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Trial registered on ANZCTR


Registration number
ACTRN12621001354875
Ethics application status
Approved
Date submitted
16/08/2021
Date registered
7/10/2021
Date last updated
9/01/2023
Date data sharing statement initially provided
7/10/2021
Date results information initially provided
9/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
An open-label study of the safety and efficacy of 12 weeks treatment with BIT225 and Combination Antiretroviral Therapy (cART) in patients with Human Immunodeficiency Virus-1 (HIV-1) with only partial immune reconstitution.
Scientific title
A Phase 2 Study of BIT225, an HIV-1 Vpu Inhibitor, in HIV-1 Infected, Treatment Experienced Individuals, Attaining Only Partial Immune Reconstitution on a Durable, Suppressive Combination Antiretroviral Therapy (cART) Regimen: An Open-Label Exploratory Evaluation of Changes in Inflammatory, Immune, Immune Activation and Viral Markers.
Secondary ID [1] 305042 0
BIT225-011
Universal Trial Number (UTN)
U1111-1268-6150
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Human Immunodeficiency Virus-1 infection 323229 0
Condition category
Condition code
Infection 320811 320811 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 12.
All study participants will continue on their ongoing Combination Antiretroviral Therapy (cART) regimen. Acceptable cART regimens include: INSTI (integrase strand transfer inhibitor) or NNRTI (non-nucleoside reverse transcriptase inhibitor), or non-ritonavir or non cobicistat boosted PI (protease inhibitor), plus one or two nucleoside/nucleotide agents (abacavir, emtricitabine, lamivudine, zidovudine and tenofovir disoproxil fumarate).
At conclusion of the study period, participants will remain on their ongoing cART as per standard treatment guidelines.
Capsule / tablet counts on return will be used to monitor adherence.
Intervention code [1] 321436 0
Treatment: Drugs
Comparator / control treatment
No control group. Open label study. Intervention will be offered after the 4 week observation period.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 328616 0
To determine change of immune, immune activation, inflammation and viral markers with the addition of BIT225 200mg QD, to stable, suppressive cART, for 12 weeks in HIV-1 infected, treatment experienced participants, who have achieved only partial immune reconstitution. To characterise changes from baseline Observation to those noted during active Treatment and Follow up Periods. The markers for these analyses include: sCD163, CD3+/ CD4+ /CD38+/HLA DR+, CD3+/ CD8+ /CD38+/HLA DR, NK cells, CD56+/CD16+/CD45+ (CD3-), and Th17 related cytokines (IFN-gamma, IL-1beta, IL-6, IL-10, IL-17A, IL-17F, IL-22, TNF-alpha). These markers will be assessed as a composite outcome and are exploratory in nature.
Timepoint [1] 328616 0
Blood samples for detection of immune activation and inflammatory markers will be collected from all participants at Screening, Observation Period Days -28, -21, -7 prior to intervention commencement as well as Treatment Period Days 1, 14, 21 , Weeks 4, 8, 12, and Follow-up Week 16 post-intervention commencement and will be determined by enzyme linked immunosorbent assay (ELISA) and flow cytometry.
Primary outcome [2] 328617 0
Determine the safety and tolerability of BIT225 (QD) administered for 12 consecutive weeks in HIV-1 infected patients on cART with partial immune reconstitution.
Safety and tolerability will be assessed by treatment emergent untoward medical changes, e.g. changes in clinical laboratory assessments, vital signs and ECG measures. Comparison will be made between the 4 week Observation Period, 12 week Treatment Period when study participants are on study medication, and 4 week post treatment Follow-up Period.
Timepoint [2] 328617 0
Medical changes and vital signs will be evaluated at Screening, Observation Period Days -28, -21, -7 prior to intervention commencement, Treatment Period Days 1, 14, 21, Weeks 4, 8, 12 and Follow-up Week 16 post-intervention commencement.
Clinical Laboratory measures will be evaluated at Screening, Observation Period Day -7 prior to intervention commencement, Treatment Period Days 1, 14, 21, Week 12 and Follow-up Week 16 post-intervention commencement.
ECG measurements will be evaluated at Screening, Observation Period Days -28, -7 prior to intervention commencement, Treatment Period Days 1, 14, Weeks 4, 8, 12 and Follow-up Week 16 post-intervention commencement
Secondary outcome [1] 399694 0
Characterise changes in low level HIV-1 viral load from baseline Observation to those noted during active Treatment and Follow-up Periods.
Timepoint [1] 399694 0
Blood samples for HIV-1 RNA assays will be analysed using the Hologic Aptima HIV-1 Quant Dx Assay and collected from all participants at Screening, Observation Period Days -28, -21, -7 prior to intervention commencement as well as Treatment Period Days 1, 14, 21 , Weeks 4, 8, 12, and Follow-up Week 16 post-intervention commencement.
Secondary outcome [2] 399695 0
Characterise changes in functional HIV reservoir from baseline Observation to those noted during active Treatment and Follow-up Periods.
Timepoint [2] 399695 0
Blood samples for functional HIV reservoir assays will be analysed using a functional HIV-1 reservoir assay and collected from all participants at Observation Period Days -28, -7 prior to intervention commencement as well as Treatment Period Days 14, 21 , Weeks 4, 12 and Follow-up Week 16 post-intervention commencement
Secondary outcome [3] 399696 0
Characterise changes in additional pro- and anti-inflammatory markers, cytokines, cellular activation and exhaustion markers, and T cell phenotypes as well as other immune cell populations from baseline Observation to those noted during active Treatment and Follow-up Periods. These markers will be assessed as a composite secondary outcome and are exploratory in nature.
Timepoint [3] 399696 0
Blood samples for detection of immune activation and inflammatory markers will be collected from all participants at Screening, Observation Period Days -28, -21, -7 prior to intervention commencement as well as Treatment Period Days 1, 14, 21 , Weeks 4, 8, 12, and Follow-up Week 16 post-intervention commencement and will be determined by enzyme linked immunosorbent assay (ELISA) and flow cytometry.

