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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03198559




Registration number
NCT03198559
Ethics application status
Date submitted
14/06/2017
Date registered
26/06/2017
Date last updated
11/04/2019

Titles & IDs
Public title
Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART
Scientific title
Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART (DIVA): A Single Arm Clinical Trial
Secondary ID [1] 0 0
MSD IIS-55750
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
HIV Infections 0 0
Condition category
Condition code
Infection 0 0 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Disulfiram, (National Drug Code) NDC 0378-4141-01
Treatment: Drugs - Vorinostat, NDC 00006-0568-40

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


Treatment: Drugs: Disulfiram, (National Drug Code) NDC 0378-4141-01
This study will provide open label disulfiram. Participants will take 2 grams (4x500mg tablets) of disulfiram per day for a total of 28 days

Treatment: Drugs: Vorinostat, NDC 00006-0568-40
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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Day 11 plasma HIV RNA relative to baseline - 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.
Timepoint [1] 0 0
11 days
Secondary outcome [1] 0 0
Incidence of Treatment-Emergent Adverse Events - 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.
Timepoint [1] 0 0
Days 8, 11, 22, 25, 28, 56 and 196
Secondary outcome [2] 0 0
Plasma HIV RNA relative to baseline at additional time points - To determine the effect of 28 days of disulfiram with intermittent administration of 3 days of vorinostat on two occasions on the frequency of latently infected CD4+ T cells in HIV infected individuals on suppressive ART.
Timepoint [2] 0 0
Days 8, 22, 25, 28, 56 and 196

Eligibility
Key inclusion criteria
- 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
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- 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

- 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Department of Infectious Diseases, Alfred Hospital - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Other
Name
The Peter Doherty Institute for Infection and Immunity
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Merck Sharp & Dohme Corp.
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
The Alfred
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
University of Melbourne
Address [3] 0 0
Country [3] 0 0

Ethics approval
Ethics application status

Summary
Brief 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. 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.
Trial website
https://clinicaltrials.gov/show/NCT03198559
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Sharon R Lewin, FRACP, PhD
Address 0 0
The Doherty Institute, University of Melbourne
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03198559