HIVPhase 4DIORRNCT02500446
Dolutegravir Impact on Residual Replication
A Phase 4 study testing dolutegravir in people with HIV, run by University of Melbourne at 2 sites in Australia.
Trial summary
Several studies have suggested that despite suppressive combination antiretroviral therapy (ART) in people who are HIV-positive, in some individuals there may be on-going viral replication. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV
- What is being tested?
- dolutegravir
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 2 sitesAustralia
- Study dates
- 28 Sep 2015to 30 Sep 2017
- Phase
- Phase 4
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented HIV-1 infection
- Minimum age 18 years
- Receiving combination ART (at least 3 agents) for at least 3 years. Twenty of the 40 study participants will be on a PI-based ART regimen.
- HIV-1 plasma RNA <50 copies/mL for >3 years and <20 copies/mL at screening.
- Two CD4+ T cell counts >350 cells/μL in the 24 months prior to screening
- Able to give informed consent
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- A female, may be eligible to enter and participate in the study if she:
- Is of non-child-bearing potential OR
- Is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the study protocol-specified methods of contraception to avoid pregnancy:
Who cannot join
- Known hypersensitivity to DTG or to any of the excipients
- Current use of dofetilide, pilsicainide or metformin
- Current use of etravirine except when etravirine is co-administered with atazanavir/ritonavir, lopinavir/ritonavir or darunavir/ritonavir
- Current or prior use of any integrase inhibitor
- Previous use of histone deacetylase inhibitors or other latency reversing agents
- Any significant acute medical illness requiring hospitalization within preceding 8 weeks
Show all 22Show fewer
- Significant renal disease (eGFR <50 milliliters per min)
- Hepatitis C co-infection (Individuals with prior hepatitis C infection that is now cleared are eligible for enrolment)
- Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh classification
- Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice), known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- Receipt of immunomodulating agents (excluding immunization) or systemic chemotherapeutic agents within 28 days prior to study entry
- Patients who intend to modify their ART regimen within the study period
- Current or recent gastrointestinal disease or surgery that may impact the absorption of the investigational drug
- Active alcohol or substance use that in the opinion of the investigator will prevent adequate compliance with study procedures
- Currently pregnant, breastfeeding or unwilling to use barrier contraception
- Women of Child Bearing Potential (WOCBP) unwilling or unable to use an acceptable method of contraception to avoid pregnancy as specified in the inclusion criteria
- Unable or unwilling to adhere to protocol procedures
- The following laboratory values within 3 weeks before starting the investigational drug (lab tests may be repeated to obtain acceptable values before failure at screening is concluded)
- Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
- Serum total bilirubin ≥1.5 x ULN
- eGFR <50 mL/min
- Haemoglobin <11.0 g/dL
Trial locations and contacts
2 sites in 1 country.
Australia2 sites
Melbourne Sexual Health Centre
Carlton, Victoria, 3053
Alfred Hospital
Prahran, Victoria, 3010
About this study
Official title: Dolutegravir Impact on Residual Replication: Dolutegravir Intensification Study
Several studies have suggested that despite suppressive combination antiretroviral therapy (ART) in people who are HIV-positive, in some individuals there may be on-going viral replication. Clarifying the extent of on-going viral replication on ART is important for the development of HIV-1 curative strategies and for reducing HIV-1 associated immune activation. The investigators hypothesize that treatment intensification with dolutegravir will inhibit residual virus replication in HIV-1 infected patients on ART. The primary objective of this study is to determine the effects of dolutegravir intensification on residual virus replication in circulating cluster of differentiation 4 (CD4+) T cells.
Read the detailed description
ART effectively suppresses HIV-1 viremia but in most patients, virus rebounds within 2-3 weeks of stopping ART. ART is unable to cure HIV due to the persistence of virus as long-lived latently infected cells, residual virus replication and anatomical reservoirs. Understanding the contribution of residual virus replication to virus persistence on ART is important because first, no interventions aimed at eliminating latency will be effective in the presence of residual virus replication; second, residual virus replication may contribute to persisting immune activation which has been associated with all-cause mortality.
