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Safety and Efficacy of Romidepsin and the Therapeutic Vaccine Vacc-4x for Reduction of the Latent HIV‐1 Reservoir (REDUC)

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ClinicalTrials.gov Identifier: NCT02092116
Recruitment Status : Completed
First Posted : March 19, 2014
Results First Posted : March 1, 2017
Last Update Posted : March 1, 2017
Sponsor:
Collaborator:
Celgene Corporation
Information provided by (Responsible Party):
Bionor Immuno AS

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HIV I Infection
Interventions Drug: Romidepsin
Biological: Vacc-4x
Biological: rhuGM-CSF
Enrollment 26
Recruitment Details

First subject screened 6 March 2014 and last subject last visit 25 June 2014 for Part A.

First subject screened 19 May 2014 and last subject last visit 29 May 2015 for Part B.

One clinical trial site at Aarhus University Hospital, Denmark

Pre-assignment Details 7 patients were screened and 6 patients were enrolled in Part A. 24 patients were screened and 20 patients were enrolled in Part B.
Arm/Group Title Part A Part B
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Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14.

Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

Period Title: Overall Study
Started 6 20
Completed 6 16
Not Completed 0 4
Reason Not Completed
Withdrawal by Subject             0             3
Adverse Event             0             1
Arm/Group Title Part A Part B Total
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Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14.

Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

Total of all reporting groups
Overall Number of Baseline Participants 6 20 26
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
>18 years Number Analyzed 6 participants 20 participants 26 participants
6 20 26
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 20 participants 26 participants
Female
1
  16.7%
3
  15.0%
4
  15.4%
Male
5
  83.3%
17
  85.0%
22
  84.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 20 participants 26 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
   5.0%
1
   3.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
1
   5.0%
1
   3.8%
White
6
 100.0%
17
  85.0%
23
  88.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
1
   5.0%
1
   3.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Denmark Number Analyzed 6 participants 20 participants 26 participants
6 20 26
Time since HIV diagnosis  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 6 participants 20 participants 26 participants
13.3
(7.0 to 22.6)
9.6
(2.6 to 28.7)
9.85
(2.6 to 28.7)
Time since HIV infection   [1] 
Median (Full Range)
Unit of measure:  Years
Number Analyzed 4 participants 19 participants 23 participants
13.5
(10.7 to 23.1)
10.2
(2.7 to 31.7)
12.2
(2.7 to 31.7)
[1]
Measure Analysis Population Description: Information was not available for 2 patients in Part A and for 1 patient in Part B.
Time since ART initiation  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 6 participants 20 participants 26 participants
10.05
(4.2 to 14.5)
6.3
(2.4 to 18.1)
6.9
(2.4 to 18.1)
Latest pre-ART viral load   [1] 
Median (Full Range)
Unit of measure:  copies/mL
Number Analyzed 6 participants 18 participants 24 participants
123300
(1977 to 2450000)
67024
(3674 to 10000000)
72597.5
(1977 to 10000000)
[1]
Measure Analysis Population Description: Pre-ART viral load was not availabel for 2 patrients in Part B.
Nadir CD4+ T-cell count  
Median (Full Range)
Unit of measure:  10^6 cells/L
Number Analyzed 6 participants 20 participants 26 participants
246.5
(40 to 340)
280
(60 to 710)
267.5
(40 to 710)
Mean CD4+ T-cell counts  
Median (Full Range)
Unit of measure:  10^6 cells/L
Number Analyzed 6 participants 20 participants 26 participants
807.5
(570 to 1015)
669.8
(465 to 1645)
712.3
(465 to 1645)
1.Primary Outcome
Title Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Hide Description Safety and tolerability evaluation as measured by adverse events (AE) and serious adverse events (SAE).
Time Frame 3 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part A
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Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14.

Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.

Overall Number of Participants Analyzed 6
Measure Type: Number
Unit of Measure: participants
Treatment emergent adverse events 6
Adverse reactions, grade 1 6
Adverse reactions, grade 2 1
Related to Romidepsin 6
Not related 3
2.Primary Outcome
Title Part B: Changes From Baseline in HIV-1 Reservoir (Total HIV-1DNA; Integrated HIV-1 DNA in Unfractionated CD4+ T Cells and Replication Competent Provirus.
Hide Description

Total HIV-1 DNA and integrated HIV-1 DNA were analysed by MMRM analysis (copies/10^6 CD4+ T cells). To estimate the frequency of infectious units per 10^6 resting memory CD4+ T cells a quantitative viral outgrowth assay (qVOA) was used.

Blood samples were obtained at Day 0, Day 105 and Day 161.

Time Frame Day 161/175
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Hide Analysis Population Description

4 patients were excluded; 3 discontinued and 1 sample was not eligible for analysis.

Sensitivity of the qVOA was low; 2/3 of all measurements were under the limit of detection. 6 subjects had quantifiable viral outgrowth on baseline, 8 had viral outgrowth after immunization (Day 105) and 6 had viral outgrowth after romidepsin (Day 161).

