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Trial registered on ANZCTR


Registration number
ACTRN12621000937819p
Ethics application status
Submitted, not yet approved
Date submitted
3/06/2021
Date registered
19/07/2021
Date last updated
19/07/2021
Date data sharing statement initially provided
19/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the safety and efficacy of 6 months treatment with BIT225 and Combination Antiretroviral Therapy (cART) in patients with Human Immunodeficiency Virus-1 (HIV-1) compared to cART alone, including measurement of BIT225 in the blood, antiviral activity and immune markers.
Scientific title
A Phase 2 Study of BIT225, a Human Immunodeficiency Virus-1 (HIV-1) Vpu Inhibitor, in Treatment Naive HIV-1 Infected Individuals Commencing Dolutegravir-based Combination Antiretroviral Therapy (cART): Evaluation of Safety, Efficacy and Inflammatory and Immune Activation Markers.
Secondary ID [1] 304392 0
BIT225-010
Universal Trial Number (UTN)
U1111-1266-9893
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Human Immunodeficiency Virus-1 infection 322189 0
Condition category
Condition code
Infection 319879 319879 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BIT225 200mg, capsules taken once daily (QD), oral, from Day 1 to Week 24.
All study participants will also receive Combination Antiretroviral Therapy (cART): one tablet dolutegravir (DTG); 50mg, and one fixed dose combination tablet tenofovir disoproxil fumarate (TDF); 300mg / emtricitabine (FTC); 200mg taken once daily (QD), oral from Day 1 to Week 24. At conclusion of the study period, participants will remain on cART as per standard treatment guidelines.
Capsule / tablet counts on return will be used to monitor adherence.
Intervention code [1] 320755 0
Treatment: Drugs
Comparator / control treatment
Placebo control, capsules containing microcrystalline cellulose, taken once daily (QD), oral, from Day 1 to Week 24.
All study participants will also receive Combination Antiretroviral Therapy (cART): one tablet dolutegravir (DTG); 50mg, and one fixed dose combination tablet tenofovir disoproxil fumarate (TDF); 300mg / emtricitabine (FTC); 200mg taken once daily (QD), oral from Day 1 to Week 24. At conclusion of the study period, participants will remain on cART as per standard treatment guidelines.
Capsule / tablet counts on return will be used to monitor adherence.
Control group
Placebo

Outcomes
Primary outcome [1] 327753 0
Evaluate the antiviral activity of BIT225 (QD) administered for 24 consecutive weeks in combination with cART in HIV-1 infected patients who are treatment naive to antiretroviral treatment.
Timepoint [1] 327753 0
HIV-1 plasma viral load will be determined by Roche COBAS TaqMan HIV-1 (Roche Diagnostics).
Blood samples for HIV-1 RNA assays will be collected at: Screening, Day 1 and 14, Weeks 4, 8, 12, 16, 20 and 24, and follow-up in Weeks 28 and 32 post intervention commencement.
Primary outcome [2] 327757 0
Determine the safety and tolerability of BIT225 (QD) administered for 24 consecutive weeks in HIV-1 infected patients on cART that are antiretroviral treatment naive.
Safety and tolerability will be assessed by comparison to placebo of treatment emergent untoward medical changes, e.g. changes in clinical laboratory assessments, vital signs and ECG measures.
Timepoint [2] 327757 0
Medical changes and vital signs will be evaluated at Screening, Days 1, 3, 7, 14 and 21, Weeks 4, 8, 10, 12, 16, 20, 24 and follow-up Weeks 28 and 32 post-intervention commencement.
Clinical Laboratory measures will be evaluated at Screening, Days 1 and 14, Weeks 4, 8, 12, 24 and follow-up Weeks 28 and 32 post-intervention commencement.
ECG measurements will be evaluated at Screening, Days 1, 7, 14, Weeks 4, 8, 12, 16, 20, 24 and follow-up Weeks 28 and 32 post-intervention commencement.
Primary outcome [3] 327758 0
Characterise changes from baseline in an aggregate panel of immune activation and inflammatory markers in individuals receiving BIT225 (QD) for 24 consecutive weeks in combination with cART. Biomarkers in this panel include: sCD163, sTNFR I and II, IL-6, IL-21, IL-15, IL-10, activated CD4 and CD8 T cell subsets and changes in NK cells. These markers will be assessed as a composite outcome and are exploratory in nature.
Timepoint [3] 327758 0
Blood samples for detection of immune activation and inflammatory markers will be collected from all participants at Screening, Days 1, 3, 7, 14, 21 and Weeks 4, 8, 10, 12, 16, 20, 24 and follow-up Weeks 28 and 32 post-intervention commencement and will be determined by enzyme linked immunosorbent assay (ELISA) and flow cytometry.
Secondary outcome [1] 396484 0
Determine if the addition of BIT225 (QD) administered for 24 consecutive weeks in HIV-1 infected treatment naive patients on cART results in changes in low level i.e. sub 50 copies/ml HIV-1 viral load.
Timepoint [1] 396484 0
Blood samples taken for HIV-1 RNA assays reporting sub 50 copies/ml will be analysed using the Hologic Aptima HIV-1 Quant Dx Assay on Screening, Day 1, 14, Weeks 4, 8, 12, 16, 20, 24 and follow-up Week 32 post-intervention commencement.
Secondary outcome [2] 396485 0
Characterise changes in additional pro- and anti-inflammatory markers, cytokines, cellular exhaustion markers, cellular activation markers, and T-cell phenotypes as well as other immune cell populations. These include sCD14, IFN-gamma, IL-1beta, TNF-alpha, IL-22, IL-17A, IL-17E/F, IL-25, PD-1, CD25, CD4 and CD8 t-cell subsets. These markers will be assessed as a composite secondary outcome and are exploratory in nature.
Timepoint [2] 396485 0
Blood samples for inflammation and immune activation markers will be collected from all participants at Screening, Days 1, 3, 7, 14, 21, Weeks 4, 8, 10, 12, 16, 20, 24 and follow-up Weeks 28 and 32 post-intervention commencement and will be determined by ELISA and flow cytometry.
Secondary outcome [3] 397702 0
Determine if the addition of BIT225 (QD) administered for 24 consecutive weeks in HIV-1 infected treatment naive patients on cART results in the HIV reservoir.
Timepoint [3] 397702 0
Blood samples to measure HIV reservoir will be determined by a functional HIV-1 reservoir assay on Day 1, Weeks 12, 24 and follow-up Week 32 post-intervention commencement.

