HIV InfectionsPhase 1/2NCT03198559
Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART
A Phase 1/2 study testing Disulfiram, (National Drug Code) NDC 0378-4141-01 and Vorinostat, NDC 00006-0568-40 in people with HIV Infections, run by University of Melbourne at 1 site in Australia.
Trial summary
Antiretroviral therapy (ART) dramatically reduces Human Immunodeficiency Virus (HIV) replication leading to restoration of immune function and a near normal life expectancy, but treatment is lifelong and there is no cure. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- HIV Infections
- What is being tested?
- Disulfiram, (National Drug Code) NDC 0378-4141-01 and Vorinostat, NDC 00006-0568-40
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5 participants
- Where
- 1 siteAustralia
- Study dates
- 8 Aug 2017to 9 Apr 2019
- Phase
- Phase 1/2
- 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 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18-65 years with documented HIV-1 infection (antibody positive or detectable plasma HIV-1 RNA)
- Receiving combination ART with plasma HIV RNA <50 copies/mL for >3 years
- CD4+ T cell count >350 microliter at screening
- Able to provide informed consent
- Willing to abstain from alcohol consumption from one day before to 14 days after completing 28 days of disulfiram
- One month post influenza vaccine (from screening visit)
- Women of non-child-bearing potential defined as > 12 months of spontaneous amenorrhea and ≥ 45 years of age, or documented medical history of one of the following: hysterectomy, bilateral oophorectomy or tubal ligation.
- Women of Child Bearing Potential (WOCBP) with a negative pregnancy test at Screening and agrees to use one of the study protocol specified methods of contraception to avoid pregnancy
Who cannot join
- Current alcohol use disorder or hazardous alcohol use (>7 drinks per week for women or > 14 drinks per week for men) as determined by clinical evaluation
- Current or recent (in the last 4 days) use of metronidazole or any drug formulation that contains alcohol or that might contain alcohol, including the gelatin capsule and liquid formulations of ritonavir, ritonavir/lopinavir, amprenavir and fosamprenavir, and alcohol-containing preparations such as cough syrups, tonics etc.
- Current use of tipranavir or Maraviroc
- Current use of zidovudine, stavudine or didanosine (as disulfiram potentially has potent irreversible inhibitory effects on mitochondrial metabolism and hence could exacerbate the toxicity of these drugs)
- Concurrent use of rivaroxaban (a CYP3A metabolized medication) as the cytochrome P450 inhibitory effects of disulfiram on rivaroxaban are unknown
- Current use of warfarin
Show all 30Show fewer
- Individuals who intend to modify antiretroviral therapy during the study period for any reason
- Significant myocardial disease (current myocarditis or reduced left ventricular ejection fraction below the lower limit of normal) or diagnosed coronary artery disease
- Significant renal disease (eGFR <50 milliliter/minute)
- History of psychosis, seizure disorder, abnormal electroencephalogram or brain damage with significant persisting neurological deficit
- Prior malignancy active within the previous 3 years except for local curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the prostate, cervix or breast.
- Known hypersensitivity to disulfiram or vorinostat or contraindications to treatment with these agents
- Participation in another latency reversal study or receipt of vorinostat or disulfiram in the previous 12 months before starting the investigational treatment
- Any significant acute medical illness requiring hospitalization within preceding 8 weeks
- Hepatitis B (HBV) or hepatitis C (HCV) co-infection as determined by detection of HBsAg or HCV RNA (Individuals with prior hepatitis infection that is now cleared are eligible for enrolment)
- Receipt of immunomodulating agents (excluding immunization) or systemic chemotherapeutic agents within 28 days prior to study entry
- Current or recent gastrointestinal disease or surgery that may impact the absorption of the investigational drug
- Active substance use that in the opinion of the investigator will prevent adequate compliance with study procedures
- Women who are currently pregnant or breastfeeding
- Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy
- Unable or unwilling to adhere to protocol procedures
- The following laboratory values within 6 weeks before starting the investigational drug (lab tests may be repeated to obtain acceptable values before failure at screening is concluded)
- Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
- Serum total bilirubin ≥1.5 x ULN
- eGFR <50 milliliter/min
- Hemoglobin <11.0 g/deciliter
- Platelet count ≤100 x10^9/L (liter)
- Absolute neutrophil count ≤1.5x10^9/L
- Serum potassium, magnesium, phosphorus outside normal limits
- Total calcium (corrected for serum albumin) or ionized calcium ≤ lower normal limits
Trial locations and contacts
1 site in 1 country.
