Trial Outcomes & Findings for 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 (NCT NCT03029689)
NCT ID: NCT03029689
Last Updated: 2025-06-17
Results Overview
-\* 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
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
61 participants
Primary outcome timeframe
From baseline to 48 weeks
Results posted on
2025-06-17
Participant Flow
Participant milestones
| Measure |
Current ART + Raltegravir
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Overall Study
STARTED
|
40
|
21
|
|
Overall Study
COMPLETED
|
37
|
17
|
|
Overall Study
NOT COMPLETED
|
3
|
4
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
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
Baseline characteristics by cohort
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Total
n=54 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
36 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
52 Participants
n=5 Participants
|
|
Age, Categorical
>=65 years
|
1 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
2 Participants
n=5 Participants
|
|
Age, Continuous
|
52 years
n=5 Participants
|
52 years
n=7 Participants
|
52 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
5 Participants
n=5 Participants
|
1 Participants
n=7 Participants
|
6 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
32 Participants
n=5 Participants
|
16 Participants
n=7 Participants
|
48 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
2 Participants
n=5 Participants
|
2 Participants
n=7 Participants
|
4 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
21 Participants
n=5 Participants
|
6 Participants
n=7 Participants
|
27 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
14 Participants
n=5 Participants
|
9 Participants
n=7 Participants
|
23 Participants
n=5 Participants
|
|
Region of Enrollment
Spain
|
37 participants
n=5 Participants
|
17 participants
n=7 Participants
|
54 participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 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
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
Gene richness at baseline
|
768358 Number of unique genes detected
Interval 663708.0 to 879113.0
|
730732 Number of unique genes detected
Interval 552699.0 to 869340.0
|
|
Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
Gene richness at timepoint 12
|
767756 Number of unique genes detected
Interval 600703.0 to 834276.0
|
808911 Number of unique genes detected
Interval 721094.0 to 832215.0
|
|
Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
Gene richness at timepoint 24
|
724452 Number of unique genes detected
Interval 605639.0 to 825037.0
|
777452 Number of unique genes detected
Interval 695461.0 to 872279.0
|
|
Bacterial Gene Richness (Observed Unique Genes). Analysis of the Composition, Structure and Function of the Intestinal Microbiome. *
Gene richness at timepoint 48
|
718824 Number of unique genes detected
Interval 624788.0 to 848524.0
|
860913 Number of unique genes detected
Interval 745053.0 to 882858.0
|
SECONDARY outcome
Timeframe: From baseline to week 48IL-6, IP-10
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome With Inflammation Markers
IL-6 at baseline
|
1.32 pg/ml
Interval 1.14 to 1.78
|
1.53 pg/ml
Interval 1.41 to 1.78
|
|
Association of the Gut Microbiome With Inflammation Markers
IL-6 at week 12
|
1.52 pg/ml
Interval 1.09 to 1.81
|
1.48 pg/ml
Interval 1.23 to 1.67
|
|
Association of the Gut Microbiome With Inflammation Markers
IL-6 at week 24
|
1.25 pg/ml
Interval 1.06 to 1.65
|
1.38 pg/ml
Interval 1.14 to 1.58
|
|
Association of the Gut Microbiome With Inflammation Markers
IL-6 at week 48
|
1.28 pg/ml
Interval 1.13 to 1.58
|
1.3 pg/ml
Interval 1.1 to 1.51
|
|
Association of the Gut Microbiome With Inflammation Markers
IP-10 at baseline
|
102.99 pg/ml
Interval 84.95 to 126.16
|
97.44 pg/ml
Interval 80.65 to 123.53
|
|
Association of the Gut Microbiome With Inflammation Markers
IP-10 at week 12
|
104.7 pg/ml
Interval 84.7 to 125.17
|
108.6 pg/ml
Interval 79.13 to 127.13
|
|
Association of the Gut Microbiome With Inflammation Markers
