and African Adults
Brief summary describing the background and objectives of the trial This is a Phase 1/2 study to evaluate the safety, tolerability, and pharmacokinetics of two broadly neutralizing monoclonal human antibodies (bNAbs), 3BNC117-LS-J, which targets the CD4 binding site on HIV-1 envelope protein, and 10-1074-LS-J which targets the V3 loop of HIV-1 envelope protein. The hypothesis is that the two antibodies will be safe for healthy HIV-1 uninfected adults when co-administered subcutaneously or intravenously and, after subcutaneous administration in the optimal ratio, each antibody will maintain serum levels >10 µg/ml for at least 3 months in HIV-uninfected participants. Primary: 1. To evaluate the safety and tolerability of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LS-J, when given alone and in combination, intravenously (IV) or subcutaneously (SC) to healthy American and African adults. 2. To evaluate the pharmacokinetic profile of two broadly neutralizing monoclonal human antibodies, 3BNC117-LS-J and 10-1074-LS-J, when given alone or in combination, IV or SC to healthy American and African adults. 3. To identify a regimen of the two antibodies that, when given SC every 3 months, will maintain a serum trough level of >10 μg/mL for each antibody in >80% of the study population. Secondary: 1. To evaluate the effect of participant characteristics, e.g., sex, body weight or body mass index (BMI), on pharmacokinetic parameters. 2. To conduct pharmacokinetic modelling to assess the effect of dose, dose ratio, dosing frequency and loading dose on serum trough levels of each antibody. 3. To assess the incidence and titers of anti-drug antibodies (ADA) against each antibody. Exploratory: 1. To evaluate the effect of geographic region, immunoglobulin levels, and the subcutaneous site on injection (abdomen vs. arm) on pharmacokinetic parameters. 2. To characterize the bNAb neutralization potency in serum or plasma. 3. To investigate the effect of ADA on antibody concentration and neutralizing potency and th
Type of trial RCT
Acronym (If the trial has an acronym then please provide) C100
Disease(s) or condition(s) being studied Infections and Infestations
Sub-Disease(s) or condition(s) being studied HIV/AIDS
Purpose of the trial Treatment: Other
Anticipated trial start date 12/01/2019
Actual trial start date 18/02/2020
Anticipated date of last follow up 30/04/2023
Actual Last follow-up date 13/07/2023
Anticipated target sample size (number of participants) 176
Actual target sample size (number of participants) 184
Recruitment status Completed
Publication URL
Secondary Ids Issuing authority/Trial register
140344 FDA IND Regulatory Investigational Product
NCT04173819 ClinicalTrials.gov
DOH 27 102022 506 South African National Clinical Trial Registry
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 Allocation was determined by the holder of the sequence who is situated off site Masking/blinding used Outcome Assessors
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Control Group Sodium Chloride 20mM sodium acetate, 3% proline, 0.015% polysorbate-80 Placebo for SC N/A SC With Loading dose 1.57 mL 2 injections, up to 2.5 mL each Without Loading dose 1 injection, up to 2.5 mL 0.9% Sodium Chloride Injection, USP N/A IV 100 mL 100 mL The anticipated study duration for each participant is approximately 68-92weeks from screening through last study visit. Placebo IV administrations will utilize 0.9% Sodium Chloride Injection, USP alone. Group Size: 3 for Thika site and 27 for KAVI site 20 Placebo
Experimental Group Antibodies 3BNC117 LS J and 10 1074 LS J Groups 1-5: Twelve participants per group, receiving administrations at a single timepoint, will be randomized in a 10:2 ratio of active product to placebo in Groups 1-2A (SC, abdominal area) and 3-5 (IV). REPEATED DOSE GROUPS, African sites Groups 6-10: Thirty-three participants per group in Groups 6-10 will be dosed subcutaneously with different ratios of antibodies or with a placebo (30:3). Dosage ratios chosen for Groups 6-10 will be those considered worthy of further investigation based on the safety and preliminary PK observed in Groups 1-2A. These participants will receive administrations of combined bNAbs or placebo subcutaneously. On Day 0, participants in Groups 6-8 and 10 will receive two administrations in order to more rapidly achieve steady state level (loading dose), and one administration thereafter at Weeks 12 and 24. Group 9 will receive one administration on three occasions. Participants in Groups 1-2A and 6-9 will receive subcutaneous injections in the abdomen, whilst participants in Group 10 will receive subcutaneous injections in the upper arm to explore the impact of the differing SC injection sites on PK. The anticipated study duration for each participant is approximately 68-92 weeks from screening through last study visit. 