Australia1 site
Department of Infectious Diseases, Alfred Hospital
Melbourne, Victoria, 3004
About this study
Official title: Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART (DIVA): A Single Arm Clinical Trial
Antiretroviral therapy (ART) dramatically reduces Human Immunodeficiency Virus (HIV) replication leading to restoration of immune function and a near normal life expectancy, but treatment is lifelong and there is no cure. The major barrier to a cure is the persistence of long lived cluster of differentiation 4 (CD4+) T-cells that contain a "silenced" form of HIV, called HIV latency.
The purpose of this research is to investigate whether it may be possible to reduce the amount of dormant HIV infection in immune cells, by "turning on" or activating the virus and hence force it out of the latently infected memory T cells. This leads to production of HIV by the cell, which will either die or will be recognized and eliminated by the immune system. As very few T cells are latently infected with HIV, the death of these cells is not expected to affect the function of the immune system and further infection of new cells is expected to be prevented by ART.
Read the detailed description
One strategy aimed at reducing the frequency of latently infected cells in HIV-infected individuals on antiretroviral therapy (ART) is the use of pharmacological agents to reverse HIV latency, thereby initiating virus-mediated cell lysis or immune-mediated killing. Recent clinical trials of latency reversing agents (LRAs) in HIV infected subjects on ART, including histone deacetylase inhibitors (HDACi) and the anti-alcoholism drug disulfiram, have shown that inducing an increase in Cell Associated Unspliced (CA-US) HIV RNA or plasma HIV RNA is possible. Yet, these interventions did not have a demonstrable effect on the frequency of latently infected cells or time to viral rebound after cessation of ART, potentially because latency reversal alone didn't trigger an adequate immune response or cell death or that the potency of latency reversal with a single-agent intervention over a very short period of time, lacked sufficient potency, as suggested by recent in vitro studies. It is highly likely that long-term remission off ART will require interventions that lead to both a reduction in latently infected cells and an increase in HIV-specific immunity, therefore identifying a strategy to increase viral antigens on the surface of latently infected cells will be a key component of this strategy.
- Conditions
- HIV Infections
- Being tested
- Disulfiram, (National Drug Code) NDC 0378-4141-01, Vorinostat, NDC 00006-0568-40
- Keywords
- HIV latency, Disulfiram, Vorinostat, Latency Reversing Agents, Histone Deacetylase Inhibitors (HDACi)
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Disulfiram, (National Drug Code) NDC 0378-4141-01Drug
This study will provide open label disulfiram. Participants will take 2 grams (4x500mg tablets) of disulfiram per day for a total of 28 days
Vorinostat, NDC 00006-0568-40Drug
Also called Zolinza
This study will provide open label vorinostat. Participants will take 400mg (4x100mg capsules) of vorinostat per day on days 8, 9, 10 and days 22, 23, 24.
| Study group | Role | What they receive |
|---|---|---|
| Experimental | Experimental | Participants current ART regimen:
2 grams disulfiram by mouth per day for a total of 28 days
400mg vorinostat by mouth per day on days 8, 9,10 and days 22, 23, 24 Receives: Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01; Drug: Vorinostat, NDC 00006-0568-40 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Day 11 Plasma HIV RNA Relative to Baseline
The primary endpoint was to determine the change from baseline to day 11 of plasma HIV RNA levels after 11 continuous days of disulfiram with administration of vorinostat on days 8, 9 and 10 in HIV infected individuals on suppressive ART.
Measured: Baseline and 11 days
Secondary outcomes (2)
Incidence of Treatment-Emergent Adverse Events
This secondary outcome was to determine the Incidence of treatment-emergent adverse events [Safety and Tolerability] during a 28 day course of continuous disulfiram with intermittent administration of 3 days of vorinostat on two occasions in HIV infected individuals on suppressive ART.
An adverse event is defined as any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that; results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations as judged by physician.
Systematic assessments of adverse events were performed at each visit, including unscheduled visits
Measured: Adverse events were collected continuously throughout the study duration from day 1 on treatment until 2 months since last dose of study drug, an average duration of 3 months
Plasma HIV RNA Relative to Baseline at Additional Time Points
This secondary outcome was to determine the fold change in plasma HIV RNA levels at additional time points during and after 11 continuous days of disulfiram with administration of vorinostat on days 8, 9 and 10 in HIV infected individuals on suppressive ART.