Eligibility
Key inclusion criteria
1. Males or females aged 18 to 65 years.

2. HIV-1 infection, as documented by rapid HIV-1 test or any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 antigen, plasma RNA, or a second antibody test by a method other than rapid HIV-1 and ELISA is acceptable as an alternative confirmatory test.

3. Individuals initiating the standarised cART regimen (defined as DTG plus TDF and FTC once daily).

4. Antiretroviral therapy naive (defined as no previous cART except if used for pre- or post-exposure prophylaxis, or women who were administered cART for prevention of mother to child transmission; in all cases, prior cART therapy cannot have exceeded 12 weeks in duration; no cART use is permitted within the last 45 days prior to screening).

5. Plasma HIV-1 RNA > 5,000 copies/mL at screening by any FDA-approved test for quantifying HIV-1 RNA (to < 50 copies/mL).

6. CD4+ count >/= 50 cells/mm3 and =/< 350 cells/mm3 at Screening.

7. Negative test for SARS-CoV-2 during screening period.

8. Females of reproductive potential (defined as women who have not been post-menopausal for at least 24 consecutive months, or women who have not undergone surgical sterilization; specifically, hysterectomy, or bilateral oophorectomy and/or tubal ligation), must have a negative serum or urine pregnancy test with a sensitivity of at least 50mlU/mL at Screening and within 24 hours of starting study treatment on Day 1.

9. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the course of the study.
If participating in sexual activity that could lead to pregnancy, the participant and partner must agree to use two reliable methods of contraception simultaneously while receiving study treatment.
A combination of TWO of the following methods MUST be used appropriately:
Condoms (male or female) with or without a spermicidal agent
Diaphragm or cervical cap with spermicide
Intrauterine device (IUD)
Hormonal-based contraception

10. Participants who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraceptives. Acceptable documentation of sterilization, menopause or male partner’s azoospermia must be provided; follicle stimulating hormone-release factor (FSH) measurement can be used to document menopausal range.

11. Provide written informed consent to participate in the study and be willing to comply with the study procedures.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Currently have any active AIDS defining illness (according to the CDC Surveillance Case Definition for HIV infection, AIDS-Defining Conditions, revised April 11, 2014).

2. Participants who have received an investigational drug for HIV-1, HIV-1 vaccine, immunomodulators, systemic cytotoxic chemotherapy, or other investigational therapy within 45 days prior to study entry (Day 1).

3. Participants who have received a SARS-CoV-2 vaccination within the past thirty (30) days prior to screening.

4. Acute or chronic viral hepatitis as defined by the presence of: 1) anti-HAV IgM Ab (acute hepatitis A), 2) HCV Ab with a detectable HCV RNA by PCR (acute or chronic hepatitis C) or 3) hepatitis B surface antigen or HBV DNA in subjects with isolated HBcAb, defined as negative HBsAg, negative HBsAb and positive HBcAb (acute or chronic hepatitis B).

5. Confirmed or suspected active tuberculosis (TB) disease.

6. History or laboratory evidence of clinically significant renal disease.

7. Pregnancy or breastfeeding, as well as male partners of pregnant females.

8. Abnormal haematological and biochemical parameters at screening (any of the following):
a. Absolute neutrophil count <1000/mm3
b. Haemoglobin <10 g/dL in females or less than or equal to 12 g/dL in males
c. Platelet count <150,000/mm3
d. International normalised ratio (INR) >1.5
e. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and/or alkaline phosphatase greater than or equal to 2.5 times upper limit of normal
f. Creatinine > 1.5 mg/dL
g. Estimated creatinine clearance < 60 mL/minute at screening. Value will be calculated using the Cockcroft-Gault formula.