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

2. INSTI, NNRTI or non-ritonavir or non cobisistat boosted PI, plus one or two nucleoside/nucleotide agents therapy for >/= 24 months with HIV-1 RNA < 50 copies/mL.

3. Screening plasma HIV-1 RNA < 50 copies/mL.

4. Screening CD4 count =/< 350 cells/mm3, or CD4 count < 500 cells/mm3 with CD4/CD8 ratio =/< 0.6.

5. 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.

6. 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)
Diaphragm or cervical cap
Intrauterine device (IUD)
Hormonal-based contraception

7. 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.

8. Negative test for SARS-CoV during the Screening period. If SARS-CoV-2 vaccinated, vaccination regimen must be completed >/= 30 days before screening.

9. 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
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Currently have an active AIDS defining illness (according to the CDC Surveillance Case Definition for HIV infection, AIDS-Defining Conditions, revised April 11, 2014).

2. Participants currently receiving HIV-1 cART regimen containing ritonavir-boosted or cobicistat boosted protease inhibitor, or therapy for other conditions that include agents with clinically significant drug metabolising enzyme induction properties.

3. Participants who have received an investigational drug for HIV-1, HIV 1 vaccine, immunomodulators (e.g. interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy, or other investigational therapy within 45 days prior to initiation of the study observation period (Day -28).

4. Acute or chronic viral hepatitis as defined by the presence of: 1) anti-HAV IgM Ab; 2) HCV requiring treatment during the course of the study; 3) HBV requiring treatment during the course of the study.

5. Confirmed or suspected active TB disease

6. Pregnancy or breastfeeding

7. 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 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 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.

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

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

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

11. A positive result on urine screen for illicit drugs at Screening, during the observation period or Day 1 which in the opinion of the Investigator should preclude them from participation in the study.

12. 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.).

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

14. History of a severe seizure disorder, or current anticonvulsant use.

15. Evidence of an active cancer or suspected cancer or a history of malignancy within 2 years of the initiation of the observation period of the study.

16. History of having received any systemic anti-neoplastic or immunomodulatory treatment within 6 months prior to the initiation of the observation period of the study, or the expectation that such treatment will be needed at any time during the study.

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

18. Serious illness requiring systemic treatment and/or hospitalisation 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 the initiation of the observation period.

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

20. Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to anticipated observation period of the study.

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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
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 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
18/10/2021
Actual
10/01/2022
Date of last participant enrolment
Anticipated
Actual
27/09/2022
Date of last data collection
Anticipated
9/02/2023
Actual
Sample size
Target
20
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20246 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 20247 0
Holdsworth House Medical Practice - Sydney
Recruitment hospital [3] 22777 0
East Sydney Doctors - Darlinghurst
Recruitment postcode(s) [1] 34985 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 34986 0
2010 - Sydney

Funding & Sponsors
Funding source category [1] 309430 0
Commercial sector/Industry
Name [1] 309430 0
Biotron Limited
Country [1] 309430 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] 310402 0
None
Name [1] 310402 0
Address [1] 310402 0
Country [1] 310402 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309231 0
St Vincent's Hospital, Sydney
Ethics committee address [1] 309231 0
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 309231 0
Australia
Date submitted for ethics approval [1] 309231 0
21/10/2021
Approval date [1] 309231 0
25/11/2021
Ethics approval number [1] 309231 0
Ethics committee name [2] 309242 0
Bellberry Limited
Ethics committee address [2] 309242 0
123 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [2] 309242 0
Australia
Date submitted for ethics approval [2] 309242 0
31/08/2021
Approval date [2] 309242 0
26/10/2021
Ethics approval number [2] 309242 0

Summary
Brief summary
The proposed study aims to expand previous observations of immune activation and inflammation marker changes noted in the BIT225-009 study (ACTRN12617000025336) amongst treatment naïve individuals, to include a population of HIV-1 infected individuals maintained on a fully suppressive, chronic cART regimen, but not achieving full immune reconstitution.
This population has not realised the same benefits of cART as those achieving more complete immune reconstitution, and as such has clear, unmet medical need. This study will investigate whether treatment with BIT225 over twelve (12) weeks can restore elements of immune reconstitution when compared to baseline by examining changes in inflammatory, immune, immune activation and viral markers.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113430 0
Prof Anthony Kelleher
Address 113430 0
St Vincent's Hospital, Sydney
390 Victoria Street
Darlinghurst NSW 2010
Country 113430 0
Australia
Phone 113430 0
+61 2 8382 3707
Fax 113430 0
Email 113430 0
[email protected]
Contact person for public queries
Name 113431 0
Dr Michelle Miller
Address 113431 0
Biotron Limited
Suite 3.3, 56 Delhi Road
North Ryde NSW 2113
Country 113431 0
Australia
Phone 113431 0
+61 2 9805 0488
Fax 113431 0
61 2 9805 0688
Email 113431 0
[email protected]
Contact person for scientific queries
Name 113432 0
Dr Michelle Miller
Address 113432 0
Biotron Limited
Suite 3.3, 56 Delhi Road
North Ryde NSW 2113
Country 113432 0
Australia
Phone 113432 0
+61 2 9805 0488
Fax 113432 0
61 2 9805 0688
Email 113432 0
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.