Measured: Baseline to Days 8, 15, 21, 38, 59, 196, 197. Data is reported for days where samples were collected for each participant.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jun 2017
- Study start8 Aug 2017
- Primary completion9 Apr 2019
- Study completion9 Apr 2019
Why it stopped: A re-evaluation of research risks to participants were greater than originally anticipated
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.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Single arm, single site,
- Masking
- None (open label)
- Enrolment
- 5 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Melbourne
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, The Alfred
- Responsible party
- Sponsor
- Investigators
- Sharon R Lewin, FRACP, PhD, Principal investigator, The Doherty Institute, University of Melbourne
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03198559
- Sponsor's protocol ID
- MSD IIS-55750
- Status last verified
- Jun 2023
- First submitted
- 14 Jun 2017
- Last updated
- 9 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No: No plan to share individual participant data
Publications
McMahon JH, Evans VA, Lau JSY, Symons J, Zerbato JM, Chang J, Solomon A, Tennakoon S, Dantanarayana A, Hagenauer M, Lee S, Palmer S, Fisher K, Bumpus N, Heck CJS, Burger D, Wu G, Zuck P, Howell BJ, Zetterberg HH, Blennow K, Gisslen M, Rasmussen TA, Lewin SR. Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal. AIDS. 2022 Jan 1;36(1):75-82. doi: 10.1097/QAD.0000000000003091.
PubMed 34586085
Study at a glance
From the registry record, last updated by the sponsor on 9 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART (DIVA): A Single Arm Clinical Trial
- ClinicalTrials.gov ID
- NCT03198559
- Acronym / sponsor ID
- MSD IIS-55750
- Conditions
- HIV Infections
- Keywords
- HIV latency, Disulfiram, Vorinostat, Latency Reversing Agents, Histone Deacetylase Inhibitors (HDACi)
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: A re-evaluation of research risks to participants were greater than originally anticipated
- Enrolment
- 5 participants (actual)
- Lead sponsor
- University of MelbourneUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, The Alfred
- Study start
- 8 Aug 2017 (actual)
- Primary completion
- 9 Apr 2019 (actual)
- Study completion
- 9 Apr 2019 (actual)
- First posted
- 26 Jun 2017 (actual)
- Results
- Posted 9 Feb 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Antiretroviral therapy (ART) dramatically reduces Human Immunodeficiency Virus (HIV) replication leading to restoration of immune function and a near normal life expectancy, but treatment is lifelong and there is no cure. The major barrier to a cure is the persistence of long lived cluster of differentiation 4 (CD4+) T-cells that contain a "silenced" form of HIV, called HIV latency.
The purpose of this research is to investigate whether it may be possible to reduce the amount of dormant HIV infection in immune cells, by "turning on" or activating the virus and hence force it out of the latently infected memory T cells. This leads to production of HIV by the cell, which will either die or will be recognized and eliminated by the immune system. As very few T cells are latently infected with HIV, the death of these cells is not expected to affect the function of the immune system and further infection of new cells is expected to be prevented by ART.
