HIV-1-infectionPhase 2TITANNCT03837756
Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV
A Phase 2 study testing Saline, Lefitolimod and 3BNC117 and 10-1074 in people with HIV-1-infection, run by University of Aarhus at 8 sites in 4 countries.
Trial summary
This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074 in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1 reservoir Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV-1-infection
- What is being tested?
- Saline, Lefitolimod and 3BNC117 and 10-1074
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 47 participants
- Where
- 8 sitesin 4 countries
- Study dates
- 6 May 2019to 1 May 2023
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented HIV-1 infection
- Adults age 18-65 years
- On ART for a minimum of 18 months.
- CD4+ T cell count >500 at screening
- HIV-1 RNA plasma level of < 50 copies/mL by standard assays for at least 15 months (a single viral load measurement > 50 but < 500 copies/mL during this time period is allowable).
- Able to give informed consent
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- Viral reservoir sensitivity to 3BNC117 and 10-1074. (Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to randomization)).
- Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to enrollment and randomization). Isolated PBMCs will be analyzed using the PhenoSense HIV mAb Assay, Monogram Biosciences. The sensitivity of an individuals archieved proviruses to bNAb neutralization will be determined by the IC50 value of PBMC derived pseudovirus inhibition. Subjects that are considered sensitive to both 3BNC117 (IC90<=1.5 μg/mL) and 10-1074 (IC90<=2.0 μg/mL) AND MPI>97 AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization.
- If sensitivity cannot be determined by the PhenoSense HIVmAb Assay, participants will be screened for 3BNC117 and 10-1074 sensitivity using HIV env sequencing carried out in-house (Aarhus, Denmark). The method was originally established and validated by Rockefeller University that already has this method implemented. The method utilizes HIV-1 DNA envelope sequencing and a mathematical prediction binding algoritm of known binding sites of the antibodies. Based on the individual HIV env sequence, proviruses are categorized as "sensitive" or "resistant". Subjects that are determined to be sensitive to both 3BNC117 and 10-1074 (defined as at least 90% of known sequences sensitive to either bNAb) AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization.
Who cannot join
- Any significant acute medical illness requiring hospitalization in the past 4 weeks
- Any evidence of an active AIDS-defining opportunistic infection
- Any condition that, in the Investigator's opinion, will prevent adequate compliance with study therapy
- The following laboratory values at screening, the values can be repeated within the screening period, but test results must be available before baseline (Day 0) and checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) // Serum total bilirubin ≥3 ULN // Estimated glomerular filtration rate (eGFR) ≤50 mL/min (based on serum creatinine) // Platelet count ≤100 x109/L // Absolute neutrophil count ≤1x109/L
- Hepatitis B or C infection
- History of: Malignancy, excluding non-melanoma skin cancers, or organ transplantation
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- Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to study entry
- Known resistance to >2 classes of ART
- Known hypersensitivity to the components of lefitolimod, 3BNC117, 10-1074 or their analogues
- Pre-existing autoimmune or antibody-mediated diseases
- Women who are pregnant or breastfeeding, or unwilling/ unable to use an acceptable method of contraception (if of child bearing potential)
- Males or females who are unwilling or unable to use barrier contraception during sexual intercourse until plasma HIV-1 RNA is undetectable using standard assays
Trial locations and contacts
8 sites in 4 countries.
8 sites in 4 countries
Denmark5 sites
Dept. of Infectious Diseases, Aalborg University Hospital
Aalborg, 9000
Dept. of Infectious Diseases, Aarhus University Hospital
Aarhus, 8200
Dept. of Infectious Diseases, Rigshospitalet
Copenhagen, 2100
Dept. of Infectious Diseases, Amager and Hvidovre Hospitals
Hvidovre, 2650
Dept. of Infectious Diseases, Odense University Hospital
Odense, 5000
United States1 site
Dept. of Internal Medicine, University of Utah
Salt Lake City, Utah, 84132
About this study
Official title: Combining a TLR9 Agonist With Broadly Neutralizing Antibodies for Reservoir Reduction and Immunological Control of HIV Infection: An Investigator-initiated Randomized, Placebo-controlled, Phase IIa Trial.
This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074 in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1 reservoir
- Conditions
- HIV-1-infection
- Being tested
- Saline, Lefitolimod, 3BNC117 and 10-1074
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SalineDrug
Placebo
LefitolimodDrug
Also called MGN1703
A TLR9 agonist administered s.c. once weekly for 8 weeks.