3BNC117 and 10-1074 are two of the most potent broadly neutralizing antibodies available. 3BNC117 targets the CD4 binding site, while 10-1074 targets the V3 loop of HIV-1 gp 120. They were chosen for clinical development for their neutralizing breadth and potency, and their antiretroviral activity when tested in humanized mice (hu-mice) and non-human primate (NHP) models. The neutralizing activities of 3BNC117 and 10-1074 were evaluated in vitro against large pseudovirus panels including diverse clades. 3BNC117 showed neutralizing activity against 82.5% of 399 pseudoviruses tested, while 10-1074 neutralized 61.7% of 295 pseudoviruses tested. The combination of these two antibodies, which target two nonoverlapping epitopes on HIV-1 gp 120 provides higher breadth and potency than either antibody alone. In vitro, the combination showed neutralizing activity against 96% of 125 viruses from multiple clades, with average IC80 0.15 μg/mL [15]. The 3BNC117 and 10-1074 combination neutralizing titers against a panel of 200 clade C viruses were predicted using the Bliss-Hill model. Against this panel, the 3BNC117 plus 10-1074 combination covered 87% of viral strains with IC80 of 0.16 μg/mL. Group Size: 16 for Thika site and 237 for KAVI site 176
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
1. Healthy individuals, as assessed by medical history, physical exam, and laboratory tests 2. At least 18 years of age on the day of screening and have not reached their 46th birthday on the day of the first administration 3. Willing to undergo HIV testing, risk reduction counseling, and receive HIV test results; committed to maintaining low-risk behavior for the trial duration 4. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study; 5. According to the PI/designee and based on Assessment of Understanding results, has understood the information provided and potential impact and/or risks linked to IP administration and participation in the trial; written IC will be obtained from the participant before any study-related procedures are performed; 6. All participants of reproductive potential who are engaging in sexual activity that could lead to pregnancy must commit to using an effective method of contraception from enrollment until 9 months after the last administration, including Condoms, with or without spermicide, IUD & implant Hormonal contraception, Successful vasectomy (male -considered successful if a woman reports that a male partner has; documentation of azoospermia by microscopy (< 1 year ago), or a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post-vasectomy) Note: More restrictive measures may be required by study site. '7. Willing to forgo donations of blood, or any other tissues during the study following confirmation of study eligibility and, for those who test HIV-positive due to antibody-induced seropositivity, until the ant-HIV antibody titers become undetectable on HIV tests used in the community. 8. Body mass index (BMI) >40 9. 1. Confirmed HIV infection; 2. Reported risk for HIV infection within 6 months prior to investigational product administration, as defined by: Unprotected sexual intercourse with a known HIV-infected person, a partner known to be at high risk for HIV infection and/or a casual partner (i.e. no continuing established relationship) Engaged in sex work Frequent excessive daily alcohol use or frequent binge drinking or any other use of illicit drugs History of newly-acquired syphilis, gonorrhea, non-gonococcal urethritis, HSV-2, chlamydia, pelvic inflammatory disease (PID), trichomonas, mucopurulent cervicitis, epididymitis, proctitis, lymphogranuloma venereum, chancroid, or hepatitis B or hepatitis C; Three or more sexual partners; 3. Any clinically relevant abnormality on history or examination, including history of immunodeficiency or autoimmune disease; use of systemic corticosteroids (the use of topical or inhaled steroids is permitted), immunosuppressive, anticancer, antituberculosis or other medications considered significant by the investigator within the previous 6 months; The following exceptions are permitted and will not exclude study participation: use of corticosteroid nasal spray for rhinitis, topical corticosteroids