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Research In Viral Eradication of HIV Reservoirs (RIVER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02336074
Recruitment Status : Active, not recruiting
First Posted : January 12, 2015
Results First Posted : September 25, 2019
Last Update Posted : March 17, 2020
Sponsor:
Collaborators:
Medical Research Council
University of Oxford
University of Cambridge
Chelsea and Westminster NHS Foundation Trust
Royal Free Hospital NHS Foundation Trust
Brighton and Sussex University Hospitals NHS Trust
Guy's and St Thomas' NHS Foundation Trust
Central and North West London NHS Foundation Trust
Information provided by (Responsible Party):
Imperial College London

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV
Interventions Drug: Combination Antiretroviral Therapy (cART)
Drug: Raltegravir
Drug: Vorinostat
Biological: ChAdV63.HIVconsv (ChAd)
Biological: MVA.HIVconsv (MVA)
Enrollment 60
Recruitment Details Participants were recruited from 6 UK clinical sites. The recruitment period was from November 2015 until July 2017. Last patient last visit was completed in November 2017.
Pre-assignment Details

Participants were recruited from two Strata:

  1. Recently diagnosed with primary HIV-1 infection - Eligible participants were enrolled at week 0 when combination ART (cART) began. Randomisation occurred at week 22
  2. Previously diagnosed with primary HIV-1 infection - Randomisation occurred within 2 weeks of screening.
Arm/Group Title Control Intervention
Hide Arm/Group Description Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study Participants received combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed for the duration of the study Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Period Title: Overall Study
Started 30 30
Completed 30 28
Not Completed 0 2
Reason Not Completed
Adverse Event             0             2
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat) Total
Hide Arm/Group Description Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total). Total of all reporting groups
Overall Number of Baseline Participants 30 30 60
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
30
 100.0%
30
 100.0%
60
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 30 participants 30 participants 60 participants
31
(30 to 38)
35
(28 to 44)
32
(29 to 40)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
Female
0
   0.0%
0
   0.0%
0
   0.0%
Male
30
 100.0%
30
 100.0%
60
 100.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
White
16
  53.3%
26
  86.7%
42
  70.0%
South Asian
0
   0.0%
1
   3.3%
1
   1.7%
South East Asian
1
   3.3%
0
   0.0%
1
   1.7%
Hispanic/Latino
3
  10.0%
2
   6.7%
5
   8.3%
Black Caribbean/American
2
   6.7%
0
   0.0%
2
   3.3%
Black African
2
   6.7%
0
   0.0%
2
   3.3%
Mixed ethnic group
5
  16.7%
1
   3.3%
6
  10.0%
Other
1
   3.3%
0
   0.0%
1
   1.7%
Mode of HIV Infection   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
MSM
26
  86.7%
29
  96.7%
55
  91.7%
MSW
1
   3.3%
1
   3.3%
2
   3.3%
MSM + IDU
2
   6.7%
0
   0.0%
2
   3.3%
Unknown
1
   3.3%
0
   0.0%
1
   1.7%
[1]
Measure Description: MSM = men who have sex with men MSW = men who have sex with women IDU = Injection Drug Use
CD4 at randomisation  
Median (Inter-Quartile Range)
Unit of measure:  Cells/mm3
Number Analyzed 30 participants 30 participants 60 participants
694
(561 to 844)
710
(579 to 759)
708
(568 to 788)
HIV RNA at randomisation (copies/ml)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
<50
29
  96.7%
30
 100.0%
59
  98.3%
50 - <200
1
   3.3%
0
   0.0%
1
   1.7%
Weeks since PHI diagnosis   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants 30 participants 60 participants
<= 1 week
1
   3.3%
0
   0.0%
1
   1.7%
>1 - 2 weeks
3
  10.0%
3
  10.0%
6
  10.0%
>2 - 3 weeks
7
  23.3%
7
  23.3%
14
  23.3%
>3 - 4 weeks
15
  50.0%
16
  53.3%
31
  51.7%
> 4 weeks
4
  13.3%
4
  13.3%
8
  13.3%
[1]
Measure Description: PHI = Primary HIV Infection
Weeks since PHI diagnosis (at randomisation)  
Median (Inter-Quartile Range)
Unit of measure:  Weeks
Number Analyzed 30 participants 30 participants 60 participants
28
(27 to 41)
28
(27 to 34)
28
(27 to 36)
1.Primary Outcome
Title Total HIV DNA From CD4 T-cells
Hide Description The average of two measures taken at post-randomisation week 16 and 18
Time Frame Averaged across post-randomisation week 16 and 18
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:
Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total)
Combination Antiretroviral Therapy (cART) preferably including raltegravir prescribed at week 0 for the duration of the study up to post-randomisation week 18 (42 weeks in total) Plus ChAdV63.HIVconsv prime (post-randomisation week 00) and MVA.HIVconsv boost (post randomisation week 08 day 1) vaccines; followed by a 28-day course of vorinostat (10 doses in total).
Overall Number of Participants Analyzed 30 30
Mean (Standard Deviation)
Unit of Measure: HIV-DNA copies/mill CD4+ T cells (log10)
2.95  (0.50) 3.06  (0.49)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.26
Comments Treatment arms were compared in terms of absolute total HIV DNA levels (on a log10-scale) at post-randomization weeks 16 and 18 adjusted for the baseline (i.e. randomization) level and by stratum.
Method Regression, Linear
Comments [Not Specified]
2.Secondary Outcome
Title Clinical Adverse Events
Hide Description Clinical adverse events of any grade post-randomization.
Time Frame From randomization to the final visit at week 18.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 30 30
Measure Type: Count of Participants
Unit of Measure: Participants
Not had any event
8
  26.7%
1
   3.3%
Did have any event
22
  73.3%
29
  96.7%
3.Secondary Outcome
Title Quantitative Viral Outgrowth
Hide Description Number of Participants with undetectable quantitative viral outgrowth
Time Frame At week 16
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized with valid assay results at week 16.
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