3BNC117 and 10-1074Drug
Also called RUhumab-001 and RUhumab-002
Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.
| Study group | Role | What they receive |
|---|---|---|
| Arm A: Placebo/Placebo | Placebo comparator | This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074. Receives: Drug: Saline |
| Arm B: Lefitolimod/Placebo | Active comparator | This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074. Receives: Drug: Saline; Drug: Lefitolimod |
| Arm C: Placebo/3BNC117 + 10-1074 | Active comparator | This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod. Receives: Drug: Saline; Drug: 3BNC117 and 10-1074 |
| Arm D: Lefitolimod/3BNC117 + 10-1074 | Active comparator | This arm will receive both Lefitolimod and 3BNC117 + 10-1074. Receives: Drug: Lefitolimod; Drug: 3BNC117 and 10-1074 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to re-initiation of cART during analytical treatment interruption (ATI)
Time from date of cART cessation to the date of the last of three consecutive plasma HIV-1 RNA measurements >10,000 copies/mL, CD4 cell count <350 on two consecutive measurements, or end of ATI (i.e. 26 weeks after cessation of cART) - whichever comes first.
Measured: Up to 26 weeks.
Secondary outcomes (2)
Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,
Subject who receives at least one dose of the IMP(s) will be included in the evaluation for safety, measured by AEs, Adverse Reactions (ARs), SAEs, Serious ARs (SARs) and (SUSAR)
Measured: Duration of the study
Plasma HIV RNA doubling time
Plasma HIV RNA doubling time from first measurement >50 copies/mL to first measurement >1,000 copies/mL during the analytical treatment interruption (plasma HIV RNA measured by standard clinical assays, e.g. Cobas TaqMan; Lower limit of quantitation 20 copies/mL)
Measured: Duration of ATI (up to 26 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2019
- Study start6 May 2019
- Primary completion1 Jul 2022
- Study completion1 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV-1-infectionStudies of the same condition, open and under way.
- More trials run by University of AarhusThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Model description
- Participants will be randomized 1:1:1:1 in a blinded fashion to receive: Arm A: Placebo and Placebo Arm B: Lefitolimod and Placebo Arm C: Placebo and 3BNC117+10-1074 Arm D: Lefitolimod and 3BNC117+10-1074
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Collaborators
- Aalborg University Hospital, Odense University Hospital, Copenhagen University Hospital, Rigshospitalet, Hvidovre University Hospital, The Peter Doherty Institute for Infection and Immunity, University of Utah, Oslo University Hospital
- Responsible party
- Sponsor
- Investigators
- Ole S Søgaard, MD PhD, Principal investigator, Aarhus University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03837756
- Sponsor's protocol ID
- TITAN-001
- Other IDs
- 2018-001165-16, AGR-2016-8833, 2018
- Acronym
- TITAN
- Status last verified
- May 2023
- First submitted
- 7 Feb 2019
- Last updated
- 23 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data to be shared includes deidentified data points in published, peer-reviewed articles. Additional, related documents will also be available (study protocol, informed consent form, statistical analysis plan).
Publications
Gunst JD, Hojen JF, Pahus MH, Rosas-Umbert M, Stiksrud B, McMahon JH, Denton PW, Nielsen H, Johansen IS, Benfield T, Leth S, Gerstoft J, Ostergaard L, Schleimann MH, Olesen R, Stovring H, Vibholm L, Weis N, Dyrhol-Riise AM, Pedersen KBH, Lau JSY, Copertino DC Jr, Linden N, Huynh TT, Ramos V, Jones RB, Lewin SR, Tolstrup M, Rasmussen TA, Nussenzweig MC, Caskey M, Reikvam DH, Sogaard OS. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med. 2023 Oct;29(10):2547-2558. doi: 10.1038/s41591-023-02547-6. Epub 2023 Sep 11.
PubMed 37696935
Study at a glance
From the registry record, last updated by the sponsor on 23 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combining a TLR9 Agonist With Broadly Neutralizing Antibodies for Reservoir Reduction and Immunological Control of HIV Infection: An Investigator-initiated Randomized, Placebo-controlled, Phase IIa Trial.
