HIVPhase 3NCT03029689

Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME STUDY

A Phase 3 study testing Raltegravir and Current ART in people with HIV, run by Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la Ciencia at 1 site in Spain.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

The project presented here will be the first prospective, randomized evaluation of the effect of ART on the structure and function of the gut microbiome. This study provides a unique opportunity to understand the benefits of ART with high intestinal penetration on the gut microbiome. Read more about this study

Who is it for?: Ages 18 to 99 years
Conditions the study is for: HIV
What is being tested?: Raltegravir and Current ART
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 61 participants
Where: 1 siteSpain
Study dates: 28 Jul 2017to 30 Apr 2020
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

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 99 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Age ≥18 years old
Documented HIV infection
Stable 3-drug antiretroviral treatment including PI/r/c or NNRTI for at least 6 months.
Plasma HIV-1 RNA load <50 copies/mL for at least 12 months.
Signed Informed Consent

Who cannot join

PI/r monotherapy
INSTI therapy during the previous 6 months
Evidence of previous INSTI resistance
Creatine clearance <50 mL/min
Child- Pugh B or C
History of active uncontrolled GI disorders or diseases including:

Show all 17Show fewer

6.1. Major surgery of the GI tract, with the exception of cholecystectomy and appendectomy, in the previous 5 years.
6.2. Any major bowel resection at any time.
6.3. Any chronic digestive disease such as peptic ulcer, Crohn's disease, ulcerative colitis, coeliac disease, confirmed intolerance to lactose or indeterminate colitis.
6.4. Persistent infectious gastroenteritis, colitis or gastritis; persistent or chronic diarrhea of unknown etiology; Clostridium difficile infection (recurrent) or Helicobacter pylori infection (untreated)
6.5. Irritable bowel syndrome (moderate-severe)
6.6. Chronic constipation
6.7. Active proctitis
Antibiotic therapy within the previous 2 months
In women, pregnancy or breastfeeding*.
Female subjects of childbearing potential must not be pregnant, not be planning a pregnancy or breast-feeding. Sexually active women must be willing to use two approved methods of contraception (including condoms, diaphragm, spermicides, hormonal methods and/or intrauterine devices) from baseline until the end of the clinical trial. Sexually active men in heterosexual relationships must be willing to use two approved method of contraception with their partners from baseline until the end of the clinical trial.
condom use is considered as an additional method of contraception only and cannot be the only method of contraception used as not been considered an effective method by the Clinical Trial Facilitation Group (CTFG) guidelines.

Trial locations and contacts

1 site in 1 country.

Spain1 site

Germans Trias i Pujol Hospital
Badalona, Barcelona, 08916

Other trials in Spain

About this study

Official title: Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME

Read the detailed description

The gut microbiome is essential for the maturation of the neonatal immune system and the adequate development and function of adult immune responses. HIV-1 infection in children and adults exerts a rapid and severe depletion of gut-associated lymphoid tissue, which damages the intestinal barrier, allowing translocation of gut commensal bacteria into the systemic circulation. Bacterial translocation causes chronic inflammation and immune activation, which lead to immune deterioration and premature aging of HIV-1-infected subjects, including metabolic disturbances, cardiovascular diseases, cognitive disorders and HIV-associated cancers. Persistence of residual HIV-1 replication in the presence of ART has been associated to incomplete HIV-1 suppression in gut lymphatic tissues due to suboptimal tissular penetration of PI/s or NNRTIs.

In previous work in our institute, the investigators have observed that HIV-1 infection is independently associated with significant reductions in the gut microbiome richness, which is, in turn, are inversely correlated with systemic inflammation. Reduced microbial richness, for example, has been associated with intestinal inflammatory diseases and well as with metabolic syndrome, diabetes and obesity and correlated with metabolic markers.