IP-10 at week 24
|
104.6 pg/ml
Interval 81.04 to 122.69
|
99.58 pg/ml
Interval 81.34 to 128.9
|
|
Association of the Gut Microbiome With Inflammation Markers
IP-10 at week 48
|
106.43 pg/ml
Interval 86.79 to 137.85
|
108.55 pg/ml
Interval 85.09 to 118.36
|
SECONDARY outcome
Timeframe: From baseline to 48 weeksD-Dimer
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome With Coagulation
D-Dimer at baseline
|
1.99 ug/ml
Interval 1.77 to 2.41
|
2.1 ug/ml
Interval 1.91 to 2.89
|
|
Association of the Gut Microbiome With Coagulation
D-Dimer at week 12
|
2.155 ug/ml
Interval 1.85 to 2.77
|
2.19 ug/ml
Interval 2.03 to 2.45
|
|
Association of the Gut Microbiome With Coagulation
D-Dimer at week 24
|
2.14 ug/ml
Interval 1.69 to 2.47
|
2.22 ug/ml
Interval 1.79 to 2.5
|
|
Association of the Gut Microbiome With Coagulation
D-Dimer at week 48
|
2.22 ug/ml
Interval 1.89 to 2.73
|
2.18 ug/ml
Interval 1.81 to 2.66
|
SECONDARY outcome
Timeframe: From baseline to 48 weeksIntestinal Fatty Acid Binding Protein (I-FABP)
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome With Enterocyte Damage
IFABP at baseline
|
0.92 ng/ml
Interval 0.68 to 1.33
|
0.69 ng/ml
Interval 0.6 to 0.89
|
|
Association of the Gut Microbiome With Enterocyte Damage
IFABP at week 12
|
0.94 ng/ml
Interval 0.57 to 1.43
|
0.82 ng/ml
Interval 0.65 to 1.19
|
|
Association of the Gut Microbiome With Enterocyte Damage
IFABP at week 24
|
1.04 ng/ml
Interval 0.72 to 1.39
|
0.76 ng/ml
Interval 0.65 to 0.98
|
|
Association of the Gut Microbiome With Enterocyte Damage
IFABP at week 48
|
0.81 ng/ml
Interval 0.64 to 1.26
|
1.06 ng/ml
Interval 0.75 to 1.13
|
SECONDARY outcome
Timeframe: From baseline to 48 weeksLPS-binding protein (LBP), soluble CD14
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
LBP at baseline
|
4238 ng/ml
Interval 3395.0 to 4537.0
|
4274 ng/ml
Interval 3664.0 to 5056.0
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
LBP at week 12
|
4478 ng/ml
Interval 3387.0 to 4991.0
|
4313 ng/ml
Interval 3047.0 to 4792.0
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
LBP at week 24
|
3879 ng/ml
Interval 3443.0 to 4839.0
|
4221 ng/ml
Interval 3467.0 to 4414.0
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
LBP at week 48
|
4172 ng/ml
Interval 3649.0 to 4637.0
|
4203 ng/ml
Interval 3316.0 to 4946.0
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
sCD14 at baseline
|
2.41 ng/ml
Interval 2.18 to 2.69
|
2.63 ng/ml
Interval 2.38 to 2.75
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
sCD14 at week 12
|
2.5 ng/ml
Interval 2.26 to 2.6
|
2.61 ng/ml
Interval 2.33 to 2.85
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
sCD14 at week 24
|
2.36 ng/ml
Interval 2.2 to 2.79
|
2.62 ng/ml
Interval 2.35 to 2.73
|
|
Association of the Gut Microbiome With Bacterial Translocation and Monocyte Activation
sCD14 at week 48
|
2.48 ng/ml
Interval 2.36 to 2.85
|
2.5 ng/ml
Interval 2.4 to 2.99
|
SECONDARY outcome
Timeframe: Differences at week 48CCR7, CD28, CD27, HLA-DR, CD38, PD-1, CD57
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
CD28
|
8051 MFI
Interval 1471.0 to 12096.0
|
8076 MFI
Interval 1624.0 to 12144.0
|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
CD27
|
26002 MFI
Interval 676.0 to 46096.0
|
27604 MFI
Interval 1306.0 to 47312.0
|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
HLA-DR
|
954 MFI
Interval 540.0 to 1955.0
|
990 MFI
Interval 566.0 to 2244.0
|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
CD38
|
165 MFI
Interval -23.1 to 552.0
|
130 MFI
Interval -55.6 to 443.0
|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
PD-1
|
1074 MFI
Interval 550.0 to 2086.0
|
1246 MFI
Interval 659.0 to 2432.0
|
|
Mean Fluorescence Intensity (MFI) Measure of Maturation, Activation, Exhaustion and Immune Senescence Markers in CD4+ and CD8+ T-cells
CD57
|
239 MFI
Interval 83.4 to 525.0
|
226 MFI
Interval 75.6 to 524.0
|
SECONDARY outcome
Timeframe: BaselineCD4 and CD8+ counts
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome Composition and Richness With CD4 and CD8+ Counts.