Numerous studies have demonstrated that intensifying a suppressive ART regimen with an additional antiretroviral drug does not alter the frequency of latently infected cells or low-level viremia. However, in studies that have intensified ART with the integrase inhibitor raltegravir, an increase in circularised HIV episomes containing 2 copies of the viral long terminal repeat (2-LTR) circles within 2 weeks of intensification, was observed in ~30% of study participants. 2-LTR circles have a short half- life, which may explain why an increase in 2-LTR circles was only observed in studies that measured 2-LTR circles within 2 weeks of raltegravir intensification. In these two randomized controlled trials, the level of 2-LTR circles increased transiently in patients randomized to intensification with raltegravir as compared with placebo and this effect was more pronounced in subjects receiving a protease inhibitor (PI)-containing ART regimen. Other studies have failed to demonstrate an increase in 2-LTR circles following raltegravir intensification but this is likely because sampling was delayed beyond 2 weeks.
One possible explanation for the additional effect observed with raltegravir intensification is the extensive penetration of this compound into gastrointestinal (GI) tissue where it reaches concentrations 39- to 650-fold higher than those in plasma.
To date, raltegravir is the only integrase inhibitor that has been investigated in ART intensification trials. Dolutegravir (DTG) is a recently licensed once-daily integrase inhibitor that is non-inferior to raltegravir and with a similar safety profile, however DTG levels in GI tissue is only 17% of that in plasma. DTG has not been investigated in intensification studies, so whether adding dolutegravir to a suppressive ART regimen is able to inhibit residual replication is currently unknown.
Thus, there are several unresolved issues related to residual viral replication in the presence of ART and the potential benefit of integrase inhibitors in this context: How frequent is this phenomenon and does it occur more frequently in patients receiving a PI-containing regimen? Given that raltegravir does seem to impact residual replication in approximate 30% of HIV infected patients on ART when assessed early after intensification, what is the effect of DTG in this setting? Finally, what are the dynamics of 2-LTR levels in blood in the early phases after intensification with an integrase inhibitor? To address those questions, the investigators have designed a randomized, controlled study to compare the impact of intensification with DTG or placebo in HIV-infected patients on suppressive ART. In this study, the investigators will closely define the effects of dolutegravir intensification on 2-LTR levels in circulating CD4+ T cells.
Study participants will be in the study for up to 133 days. The duration of participation is calculated from the initial screening visit to the last study visit (visit 9), with 9 visits in total.
- Conditions
- HIV
- Being tested
- dolutegravir, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
dolutegravirDrug
Also called Tivicay®
Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir.
PlaceboOther
A film-coated tablet identical in appearance to the active drug tablet but not containing any dolutegravir or any other active ingredient
| Study group | Role | What they receive |
|---|---|---|
| Intensification | Active comparator | Oral dolutegravir 50 mg once daily for 8 weeks added to their current ART regimen. Receives: Drug: dolutegravir |
| Placebo | Placebo comparator | Oral placebo once daily for 8 weeks added to their current ART regimen. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Level of residual HIV replication in circulating CD4+ T cells
Change in the level of 2-LTR circles as measured by polymerase chain reaction (PCR) in the dolutegravir arm versus the placebo arm after 7 days of treatment
Measured: day 7 of treatment
Secondary outcomes (4)
Level of Human Leukocyte Antigen D-related (HLA-DR)
Change in level of Human Leukocyte Antigen D-related (HLA-DR), a marker of T cell activation from baseline within and across study arms.
Measured: time points to day 84 (28 days after treatment)
Level of Programmed cell death-1 receptor (PD-1)
Change in level of Programmed cell death-1 receptor (PD-1), a marker of T cell activation from baseline within and across study arms.
Measured: time points to day 84 (28 days after treatment)
Level of Cluster of Differentiation 38 (CD-38)
Change in level of Cluster of Differentiation 38 (CD-38), a marker of T cell activation, from baseline within and across study arms.