9. Screening ECG QTcF value greater than or equal to 450 ms.

10. The consumption / administration of concomitant medication (prescribed, over-the-counter or complementary) at the time of the Screening visit.

11. Active drug or alcohol use or dependence that, in the opinion of the site Investigator, would interfere with adherence to study requirements.

12. A positive result on urine screen for drugs of abuse at Screening or Day 1 which in the opinion of the Investigator should preclude them from participation in the study.

13. History of immunologically mediated disease (e.g., inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune haemolytic anaemia, scleroderma, severe psoriasis, rheumatoid arthritis requiring more than intermittent non-steroidal anti-inflammatory medications for management, etc.)

14. History of documented or presumed coronary artery disease, clinically significant cardiovascular disease, or clinically significant arrhythmia.

15. History of a severe seizure disorder or current anticonvulsant use.

16. Evidence of an active or suspected cancer or a history of malignancy within 2 years of commencement of the study.

17. History of having received any systemic anti-neoplastic or immunomodulatory treatment within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.

18. Active thyroid disease (use of thyroid hormone replacement therapy permitted but TSH or free T4 must be in normal range.)

19. Serious illness requiring systemic treatment and/or hospitalization until the participant either completes therapy or is clinically stable on therapy, in the opinion of the site Investigator, or at least 7 days prior to study entry.

20. Known allergy/sensitivity or any hypersensitivity to components of study drug or its formulation.

21. Difficulty abstaining from grapefruit, starfruit, and pomelo, including products containing these fruit, from 7 days prior to the first dose of investigational product until the end of the dosing period.

22. Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to anticipated dose administration.

23. Current use of herbal medications or unwillingness to cease use during study participation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be assigned to treatment in accordance with the randomisation schedule following confirmation of eligibility on day 1. An unblinded pharmacist at the site will dispense the study medication to the blinded site staff according to the randomisation schedule. The dispensed medication will carry the participant's unique study number.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation
Allocation of treatment is in a ratio of 2:1, BIT225 to placebo
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
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 outside Australia
Country [1] 23752 0
Thailand
State/province [1] 23752 0

Funding & Sponsors
Funding source category [1] 308762 0
Commercial sector/Industry
Name [1] 308762 0
Biotron Limited
Address [1] 308762 0
Suite 3.3
56 Delhi Road
North Ryde NSW 2113
Country [1] 308762 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Biotron Limited
Address
Suite 3.3
56 Delhi Road
North Ryde NSW 2113
Country
Australia
Secondary sponsor category [1] 309665 0
None
Name [1] 309665 0
Address [1] 309665 0
Country [1] 309665 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 308678 0
Institutional Review Board, Faculty of Medicine, Chulalongkorn University
Ethics committee address [1] 308678 0
1873 Rama 4 Road
Pathumwan,
Bangkok 10330 Thailand
Ethics committee country [1] 308678 0
Thailand
Date submitted for ethics approval [1] 308678 0
10/06/2021
Approval date [1] 308678 0
Ethics approval number [1] 308678 0

Summary
Brief summary
The proposed study will determine the potential efficacy and safety of a first-in-class HIV-1 Vpu inhibitor, BIT225, The study involves the addition of BIT225 for a 24-week period at commencement of initiation of cART. In a previous 12-week clinical study (BIT225-009, ACTRN12617000025336), in combination with cART in HIV-1 infected treatment naïve subjects, BIT225 was shown to induce immunomodulation effects and improve key markers of health outcomes.

This study aims to demonstrate that the addition of BIT225 to cART will result in comparable reductions in plasma viral load, and result in clinically favourable changes in viral, inflammatory and immune activation markers, beyond those seen in the cART alone arm.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111530 0
Dr Anchalee Avihingsanon
Address 111530 0
HIV-NAT, Thai Red Cross AIDS Research Centre
104 Ratchadamri Rd Pathumwan,
Bangkok, 10330, Thailand
Country 111530 0
Thailand
Phone 111530 0
+66 2 652 6040
Fax 111530 0
+66 2 252 5779
Email 111530 0
anchaleea2009@gmail.com
Contact person for public queries
Name 111531 0
Dr Michelle Miller
Address 111531 0
Biotron Limited
Suite 3.3, 56 Delhi Rd
North Ryde NSW 2113
Australia
Country 111531 0
Australia
Phone 111531 0
+61 2 9805 0488
Fax 111531 0
+61 2 9805 0688
Email 111531 0
mmiller@biotron.com.au
Contact person for scientific queries
Name 111532 0
Dr Michelle Miller
Address 111532 0
Biotron Limited
Suite 3.3, 56 Delhi Rd
North Ryde NSW 2113
Australia
Country 111532 0
Australia
Phone 111532 0
+61 2 9805 0488
Fax 111532 0
+61 2 9805 0688
Email 111532 0
mmiller@biotron.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results