ART only

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 29 27
Measure Type: Number
Unit of Measure: Participants with undetectable outgrowth
12 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Control (Arm A - ART Only), Intervention (Arm B - ART + Vaccines + Vorinostat)
Comments

Comparison of the proportion of patients with undetectable viral outgrowth using logistic regression.

The analysis was adjusted for stratum and baseline viral outgrowth. Missing baseline values were imputed.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.145
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.41
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of CD4+ CD154+ IFNγ+ T Cells
Hide Description Percentage of CD4+ CD154+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized with valid assay results
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

ART only

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 27 30
Median (Inter-Quartile Range)
Unit of Measure: % cells CD4+ CD154+ IFNγ+
Post randomisation week 9
0.006
(0.000 to 0.015)
0.097
(0.043 to 0.161)
Post randomisation week 12
0.006
(0.000 to 0.015)
0.109
(0.050 to 0.214)
5.Secondary Outcome
Title CD8+ T-cell Responses
Hide Description Percentage of CD8+ CD107a+ IFNγ+ T cells , assessed using an optimized and qualified flow cytometry panel.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

ART only

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 27 30
Median (Inter-Quartile Range)
Unit of Measure: % cells CD8+ CD107a+ IFNγ+
Post randomisation week 9
0.052
(0.014 to 0.142)
0.194
(0.142 to 0.722)
Post randomisation week 12
0.062
(0.008 to 0.106)
0.263
(0.105 to 0.620)
6.Secondary Outcome
Title Viral Inhibition
Hide Description

CD8+ T cell antiviral suppressive activity was expressed as percentage elimination and determined as follows: [(fraction of p24+ cells in CD4+ T cells cultured alone) - (fraction of p24 + in CD4+ T cells cultured with CD8+ cells)]/(fraction of p24+ cells in CD4+ T cells cultured alone) × 100.