Measured: time points to day 84 (28 days after treatment)
Level of residual HIV replication in circulating CD4+ T cells in a protease inhibitor -containing regimen
Change in the level of 2-LTR circles as measured by polymerase chain reaction (PCR) in the dolutegravir arm versus the placebo arm in those participants on regimen which includes a protease inhibitor
Measured: time points up to day 84 (28 days after treatment)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jul 2015 (estimated)
- Study start28 Sep 2015
- Primary completion16 Sep 2016
- Study completion30 Sep 2017
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 HIVStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Melbourne
- Sponsor type
- University, hospital or other
- Collaborators
- The Alfred, ViiV Healthcare
- Responsible party
- Principal investigator, Sharon Lewin, University of Melbourne
- Investigators
- Sharon Lewin, Principal investigator, Doherty Institute for Immunity and Infection
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02500446
- Sponsor's protocol ID
- DIORR_20150306
- Acronym
- DIORR
- Status last verified
- Nov 2017
- First submitted
- 30 Jun 2015
- Last updated
- 20 Nov 2017
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan to share individual participant data
Publications
Rasmussen TA, McMahon JH, Chang JJ, Audsley J, Rhodes A, Tennakoon S, Dantanarayana A, Spelman T, Schmidt T, Kent SJ, Morcilla V, Palmer S, Elliott JH, Lewin SR. The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a randomised, placebo-controlled, double-blind trial. Lancet HIV. 2018 May;5(5):e221-e230. doi: 10.1016/S2352-3018(18)30040-7. Epub 2018 Apr 8.
PubMed 29643011
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Dolutegravir Impact on Residual Replication: Dolutegravir Intensification Study
- ClinicalTrials.gov ID
- NCT02500446
- Acronym / sponsor ID
- DIORR / DIORR_20150306
- Conditions
- HIV
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of MelbourneUniversity, hospital or other
- Collaborators
- The Alfred, ViiV Healthcare
- Study start
- 28 Sep 2015 (actual)
- Primary completion
- 16 Sep 2016 (actual)
- Study completion
- 30 Sep 2017 (actual)
- First posted
- 16 Jul 2015 (estimated)
- 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.
Several studies have suggested that despite suppressive combination antiretroviral therapy (ART) in people who are HIV-positive, in some individuals there may be on-going viral replication. Clarifying the extent of on-going viral replication on ART is important for the development of HIV-1 curative strategies and for reducing HIV-1 associated immune activation. The investigators hypothesize that treatment intensification with dolutegravir will inhibit residual virus replication in HIV-1 infected patients on ART. The primary objective of this study is to determine the effects of dolutegravir intensification on residual virus replication in circulating cluster of differentiation 4 (CD4+) T cells.
Detailed description
ART effectively suppresses HIV-1 viremia but in most patients, virus rebounds within 2-3 weeks of stopping ART. ART is unable to cure HIV due to the persistence of virus as long-lived latently infected cells, residual virus replication and anatomical reservoirs. Understanding the contribution of residual virus replication to virus persistence on ART is important because first, no interventions aimed at eliminating latency will be effective in the presence of residual virus replication; second, residual virus replication may contribute to persisting immune activation which has been associated with all-cause mortality.
Numerous studies have demonstrated that intensifying a suppressive ART regimen with an additional antiretroviral drug does not alter the frequency of latently infected cells or low-level viremia. However, in studies that have intensified ART with the integrase inhibitor raltegravir, an increase in circularised HIV episomes containing 2 copies of the viral long terminal repeat (2-LTR) circles within 2 weeks of intensification, was observed in ~30% of study participants. 2-LTR circles have a short half- life, which may explain why an increase in 2-LTR circles was only observed in studies that measured 2-LTR circles within 2 weeks of raltegravir intensification. In these two randomized controlled trials, the level of 2-LTR circles increased transiently in patients randomized to intensification with raltegravir as compared with placebo and this effect was more pronounced in subjects receiving a protease inhibitor (PI)-containing ART regimen. Other studies have failed to demonstrate an increase in 2-LTR circles following raltegravir intensification but this is likely because sampling was delayed beyond 2 weeks.
One possible explanation for the additional effect observed with raltegravir intensification is the extensive penetration of this compound into gastrointestinal (GI) tissue where it reaches concentrations 39- to 650-fold higher than those in plasma.
To date, raltegravir is the only integrase inhibitor that has been investigated in ART intensification trials. Dolutegravir (DTG) is a recently licensed once-daily integrase inhibitor that is non-inferior to raltegravir and with a similar safety profile, however DTG levels in GI tissue is only 17% of that in plasma. DTG has not been investigated in intensification studies, so whether adding dolutegravir to a suppressive ART regimen is able to inhibit residual replication is currently unknown.