for an acute uncomplicated dermatitis; or a short course (duration of 10 days or less, or a single injection) of corticosteroid for a non-chronic condition (based on investigator clinical judgment) at least 2 weeks prior to enrollment in this study; 4. Any clinically significant acute or chronic medical condition that is considered progressive or in the opinion of the investigator makes the participant unsuitable for participation in the study; 5. Asthma that is not well controlled; 6. If female, pregnant or planning a pregnancy during the period of enrollment until 9 months after the final IP administration; or lactating; 7. Bleeding disorder diagnosed by a physician (e.g., factor deficiency, coagulopathy or platelet disorder 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 25/03/2020 KEMRI SERU
Ethics Committee Address
Street address City Postal code Country
Mbagathi way Nairobi 00100 Kenya
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 04/05/2020 KNH UoN ERC
Ethics Committee Address
Street address City Postal code Country
Ngong Road Nairobi 00202 Kenya
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 04/05/2020 University of Witwatersrand Human Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
31 Princess of Wales Terrace Parktown Johannesburg 2193 South Africa
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 04/11/2019 CFHR Rwanda National Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Ministry of Health Kigali 84 Rwanda
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 21/11/2019 Uganda Virus Research Institute
Ethics Committee Address
Street address City Postal code Country
Plot 51-59, Nakiwongo Road Entebbe 49 Uganda
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Safety and tolerability: 1. Proportion of participants with solicited and IP-related unsolicited adverse events that are Grade 2 and above (including confirmed laboratory abnormalities) and their duration. 2. Proportion of participants with solicited and IP-related unsolicited adverse events that are Grade 3 and above (including confirmed laboratory abnormalities) and their duration. 3. Proportion of participants with serious adverse events (SAEs) throughout the study period that are considered related to investigational product and their duration. Pharmacokinetics (PK): 4. The ratio of 3BNC117-LS-J to 10-1074-LS-J that, when injected SC, will maintain similar levels of each bNAb at steady state. Day 0, week 12, week 24 as per protocol
Secondary Outcome Secondary Endpoints: 1. Serum concentration of each bNAb in each group at multiple timepoints along with participant characteristics (e.g., sex, weight, and BMI). 2. Serum concentration of 3BNC117-LS-J and 10-1074-LS-J in each group at multiple timepoints along with dose, dose ratio, dosing frequency and loading dose. 3. Serum concentration of anti-3BNC117-LS-J and anti-10-1074-LS-J antibodies in each group at multiple timepoints. Exploratory Endpoints: 1. Serum concentration of the bNAb in each group at multiple timepoints along with geographical region, immunoglobulin levels and the subcutaneous site of administration (abdomen vs. arm). 2. Magnitude of serum neutralization of virus isolates sensitive to each antibody at 7 days and 12 weeks after each SC administration in selected participants in America and Africa. 3. Proportion of participants with reduction in bNAb half-life concomitant with ADA. 4. Proportion of participants with reduction in bNAb neutralization potency concomitant with ADA. 5. Proportion of participants with pIMDs throughout the study period that are considered related to investigational product and their duration. 6. Relationship of solicited and unsolicited adverse events, and pIMDs, to ADA. 7. bNAb concentrations in mucosal secretions in a subset of participants enrolled in African sites. Day 0, Week 12, 24
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Partners in Health Research and Development CCR KEMRI OAU Road, Thika Section 9 Thika Kenya
Kenya Aids Vaccine Initiative University of Nairobi College of Health Sciences Nairobi 0010 Kenya
UVRI IAVI Plot 51-49 Nakiwogo Road, Nsamizi Hill Entebbe 0000 Uganda
Infectious Diseases Institute Kasangati Health Center IV Gayaza Road Kampala 719525 Uganda
Center for Family Health Research KK 19 Ave 57 Kicukiro, Kigali Kigali 0000 Rwanda
The Wits RHI 22 Esselen Street Hillbrow Johannesburg 2001 South Africa
FUNDING SOURCES
Name of source Street address City Postal code Country