Arm/Group Title Part B
Hide Arm/Group Description:

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

Overall Number of Participants Analyzed 16
Mean (95% Confidence Interval)
Unit of Measure: Estimated % change from baseline
Total HIV-1 DNA, day 161 Number Analyzed 16 participants
-39.71
(-58.94 to -11.47)
Integrated HIV-1 DNA, day 175 Number Analyzed 16 participants
-19.21
(-38.61 to 6.31)
Replication competent provirus, day 161 Number Analyzed 6 participants
-38
(-67 to -8)
3.Secondary Outcome
Title Part A: Changes From Baseline in HIV-1 Reservoir (Total HIV-1DNA; Integrated HIV-1 DNA in Unfractionated CD4+ T Cells and Replication Competent Provirus. Estimates of Change From Baseline of the Size of the Latent HIV-1 Reservoir in CD4+ Cells.
Hide Description

Total HIV-1 DNA and integrated HIV-1 DNA were analysed by MMRM analysis (copies/10^6 CD4+ T cells). To estimate the frequency of infectious units per 10^6 resting memory CD4+ T cells a quantitative viral outgrowth assay (qVOA) was used.

Total HIV-1 DNA was measured at Day 84

Time Frame Day 56/84
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Hide Analysis Population Description
1 patient did not have a quantifiable load of total HIV-1 DNA at Day 84 and 2 patients diod not have a quantifiable load of replication competent provirus at day 56.
Arm/Group Title Part A
Hide Arm/Group Description:

Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14.

Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.

Overall Number of Participants Analyzed 6
Mean (Standard Deviation)
Unit of Measure: copies/10^6 CD4+ T cells
Total HIV-1 DNA, Basline Number Analyzed 6 participants
791.7  (790.6)
Total HIV-1 DNA, Day 84 Number Analyzed 5 participants
718.8  (530.2)
Integrated HIV-1 DNA, Baseline Number Analyzed 6 participants
2825.6  (1145.6)
Integrated HIV-1 DNA, Day 84 Number Analyzed 6 participants
4846.9  (3698.4)
Replication competent provirus, Baseline Number Analyzed 4 participants
0.39  (0.26)
Replication competent provirus, Day 56 Number Analyzed 4 participants
0.43  (0.31)
4.Secondary Outcome
Title Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Hide Description Safety and tolerability evaluation of romidepsin and Vacc-4x in combination with GM-CSF as measured by adverse events (AE) and serious adverse events (SAE).
Time Frame 287 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part B
Hide Arm/Group Description:

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

Overall Number of Participants Analyzed 20
Measure Type: Number
Unit of Measure: participants
Non-treatment emergent adverse events 1
Treatment emergent adverse events 20
Serious adverse event 1
Adverse reaction, grade 1 20
Adverse reaction, grade 2 5
Adverse reaction, grade 3 1
Related to Vacc-4x and GM-CSF 19
Related to Romidepsin 17
Not related 16
5.Secondary Outcome
Title Part B: Level of HIV-1 Transcription.
Hide Description At day 105, 112 and 119 patients receive romidepsin and 4 hours after each administration HIV transcription is measured as unspliced HIV-1 RNA.
Time Frame Day 105, 112 and 119
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All available samples were included in this analysis; 3 withdrew consent and 2 (3 for day 119) did not have analyzable samples.
Arm/Group Title Part B
Hide Arm/Group Description:

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of 3 romidepsin infusions (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

Overall Number of Participants Analyzed 15
Mean (Standard Deviation)
Unit of Measure: copies/10^6 CD4+ T cells
Day 105, before romidepsin Number Analyzed 15 participants
6.95  (5.29)
Day 105, 4 hours post romidepsin Number Analyzed 15 participants
12.77  (11.19)
Day 112, 4 hours post romidepsin Number Analyzed 15 participants
22.98  (16.58)
Day 119, 4 hours post romidepsin Number Analyzed 14 participants
25.91  (21.78)
Time Frame Adverse events were collected from first treatment (Day 0) to the last visit (day 11 for Part A and day 287 for part B). Any signs or symptoms occurring between Screening/Visit 1 and Visit 2 (day 0)was recorded as Medical History.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Part A Part B
Hide Arm/Group Description

Pre-treatment phase of 2-4 weeks (Visit 1- Visit 2a) followed by viral reactivation phase of 3 weeks (Visit 2 to Visit 7) consisting of one cycle of romidepsin infusions at a dosing of 5 mg/m2 on days 0, 7, and 14.

Post-activation phase of ~9 weeks (Visit 8 to Visit 11) to assess the effect of romidepsin on the size of latent HIV-1 reservoir.

Pre-treatment phase of 2-4 weeks (Visit 1-Visit 2) followed by a therapeutic HIV-1 immunization phase of 12 weeks (Visit 2 to Visit 7) in which 1.2 mg Vacc-4x was administered together with 0.06 mg rhuGM-CSF at Visits 2, 3, 4, 5, 6 and 7 follow by a follow-up period of 2 weeks (Visit 8).