- ClinicalTrials.gov ID
- NCT03837756
- Acronym / sponsor ID
- TITAN / TITAN-001
- Conditions
- HIV-1-infection
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 47 participants (actual)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Collaborators
- Aalborg University Hospital, Odense University Hospital, Copenhagen University Hospital, Rigshospitalet, Hvidovre University Hospital, The Peter Doherty Institute for Infection and Immunity, University of Utah, Oslo University Hospital
- Study start
- 6 May 2019 (actual)
- Primary completion
- 1 Jul 2022 (actual)
- Study completion
- 1 May 2023 (actual)
- First posted
- 12 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074 in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1 reservoir
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- Model description
- Participants will be randomized 1:1:1:1 in a blinded fashion to receive: Arm A: Placebo and Placebo Arm B: Lefitolimod and Placebo Arm C: Placebo and 3BNC117+10-1074 Arm D: Lefitolimod and 3BNC117+10-1074
| Arm | Type | Receives |
|---|---|---|
| Arm A: Placebo/Placebo | Placebo comparator | Drug: SalineThis arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074. |
| Arm B: Lefitolimod/Placebo | Active comparator | Drug: Saline, Drug: LefitolimodThis arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074. |
| Arm C: Placebo/3BNC117 + 10-1074 | Active comparator | Drug: Saline, Drug: 3BNC117 and 10-1074This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod. |
| Arm D: Lefitolimod/3BNC117 + 10-1074 | Active comparator | Drug: Lefitolimod, Drug: 3BNC117 and 10-1074This arm will receive both Lefitolimod and 3BNC117 + 10-1074. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Documented HIV-1 infection
- Adults age 18-65 years
- On ART for a minimum of 18 months.
- CD4+ T cell count >500 at screening
- HIV-1 RNA plasma level of < 50 copies/mL by standard assays for at least 15 months (a single viral load measurement > 50 but < 500 copies/mL during this time period is allowable).
Key exclusion criteria (12 listed)
- Any significant acute medical illness requiring hospitalization in the past 4 weeks
- Any evidence of an active AIDS-defining opportunistic infection
- Any condition that, in the Investigator's opinion, will prevent adequate compliance with study therapy
- The following laboratory values at screening, the values can be repeated within the screening period, but test results must be available before baseline (Day 0) and checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) // Serum total bilirubin ≥3 ULN // Estimated glomerular filtration rate (eGFR) ≤50 mL/min (based on serum creatinine) // Platelet count ≤100 x109/L // Absolute neutrophil count ≤1x109/L
- Hepatitis B or C infection
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SalinePlacebo | Drug | Arm A: Placebo/Placebo, Arm B: Lefitolimod/Placebo, Arm C: Placebo/3BNC117 + 10-1074 |
| LefitolimodAlso: MGN1703A TLR9 agonist administered s.c. once weekly for 8 weeks. | Drug | Arm B: Lefitolimod/Placebo, Arm D: Lefitolimod/3BNC117 + 10-1074 |
| 3BNC117 and 10-1074Also: RUhumab-001 and RUhumab-002Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval. | Drug | Arm C: Placebo/3BNC117 + 10-1074, Arm D: Lefitolimod/3BNC117 + 10-1074 |
Primary outcome
Time to re-initiation of cART during analytical treatment interruption (ATI)
Time frame: Up to 26 weeks.
Time from date of cART cessation to the date of the last of three consecutive plasma HIV-1 RNA measurements >10,000 copies/mL, CD4 cell count <350 on two consecutive measurements, or end of ATI (i.e. 26 weeks after cessation of cART) - whichever comes first.
2 secondary outcomes
Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,
Time frame: Duration of the study
Plasma HIV RNA doubling time
Time frame: Duration of ATI (up to 26 weeks)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 May 2023.
- Derived from this study: PubMed 37696935Gunst JD, Hojen JF, Pahus MH, Rosas-Umbert M, Stiksrud B, McMahon JH, Denton PW, Nielsen H, Johansen IS, Benfield T, Leth S, Gerstoft J, Ostergaard L, Schleimann MH, Olesen R, Stovring H, Vibholm L, Weis N, Dyrhol-Riise AM, Pedersen KBH, Lau JSY, Copertino DC Jr, Linden N, Huynh TT, Ramos V, Jones RB, Lewin SR, Tolstrup M, Rasmussen TA, Nussenzweig MC, Caskey M, Reikvam DH, Sogaard OS. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med. 2023 Oct;29(10):2547-2558. doi: 10.1038/s41591-023-02547-6. Epub 2023 Sep 11.
- Individual participant dataSharing planned: Yes. Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data to be shared includes deidentified data points in published, peer-reviewed articles. Additional, related documents will also be available (study protocol, informed consent form, statistical analysis plan).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ole S Søgaard, MD PhD principal investigator
Aarhus University Hospital
8 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Saline, Lefitolimod and 3BNC117 and 10-1074 in people with HIV-1-infection, run by University of Aarhus at 8 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Denmark, United States, Australia, Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to re-initiation of cART during analytical treatment interruption (ATI) (time frame: Up to 26 weeks.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03837756, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 May 2023.