Bill and Melinda Gates Foundation 500 fifth Avenue North Seattle WA 98109 United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor International AIDS Vaccine Initiative IAVI 125 Broad Street, 9th Floor New York, New York 10004 USA New York 1004 United States of America Charities/Societies/Foundation
COLLABORATORS
Name Street address City Postal code Country
University of Washington Roosevelt Way NE Seattle, Washington, USA Seattle Washington 98115 United States of America
Rockefeller University 1230 York Avenue, New York New York 10065 United States of America
KAVI University of Nairobi College of Health Sciences Nairobi 010 Kenya
CONTACT PEOPLE
Role Name Email Phone Street address
Principal Investigator Nelly Mugo rwamba@uw.edu 0733629665 Ngong Road
City Postal code Country Position/Affiliation
Nairobi Kenya Principal Investigator
Role Name Email Phone Street address
Public Enquiries Walter Jaoko wjaoko@kaviuon.org +254727555254 KAVI Institute of Clinical Research, University of Nairobi
City Postal code Country Position/Affiliation
Nairobi 010 Kenya Principal Investigator KAVI
Role Name Email Phone Street address
Scientific Enquiries Gaudensia Mutua GMutua@iavi.org 0719043156 ABC PLACE
City Postal code Country Position/Affiliation
Nairobi Kenya Scientific Enquiries
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes Principal investigators and sponsors are committed to publicly sharing the findings of the study by publishing in journals and providing the results on request. Summary level results will be made available no later than12 months after trial completion via the CAVD (Coalition for AIDS Vaccine Development) public web site (https://www.cavd.org). The Abbreviated Full Data Set will be publicly listed on www.ClinicalStudyDataRequest.com (CSDR) no later than 18 months after trial completion, at which time members of the public can request access to the data via the mechanisms at CSDR. The available components of the Abbreviated Full Data Set will be listed in the CSDR catalogue of clinical studies. Post-Publication Data Packages will also be made available by means of a complete record of the data underlying the publication that will be accessed through IAVI’s open access repository https://iavi.figshare.com/. The trial completion date will be recorded on this website and for the C100 trial is the date of database lock. Clinical Study Report Principal investigators and sponsors are committed to publicly sharing the findings of the study by publishing in journals and providing the results on request. Summary level results will be made available no later than12 months after trial completion via the CAVD(Coalition for AIDS Vaccine Development) public web site (https://www.cavd.org). TheAbbreviated Full Data Set will be publicly listed on www.ClinicalStudyDataRequest.com (CSDR) no later than 18 months after trial completion, at which time members of the public can request access to the data via the mechanisms at CSDR. The available components of the Abbreviated Full Data Set will be listed in the CSDR catalogue of clinical studies. Post-Publication Data Packages will also be made available by means of a complete record of the data underlying the publication that will be accessed through IAVI's open access repository https://iavi.figshare.com/. The trial completion date will be recorded on this website and for the C100 trial is the date of the database lock. Principal investigators and sponsors are committed to publicly sharing the findings of the study by publishing in journals and providing the results on request. Summary level results will be made available no later than12 months after trial completion via the CAVD(Coalition for AIDS Vaccine Development) public web site (https://www.cavd.org). TheAbbreviated Full Data Set will be publicly listed on www.ClinicalStudyDataRequest.com (CSDR) no later than 18 months after trial completion, at which time members of the public can request access to the data via the mechanisms at CSDR. The available components of the Abbreviated Full Data Set will be listed in the CSDR catalogue of clinical studies. Post-Publication Data Packages will also be made available by means of a complete record of the data underlying the publication that will be accessed through IAVI’s open access repository https://iavi.figshare.com/. The trial completion date will be recorded on this website and for the C100 trial is the date of the database lock.
URL Results Available Results Summary Result Posting Date First Journal Publication Date
CAVD public web site: https://www.cavd.org 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