Recovering bacterial richness might thus have a positive impact on immune activation, chronic inflammation and the overall health of HIV-infected individuals. However, achieving that goal will possibly require, alongside potential bacterial supplementations, the use of ART with high penetration into gut lymphoid tissue to limit as much as possible the continued damage exerted by residual HIV replication on the GALT. Antiretroviral drugs with higher intestinal penetration like raltegravir may be more effective at recovering the intestinal microbiome composition and function than those with lower gut penetration like darunavir or the NNRTIs. Thereby, raltegravir intensification could be associated with increases in intestinal microbial richness, implying an improvement on intestinal and overall health.

Despite the lack of evidence on that regard, previous studies from our group and others would favor that hypothesis. Residual HIV-1 replication in plasma can be deterred by ART intensification with raltegravir, which is, in part, due to the high penetration of raltegravir in intestinal tissues. Moreover, raltegravir intensification decreases peripheral CD8 T-cell activation CD45RA (-) and creates a transient CD4 T-cell redistribution, which revert after raltegravir withdrawal.

Conditions: HIV
Being tested: Raltegravir, Placebo, Current ART
Keywords: HIV infection, Gut microbiome, Raltegravir, Raltegravir intensification, Bacterial richness
Medical subject headings: HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RaltegravirDrug
Also called NP
Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
PlaceboDrug
Also called NP
Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ARTDrug
Also called NP
3-drug antiretroviral treatment including PI/r/c or NNRTI

Study groups in NCT03029689
Study group	Role	What they receive
Current ART + Raltegravir	Experimental	Current ART + Raltegravir Receives: Drug: Raltegravir; Drug: Current ART
Current ART + placebo	Placebo comparator	Current ART + placebo Receives: Drug: Placebo; Drug: Current ART

What is being measured

The primary outcome is the main question the study is designed to answer.

Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
-* Structure and composition of the microbiome. DNA will be extracted and purified from fecal samples and cryopreserved at -80ºC until amplification. The purified DNA will be amplified using Illumina-tagged primers to amplify the V3 and V4 16S ribosomal DNA (rDNA) regions. PCR reactions will be performed in triplicate to preserve diversity. Pooled triplicates will be sequenced ensuring adequate sampling depth.
-Function of the bacteriome. The gene content will be inferred from the abundance of each bacteria in the intestinal bacteriome according to the 16S rDNA information
Measured: From baseline to 48 weeks

Secondary outcomes (8)

Association of the Gut Microbiome With Inflammation Markers
IL-6, IP-10
Measured: From baseline to week 48
Association of the Gut Microbiome With Coagulation
D-Dimer
Measured: From baseline to 48 weeks
Association of the Gut Microbiome With Enterocyte Damage
Intestinal Fatty Acid Binding Protein (I-FABP)
Measured: From baseline to 48 weeks
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
LPS-binding protein (LBP), soluble CD14
Measured: From baseline to 48 weeks
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57
Measured: Differences at week 48
Association of the Gut Microbiome Composition and Richness With CD4 and CD8+ Counts.
CD4 and CD8+ counts
Measured: Baseline
Other Estimators of Richness and Diversity
Shannon
Measured: From baseline to 48 weeks
Association of the Gut Microbiome Composition and Richness With CD4/CD8+ Cell Ratio.
CD4/CD8+ cell ratio
Measured: Baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Jul 201730 Apr 2020

First posted24 Jan 2017 (estimated)
Study start28 Jul 2017
Primary completion30 Apr 2020
Study completion30 Apr 2020

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
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 3
Primary purpose: Basic science
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 61 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT03029689
Sponsor's protocol ID: RAGTIME
Status last verified: Jun 2025
First submitted: 11 Jan 2017
Last updated: 17 Jun 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 17 Jun 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Raltegravir Intensification (1.200 mg QD) on the Gut Microbiota of Chronically HIV-1 Infected Subject Over Time: THE RAGTIME
ClinicalTrials.gov ID: NCT03029689
Acronym / sponsor ID: RAGTIME
Conditions: HIV
Keywords: HIV infection, Gut microbiome, Raltegravir, Raltegravir intensification, Bacterial richness
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 61 participants (actual)
Lead sponsor: Fundación FLS de Lucha Contra el Sida, las Enfermedades Infecciosas y la Promoción de la Salud y la CienciaUniversity, hospital or other
Collaborators: Merck Sharp & Dohme LLC
Study start: 28 Jul 2017 (actual)
Primary completion: 30 Apr 2020 (actual)
Study completion: 30 Apr 2020 (actual)
First posted: 24 Jan 2017 (estimated)
Results: Posted 13 Apr 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Parallel groups
Masking: Double blind (participant, investigator)
Number of arms: 2