CD8+
|
787 cells/mm^3 of blood
Interval 586.0 to 968.0
|
668 cells/mm^3 of blood
Interval 470.0 to 807.0
|
|
Association of the Gut Microbiome Composition and Richness With CD4 and CD8+ Counts.
CD4+
|
696 cells/mm^3 of blood
Interval 554.0 to 918.0
|
664 cells/mm^3 of blood
Interval 430.0 to 658.0
|
SECONDARY outcome
Timeframe: From baseline to 48 weeksPopulation: The Shannon Diversity Index (SDI), also known as Shannon-Weaver or Shannon-Wiener Index, is a commonly used metric in ecology and microbiome research to quantify microbial diversity within a sample (alpha diversity). It takes into account both richness (the number of different species and evenness (the relative abundance distribution of species). Higher SDI values reflect greater microbial diversity, while lower SDI values may indicate dysbiosis or a disrupted microbial community.
Shannon
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Other Estimators of Richness and Diversity
Shannon at baseline
|
2.90 Shannon index
Interval 2.45 to 3.16
|
2.56 Shannon index
Interval 1.86 to 3.08
|
|
Other Estimators of Richness and Diversity
Shannon at week 12
|
2.91 Shannon index
Interval 2.31 to 3.07
|
2.89 Shannon index
Interval 2.64 to 3.07
|
|
Other Estimators of Richness and Diversity
Shannon at week 24
|
2.65 Shannon index
Interval 2.23 to 3.0
|
2.56 Shannon index
Interval 2.12 to 2.92
|
|
Other Estimators of Richness and Diversity
Shannon at week 48
|
2.63 Shannon index
Interval 2.13 to 3.1
|
2.97 Shannon index
Interval 2.69 to 3.32
|
SECONDARY outcome
Timeframe: BaselinePopulation: CD4+/CD8+ ratio
CD4/CD8+ cell ratio
Outcome measures
| Measure |
Current ART + Raltegravir
n=37 Participants
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=17 Participants
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Association of the Gut Microbiome Composition and Richness With CD4/CD8+ Cell Ratio.
|
1.10 Ratio
Interval 0.74 to 1.26
|
0.91 Ratio
Interval 0.82 to 1.62
|
Adverse Events
Current ART + Raltegravir
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Current ART + Placebo
Serious events: 0 serious events
Other events: 1 other events
Deaths: 0 deaths
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Current ART + Raltegravir
n=38 participants at risk；n=37 participants at risk
Current ART + Raltegravir
Raltegravir: Raltegravir 1200 mg (2 tablets x 600mg) once daily plus current ART during 48 weeks from randomization
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
Current ART + Placebo
n=18 participants at risk；n=17 participants at risk
Current ART + placebo
Placebo: Placebo (2 tablets of placebo) once daily plus current ART during 48 weeks from randomization.
Current ART: 3-drug antiretroviral treatment including PI/r/c or NNRTI
|
|---|---|---|
|
Investigations
Adverse event not related to the treatment
|
2.6%
1/38 • Number of events 1 • From baseline to week 48
|
5.6%
1/18 • Number of events 1 • From baseline to week 48
|
Additional Information
Dr. Roger Paredes
Fundació Lluita Contra les Infeccions
Phone: (+34) 93 465 7897
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place