A viral reactivation phase of 3 weeks (Visit 9-Visit 11) consisting of one cycle of romidepsin infusion (5 mg/m2) followed by a post-treatment observation phase of ~9 weeks (Visit 12-Visit 13) to assess the effect of the investigational treatment on the size of the latent HIV-1 reservoir.

A monitored antiretroviral pause of up to 16 weeks (Visit 14-Visit 33).

All-Cause Mortality
Part A Part B
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Part A Part B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/6 (0.00%)      1/20 (5.00%)    
Psychiatric disorders     
Alcohol withdrawal syndrome  1 [1]  0/6 (0.00%)  0 1/20 (5.00%)  3
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
[1]
One subject (01-225) presented three SAEs; all three were described as “alcohol withdrawal syndrome” and assessed as not related to Vacc-4x and GM-CSF and romidepsin
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Part A Part B
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/6 (100.00%)      20/20 (100.00%)    
Blood and lymphatic system disorders     
Lymphadenitis  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Cardiac disorders     
Palpitations  1  1/6 (16.67%)  2 0/20 (0.00%)  0
Ear and labyrinth disorders     
Tinnitus  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Gastrointestinal disorders     
Nausea  1  4/6 (66.67%)  11 15/20 (75.00%)  26
Abdominal Pain upper  1  1/6 (16.67%)  1 1/20 (5.00%)  1
Constipation  1  1/6 (16.67%)  1 4/20 (20.00%)  4
Diarrhoea  1  1/6 (16.67%)  1 1/20 (5.00%)  2
Gastrointestinal pain  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Gastrooesophageal reflux disease  1  1/6 (16.67%)  1 1/20 (5.00%)  1
Vomitting  1  0/6 (0.00%)  0 2/20 (10.00%)  3
General disorders     
Gastrointestinal sounds abnormal  1  3/6 (50.00%)  4 1/20 (5.00%)  1
Fatigue  1  3/6 (50.00%)  5 15/20 (75.00%)  28
Asthenia  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Chills  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Influenza like illness  1  1/6 (16.67%)  1 4/20 (20.00%)  4
Malaise  1  1/6 (16.67%)  1 1/20 (5.00%)  1
Pyrexia  1  1/6 (16.67%)  1 3/20 (15.00%)  3
Injection site Pruritus  1  0/6 (0.00%)  0 14/20 (70.00%)  17
Injection site erythema  1  0/6 (0.00%)  0 8/20 (40.00%)  8
Injection site pain  1  0/6 (0.00%)  0 2/20 (10.00%)  2
Feeling hot  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Injection site reaction  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Colitis ulcerative  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Infections and infestations     
Fungal infection  1  0/6 (0.00%)  0 2/20 (10.00%)  2
Influenza  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Nasopharyngitis  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Parynchia  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Pneumonia  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Sinusitis  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Urinary tract infection  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Injury, poisoning and procedural complications     
Wrist Fracture  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Bone fissure  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Wound  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Investigations     
Serum ferritin descreased  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Viral load increased  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Metabolism and nutrition disorders     
Decreased appetite  1  1/6 (16.67%)  1 2/20 (10.00%)  2
Musculoskeletal and connective tissue disorders     
Back pain  1  0/6 (0.00%)  0 2/20 (10.00%)  2
Nervous system disorders     
Burning sensation  1  1/6 (16.67%)  2 0/20 (0.00%)  0
Dizziness  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Dysgeusia  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Head Discomfort  1  1/6 (16.67%)  1 0/20 (0.00%)  0
Headache  1  1/6 (16.67%)  1 4/20 (20.00%)  4
Parosmia  1  1/6 (16.67%)  1 1/20 (5.00%)  1
Petit mal epilepsy  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Sensory disturbance  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Renal and urinary disorders     
Pollakiuria  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Urethral discharge  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Respiratory, thoracic and mediastinal disorders     
Cough  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Oropharyngeal pain  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Skin and subcutaneous tissue disorders     
Alopecia  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Photosensitivity reaction  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Pruritus  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Surgical and medical procedures     
Wisdom teeth removal  1  0/6 (0.00%)  0 1/20 (5.00%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
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 Sponsor (or designee) will prepare a final report on the study. The Investigator may not publish or present any information on this study without the express written approval of the Sponsor. Additionally, the Sponsor, may, for any reason, withhold approval for publication or presentation.
Results Point of Contact
Name/Title: Maja Sommerfelt
Organization: Bionor Pharma ASA
Phone: +4723010960
Responsible Party: Bionor Immuno AS
ClinicalTrials.gov Identifier: NCT02092116     History of Changes
Other Study ID Numbers: BPC01-001
2013-004747-23 ( EudraCT Number )
First Submitted: March 3, 2014
First Posted: March 19, 2014
Results First Submitted: November 8, 2016
Results First Posted: March 1, 2017
Last Update Posted: March 1, 2017