HIV I Infection
Conditions
Brief summary
The REDUC trial's objective is to address one of the core issues with the treatment of HIV, which is that some HIV infected cells hide in so-called latent reservoirs. The reservoirs are unaffected by conventional HIV medication and invisible to the immune system. HDACi have the potential to activate these latently infected cells. This will make the HIV infected cells visible to the immune system; the immune response generate by Vacc-4x will be able to attack and eliminate the infected cells.
Detailed description
The study is divide into two parts. In Part A the safety and tolerability of romidepsin will be evaluated and the effect of romidepsin treatment on HIV-1 transcription in HIV-infected patients virologically suppressed on cART will be determined. In Part B the effect of treatment with Vacc-4x + rhuGM-CSF and romidepsin treatment on the HIV-1 latent reservoir in HIV-infected patients virologically suppressed on cART will be measured. Six patients will be enrolled for part A and the safety and tolerability profile evaluated before enrolling 20 patients in B.
Interventions
Sponsors
Celgene Corporation
Bionor Immuno AS
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>18 years 2. Currently receiving cART and having received cART for a minimum of 1 year 3. HIV-1 plasma RNA \<50 copies/mL for at least 1 year (excluding viral load blips) 4. CD4 T cell count ≥500 cells/mm3
Exclusion criteria
1. CD4 T cell count nadir \<200 cells/mm3 2. Previous treatment with an HDACi (Histone deacetylase inhibitor) within the previous 6 months 3. Any evidence of an active AIDS-defining opportunistic infection, active HBV or HCV co-infection, significant cardiac disease, malignancy, transplantation, insulin dependent diabetes mellitus or other protocol defined excluded medical condition 4. Use of any protocol defined contraindicated medication or vaccination 5. Unacceptable values of the hematologic and clinical chemistry parameters as defined in the protocol. 6. Males or females who are unwilling or unable to use protocol defined methods of contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Day 161/175 | 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. |
| Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | 3 weeks | Safety and tolerability evaluation as measured by adverse events (AE) and serious adverse events (SAE). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Day 56/84 | 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 |
| Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | 287 days | 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). |
| Part B: Level of HIV-1 Transcription. | Day 105, 112 and 119 | At day 105, 112 and 119 patients receive romidepsin and 4 hours after each administration HIV transcription is measured as unspliced HIV-1 RNA. |
Countries
Denmark
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Part A 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. | 6 |
| Part B 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). | 20 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Part A | Part B | Total |
|---|---|---|---|
| Age, Customized >18 years | 6 participants | 20 participants | 26 participants |
| Gender Female | 1 Participants | 3 Participants | 4 Participants |
| Gender Male | 5 Participants | 17 Participants | 22 Participants |
| Latest pre-ART viral load | 123300 copies/mL | 67024 copies/mL | 72597.5 copies/mL |
| Mean CD4+ T-cell counts | 807.5 10^6 cells/L | 669.8 10^6 cells/L | 712.3 10^6 cells/L |
| Nadir CD4+ T-cell count | 246.5 10^6 cells/L | 280 10^6 cells/L | 267.5 10^6 cells/L |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 17 Participants | 23 Participants |
| Region of Enrollment Denmark | 6 participants | 20 participants | 26 participants |
| Time since ART initiation | 10.05 years | 6.3 years | 6.9 years |
| Time since HIV diagnosis | 13.3 years | 9.6 years | 9.85 years |
| Time since HIV infection | 13.5 years | 10.2 years | 12.2 years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 20 / 20 |
| serious Total, serious adverse events | 0 / 6 | 1 / 20 |
Outcome results
Primary
Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Safety and tolerability evaluation as measured by adverse events (AE) and serious adverse events (SAE).
Time frame: 3 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A | Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse reactions, grade 1 | 6 participants |
| Part A | Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse reactions, grade 2 | 1 participants |
| Part A | Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Related to Romidepsin | 6 participants |
| Part A | Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Not related | 3 participants |
| Part A | Part A: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Treatment emergent adverse events | 6 participants |
Primary
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.
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
Population: 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 | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part A | 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. | Total HIV-1 DNA, day 161 | -39.71 Estimated % change from baseline |
| Part A | 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. | Integrated HIV-1 DNA, day 175 | -19.21 Estimated % change from baseline |
| Part A | 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. | Replication competent provirus, day 161 | -38 Estimated % change from baseline |
Secondary
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.
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | 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. | Total HIV-1 DNA, Basline | 791.7 copies/10^6 CD4+ T cells | Standard Deviation 790.6 |
| Part A | 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. | Total HIV-1 DNA, Day 84 | 718.8 copies/10^6 CD4+ T cells | Standard Deviation 530.2 |
| Part A | 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. | Integrated HIV-1 DNA, Baseline | 2825.6 copies/10^6 CD4+ T cells | Standard Deviation 1145.6 |
| Part A | 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. | Integrated HIV-1 DNA, Day 84 | 4846.9 copies/10^6 CD4+ T cells | Standard Deviation 3698.4 |
| Part A | 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. | Replication competent provirus, Baseline | 0.39 copies/10^6 CD4+ T cells | Standard Deviation 0.26 |
| Part A | 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. | Replication competent provirus, Day 56 | 0.43 copies/10^6 CD4+ T cells | Standard Deviation 0.31 |
Secondary
Part B: Level of HIV-1 Transcription.
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
Population: All available samples were included in this analysis; 3 withdrew consent and 2 (3 for day 119) did not have analyzable samples.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A | Part B: Level of HIV-1 Transcription. | Day 105, before romidepsin | 6.95 copies/10^6 CD4+ T cells | Standard Deviation 5.29 |
| Part A | Part B: Level of HIV-1 Transcription. | Day 105, 4 hours post romidepsin | 12.77 copies/10^6 CD4+ T cells | Standard Deviation 11.19 |
| Part A | Part B: Level of HIV-1 Transcription. | Day 112, 4 hours post romidepsin | 22.98 copies/10^6 CD4+ T cells | Standard Deviation 16.58 |
| Part A | Part B: Level of HIV-1 Transcription. | Day 119, 4 hours post romidepsin | 25.91 copies/10^6 CD4+ T cells | Standard Deviation 21.78 |
Secondary
Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Non-treatment emergent adverse events | 1 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Treatment emergent adverse events | 20 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Serious adverse event | 1 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse reaction, grade 1 | 20 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse reaction, grade 2 | 5 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse reaction, grade 3 | 1 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Related to Vacc-4x and GM-CSF | 19 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Related to Romidepsin | 17 participants |
| Part A | Part B: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | Not related | 16 participants |