Thus, there are several unresolved issues related to residual viral replication in the presence of ART and the potential benefit of integrase inhibitors in this context: How frequent is this phenomenon and does it occur more frequently in patients receiving a PI-containing regimen? Given that raltegravir does seem to impact residual replication in approximate 30% of HIV infected patients on ART when assessed early after intensification, what is the effect of DTG in this setting? Finally, what are the dynamics of 2-LTR levels in blood in the early phases after intensification with an integrase inhibitor? To address those questions, the investigators have designed a randomized, controlled study to compare the impact of intensification with DTG or placebo in HIV-infected patients on suppressive ART. In this study, the investigators will closely define the effects of dolutegravir intensification on 2-LTR levels in circulating CD4+ T cells.
Study participants will be in the study for up to 133 days. The duration of participation is calculated from the initial screening visit to the last study visit (visit 9), with 9 visits in total.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Intensification | Active comparator | Drug: dolutegravirOral dolutegravir 50 mg once daily for 8 weeks added to their current ART regimen. |
| Placebo | Placebo comparator | Other: PlaceboOral placebo once daily for 8 weeks added to their current ART regimen. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Documented HIV-1 infection
- Minimum age 18 years
- Receiving combination ART (at least 3 agents) for at least 3 years. Twenty of the 40 study participants will be on a PI-based ART regimen.
- HIV-1 plasma RNA <50 copies/mL for >3 years and <20 copies/mL at screening.
- Two CD4+ T cell counts >350 cells/μL in the 24 months prior to screening
Key exclusion criteria (22 listed)
- Known hypersensitivity to DTG or to any of the excipients
- Current use of dofetilide, pilsicainide or metformin
- Current use of etravirine except when etravirine is co-administered with atazanavir/ritonavir, lopinavir/ritonavir or darunavir/ritonavir
- Current or prior use of any integrase inhibitor
- Previous use of histone deacetylase inhibitors or other latency reversing agents
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 |
|---|---|---|
| dolutegravirAlso: Tivicay®Each film-coated tablet contains dolutegravir sodium equivalent to 50 mg dolutegravir. | Drug | Intensification |
| PlaceboA film-coated tablet identical in appearance to the active drug tablet but not containing any dolutegravir or any other active ingredient | Other | Placebo |
Primary outcome
Level of residual HIV replication in circulating CD4+ T cells
Time frame: day 7 of treatment
Change in the level of 2-LTR circles as measured by polymerase chain reaction (PCR) in the dolutegravir arm versus the placebo arm after 7 days of treatment
4 secondary outcomes
Level of Human Leukocyte Antigen D-related (HLA-DR)
Time frame: time points to day 84 (28 days after treatment)
Level of Programmed cell death-1 receptor (PD-1)
Time frame: time points to day 84 (28 days after treatment)
Level of Cluster of Differentiation 38 (CD-38)
Time frame: time points to day 84 (28 days after treatment)
Level of residual HIV replication in circulating CD4+ T cells in a protease inhibitor -containing regimen
Time frame: time points up to day 84 (28 days after treatment)
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 20 Nov 2017.
- Derived from this study: PubMed 29643011Rasmussen TA, McMahon JH, Chang JJ, Audsley J, Rhodes A, Tennakoon S, Dantanarayana A, Spelman T, Schmidt T, Kent SJ, Morcilla V, Palmer S, Elliott JH, Lewin SR. The effect of antiretroviral intensification with dolutegravir on residual virus replication in HIV-infected individuals: a randomised, placebo-controlled, double-blind trial. Lancet HIV. 2018 May;5(5):e221-e230. doi: 10.1016/S2352-3018(18)30040-7. Epub 2018 Apr 8.
- Individual participant dataSharing planned: No. No plan to share individual participant data
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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.
Sharon Lewin principal investigator
Doherty Institute for Immunity and Infection
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing dolutegravir in people with HIV, run by University of Melbourne at 2 sites in Australia.
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 22 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 20 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Australia. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
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?
Level of residual HIV replication in circulating CD4+ T cells (time frame: day 7 of treatment). 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 NCT02500446, 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 20 Nov 2017.