Detailed description
One strategy aimed at reducing the frequency of latently infected cells in HIV-infected individuals on antiretroviral therapy (ART) is the use of pharmacological agents to reverse HIV latency, thereby initiating virus-mediated cell lysis or immune-mediated killing. Recent clinical trials of latency reversing agents (LRAs) in HIV infected subjects on ART, including histone deacetylase inhibitors (HDACi) and the anti-alcoholism drug disulfiram, have shown that inducing an increase in Cell Associated Unspliced (CA-US) HIV RNA or plasma HIV RNA is possible. Yet, these interventions did not have a demonstrable effect on the frequency of latently infected cells or time to viral rebound after cessation of ART, potentially because latency reversal alone didn't trigger an adequate immune response or cell death or that the potency of latency reversal with a single-agent intervention over a very short period of time, lacked sufficient potency, as suggested by recent in vitro studies. It is highly likely that long-term remission off ART will require interventions that lead to both a reduction in latently infected cells and an increase in HIV-specific immunity, therefore identifying a strategy to increase viral antigens on the surface of latently infected cells will be a key component of this strategy.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Single arm, single site,
| Arm | Type | Receives |
|---|---|---|
| Experimental | Experimental | Drug: Disulfiram, (National Drug Code) NDC 0378-4141-01, Drug: Vorinostat, NDC 00006-0568-40Participants current ART regimen: 2 grams disulfiram by mouth per day for a total of 28 days 400mg vorinostat by mouth per day on days 8, 9,10 and days 22, 23, 24 |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Age 18-65 years with documented HIV-1 infection (antibody positive or detectable plasma HIV-1 RNA)
- Receiving combination ART with plasma HIV RNA <50 copies/mL for >3 years
- CD4+ T cell count >350 microliter at screening
- Able to provide informed consent
- Willing to abstain from alcohol consumption from one day before to 14 days after completing 28 days of disulfiram
Key exclusion criteria (30 listed)
- Current alcohol use disorder or hazardous alcohol use (>7 drinks per week for women or > 14 drinks per week for men) as determined by clinical evaluation
- Current or recent (in the last 4 days) use of metronidazole or any drug formulation that contains alcohol or that might contain alcohol, including the gelatin capsule and liquid formulations of ritonavir, ritonavir/lopinavir, amprenavir and fosamprenavir, and alcohol-containing preparations such as cough syrups, tonics etc.
- Current use of tipranavir or Maraviroc
- Current use of zidovudine, stavudine or didanosine (as disulfiram potentially has potent irreversible inhibitory effects on mitochondrial metabolism and hence could exacerbate the toxicity of these drugs)
- Concurrent use of rivaroxaban (a CYP3A metabolized medication) as the cytochrome P450 inhibitory effects of disulfiram on rivaroxaban are unknown
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 |
|---|---|---|
| Disulfiram, (National Drug Code) NDC 0378-4141-01This study will provide open label disulfiram. Participants will take 2 grams (4x500mg tablets) of disulfiram per day for a total of 28 days | Drug | Experimental |
| Vorinostat, NDC 00006-0568-40Also: ZolinzaThis study will provide open label vorinostat. Participants will take 400mg (4x100mg capsules) of vorinostat per day on days 8, 9, 10 and days 22, 23, 24. | Drug | Experimental |
Primary outcome
Day 11 Plasma HIV RNA Relative to Baseline
Time frame: Baseline and 11 days
The primary endpoint was to determine the change from baseline to day 11 of plasma HIV RNA levels after 11 continuous days of disulfiram with administration of vorinostat on days 8, 9 and 10 in HIV infected individuals on suppressive ART.
2 secondary outcomes
Incidence of Treatment-Emergent Adverse Events
Time frame: Adverse events were collected continuously throughout the study duration from day 1 on treatment until 2 months since last dose of study drug, an average duration of 3 months
Plasma HIV RNA Relative to Baseline at Additional Time Points
Time frame: Baseline to Days 8, 15, 21, 38, 59, 196, 197. Data is reported for days where samples were collected for each participant.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 34586085McMahon JH, Evans VA, Lau JSY, Symons J, Zerbato JM, Chang J, Solomon A, Tennakoon S, Dantanarayana A, Hagenauer M, Lee S, Palmer S, Fisher K, Bumpus N, Heck CJS, Burger D, Wu G, Zuck P, Howell BJ, Zetterberg HH, Blennow K, Gisslen M, Rasmussen TA, Lewin SR. Neurotoxicity with high-dose disulfiram and vorinostat used for HIV latency reversal. AIDS. 2022 Jan 1;36(1):75-82. doi: 10.1097/QAD.0000000000003091.
- Individual participant dataSharing planned: No. No plan to share individual participant data
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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.
Sharon R Lewin, FRACP, PhD principal investigator
The Doherty Institute, University of Melbourne
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Disulfiram, (National Drug Code) NDC 0378-4141-01 and Vorinostat, NDC 00006-0568-40 in people with HIV Infections, run by University of Melbourne at 1 site in Australia.
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 8 inclusion and 30 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: stopped early, as of the sponsor's last update on 9 Feb 2024. 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 Australia. 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. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
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 9 Feb 2024). 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?
Day 11 Plasma HIV RNA Relative to Baseline (time frame: Baseline and 11 days). 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 NCT03198559, which also lists 1 linked publication.
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 9 Feb 2024.