Arm	Type	Receives
Current ART + Raltegravir	Experimental	Drug: Raltegravir, Drug: Current ARTCurrent ART + Raltegravir
Current ART + placebo	Placebo comparator	Drug: Placebo, Drug: Current ARTCurrent ART + placebo

Who may qualify

Ages: 18 to 99 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (5 listed)

Age ≥18 years old
Documented HIV infection
Stable 3-drug antiretroviral treatment including PI/r/c or NNRTI for at least 6 months.
Plasma HIV-1 RNA load <50 copies/mL for at least 12 months.
Signed Informed Consent

Key exclusion criteria (17 listed)

PI/r monotherapy
INSTI therapy during the previous 6 months
Evidence of previous INSTI resistance
Creatine clearance <50 mL/min
Child- Pugh B or C

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
RaltegravirAlso: NPRaltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization	Drug	Current ART + Raltegravir
PlaceboAlso: NPPlacebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.	Drug	Current ART + placebo
Current ARTAlso: NP3-drug antiretroviral treatment including PI/r/c or NNRTI	Drug	Current ART + Raltegravir, Current ART + placebo

Primary outcome

Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
Time frame: From baseline to 48 weeks
-* Structure and composition of the microbiome. DNA will be extracted and purified from fecal samples and cryopreserved at -80ºC until amplification. The purified DNA will be amplified using Illumina-tagged primers to amplify the V3 and V4 16S ribosomal DNA (rDNA) regions. PCR reactions will be performed in triplicate to preserve diversity. Pooled triplicates will be sequenced ensuring adequate sampling depth. -Function of the bacteriome. The gene content will be inferred from the abundance of each bacteria in the intestinal bacteriome according to the 16S rDNA information

8 secondary outcomes

Association of the Gut Microbiome With Inflammation Markers
Time frame: From baseline to week 48
Association of the Gut Microbiome With Coagulation
Time frame: From baseline to 48 weeks
Association of the Gut Microbiome With Enterocyte Damage
Time frame: From baseline to 48 weeks
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
Time frame: From baseline to 48 weeks
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
Time frame: Differences at week 48
Association of the Gut Microbiome Composition and Richness With CD4 and CD8+ Counts.
Time frame: Baseline
Other Estimators of Richness and Diversity
Time frame: From baseline to 48 weeks
Association of the Gut Microbiome Composition and Richness With CD4/CD8+ Cell Ratio.
Time frame: Baseline

Results and safety

Results posted to the registry on 13 Apr 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Current ART + Raltegravir	40	37
Current ART + Placebo	21	17

Primary outcome: Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *

Time frame: From baseline to 48 weeks. Median (Inter-Quartile Range). Unit: Number of unique genes detected

Measure	Current ART + Raltegravir n = 37	Current ART + Placebo n = 17
Gene richness at baseline	768358 (663708 to 879113)	730732 (552699 to 869340)
Gene richness at timepoint 12	767756 (600703 to 834276)	808911 (721094 to 832215)
Gene richness at timepoint 24	724452 (605639 to 825037)	777452 (695461 to 872279)
Gene richness at timepoint 48	718824 (624788 to 848524)	860913 (745053 to 882858)

8 secondary outcomes are reported in the full results.

Adverse events

Time frame: From baseline to week 48. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Current ART + Raltegravir	0 of 37 (0%)	1 of 38 (2.6%)	0 of 37
Current ART + Placebo	0 of 17 (0%)	1 of 18 (5.6%)	0 of 17

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: No

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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.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

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 5 inclusion and 17 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 17 Jun 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Spain. 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 13 Apr 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. * (time frame: From baseline to 48 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 NCT03029689.

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 17 Jun 2025.