Viral inhibition Assay

Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
All participants randomized with valid assay results
Arm/Group Title Control (Arm A - ART Only) Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

ART only

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 27 30
Mean (95% Confidence Interval)
Unit of Measure: Percentage elimination
-18.25
(-29.65 to -6.85)
1.50
(-11.28 to 14.27)
7.Post-Hoc Outcome
Title Histone H4 Acetylation
Hide Description Histone H4 acetylation using a H4K5/8/12/16 immunoassay with thawed PBMC derived cell lysates added to an ELISA using anti-H4 monoclonal antibody
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Intervention arm only - histone H4 acetylation was only measured in participants in the intervention arm with the aim to compare values approximately 2 hours post vorinostat intake with values pre vorinostat intake. No data were collected from participants in the control arm.
Arm/Group Title Intervention (Arm B - ART + Vaccines + Vorinostat)
Hide Arm/Group Description:

ART plus vaccines plus vorinostat

Combination Antiretroviral Therapy (cART): Likely consisting of an Nucleoside reverse-transcriptase inhibitor (NRTI) backbone i.e. Truvada plus a ritonavir-boosted protease inhibitor (PI) e.g. Darunavir + ritonavir. Prescribed at week 0 for the duration of the study.

Raltegravir: All participants will be dispensed sufficient supplies of Raltegravir to ensure they have sufficient medication to last to the next study visit. Raltegravir is supplied in marketed pack with 30 tablets per bottle.

Vorinostat: Vorinostat (suberoylanilide hydroxamic acid abbreviated to SAHA) inhibits the histone deacetylases HDAC1, HDAC2, HDA

Overall Number of Participants Analyzed 22
Mean (95% Confidence Interval)
Unit of Measure: Fold increase pre to post vorinostat
3.19
(2.42 to 4.22)
Time Frame 18 weeks
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Control Intervention
Hide Arm/Group Description

ART only

Combination ART (cART) preferably including raltegravir (control)

ART plus vaccines plus vorinostat

Combination ART (cART) preferably including raltegravir* plus ChAdV63.HIVconsv (ChAd) prime and MVA.HIVconsv (MVA) boost vaccines; followed by a 28-day course of vorinostat (10 doses in total).

All-Cause Mortality
Control Intervention
Affected / at Risk (%) Affected / at Risk (%)
Total   0/30 (0.00%)      0/30 (0.00%)    
Hide Serious Adverse Events
Control Intervention
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/30 (0.00%)      1/30 (3.33%)    
Vascular disorders     
Vasovagal syncope * [1]  0/30 (0.00%)  0 1/30 (3.33%)  1
*
Indicates events were collected by non-systematic assessment
[1]
Vasovagal syncope likely secondary to venesection
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Control Intervention
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/30 (20.00%)      1/30 (3.33%)    
Hepatobiliary disorders     
Acute hepatitis A * [1]  1/30 (3.33%)  1 0/30 (0.00%)  0
Infections and infestations     
Influenza * [2]  1/30 (3.33%)  1 0/30 (0.00%)  0
Shingles * [3]  1/30 (3.33%)  1 0/30 (0.00%)  0
Injury, poisoning and procedural complications     
Wrist injury * [4]  1/30 (3.33%)  1 0/30 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain * [5]  1/30 (3.33%)  1 1/30 (3.33%)  1
Skin and subcutaneous tissue disorders     
Proctitis herpes * [6]  1/30 (3.33%)  1 0/30 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
[1]
Grade 3 hepatitis
[2]
Grade 3 influenza
[3]
Grade 3 shingles
[4]
Grade 3 wrist injury
[5]
Grade 3 back pain
[6]
Grade 3 proctitis herpes
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The NHS Organisations shall not publish or otherwise disseminate conclusions of the Study, including all or any part of the Results of the Study without prior written consent of the Sponsor, such consent not to be unreasonably withheld or delayed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Professor Sarah Fidler
Organization: Imperial College London
Phone: 004420331 ext 26790
EMail: s.fidler@imperial.ac.uk
Publications of Results:
Other Publications:
Layout table for additonal information
Responsible Party: Imperial College London
ClinicalTrials.gov Identifier: NCT02336074    
Other Study ID Numbers: CCT-NAPN-24772
2014-001425-32 ( EudraCT Number )
First Submitted: October 23, 2014
First Posted: January 12, 2015
Results First Submitted: June 24, 2019
Results First Posted: September 25, 2019
Last Update Posted: March 17, 2020