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Trial registered on ANZCTR


Registration number
ACTRN12617000025336
Ethics application status
Approved
Date submitted
29/12/2016
Date registered
9/01/2017
Date last updated
1/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the safety of 3 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 the concentration of BIT225 in the blood and antiviral activity.
Scientific title
A Phase 2 Intensification Study of BIT225, a Human Immunodeficiency Virus-1 Vpu Inhibitor, in HIV-1 Infected Individuals Initiating Combination Antiretroviral Therapy (cART).
Secondary ID [1] 290811 0
BIT225-009
Universal Trial Number (UTN)
U1111-1191-2194
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Human Immunodeficiency Virus-1 infection 301467 0
Condition category
Condition code
Infection 301185 301185 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BIT225 100mg or 200mg, capsule(s) taken once daily (QD), oral, from Day 1 to Week 12.
All study participants will also receive Combination Antiretroviral Therapy (cART): Atripla, fixed dose combination tablet (Tenofovir disoproxil fumarate (TDF); 300mg / emtricitabine (FTC); 200mg / efavirenz (EFV); 600mg) taken once daily (QD), oral, from Day 1 to Week 12. At conclusion of the study treatment period, particpants will remain on cART as per standard treatment guidelines..
Capsule/tablet counts on return will be used to monitor adherence.
Intervention code [1] 296735 0
Treatment: Drugs
Comparator / control treatment
Placebo control, capsule(s) containing microcrystalline cellulose, taken once daily (QD), oral, from Day 1 to Week 12.
All study participants will also receive Combination Antiretroviral Therapy (cART): Atripla, fixed dose combination tablet (Tenofovir disoproxil fumarate (TDF); 300mg / emtricitabine (FTC); 200mg / efavirenz (EFV); 600mg) taken once daily (QD), oral, from Day 1 to Week 12. At conclusion of the study treatment period, particpants 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] 300609 0
Evaluate the antiviral activity of BIT225 (QD) administered for 12 consecutive weeks in combination with cART: Atripla in HIV-1 infected patients who are treatment naive to antiretroviral treatment.
Timepoint [1] 300609 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 (BIT225 200 mg cohort only), 2, 4, 7, 10, 14, 17, 21, 24, Weeks 4, 6, 9, 12, and in follow-up in Weeks 13, 14, 16 and 24.
Plasma samples for a SCA to quantitate low level HIV-1 RNA will be collected from the BIT225 200 mg cohort only at: Screening; Day 7, 10, 14, 17, 21, Weeks 4, 6, 9, 12, and in follow-up in Weeks 16 and 24.

Primary outcome [2] 300610 0
Determine the safety and tolerability of BIT225 QD administered for 12 consecutive weeks in HIV-1 infected patients on cART: Atripla, 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] 300610 0
Medical changes and vital signs will be evaulated at Screening, Day 1, 2, 4, 7, 10, 14, 17, 21, 24, and Weeks 4, 6, 9, 12 and follow-up Weeks 13, 14, 16 and 24.
Clinical laboratory measures will be evaluated at Screening, on Day 1 (BIT225 200 mg) or Day 2 (BIT225 100 mg), and Weeks 2, 4, 6, 9, 12 and follow-up Weeks, 16 and 24.
ECG measurements will be evaluated at Screening, Days 1, 2, 4, 7 and 10, and Weeks 2, 3, 4, 6, 9, 12 and follow-up Weeks 13, 14, 16 and 24.
Secondary outcome [1] 330408 0
Evauate if 12 weeks of BIT225 treatment in addition to cART: Atripla will impact levels of sCD163, a primary biomarker of monocyte immune activation.
Timepoint [1] 330408 0
Blood samples for detection of immune marker sCD163 will be collected from all participants in the BIT225 200mg/placebo cohort at Screening, and then at Day 7, 10, 14, 17, 21, and at Weeks 4, 6, 9 12 and follow-up Weeks 16, and 24 and will be determined by ELISA.
Secondary outcome [2] 330409 0
To evaluate the pharmacokinetics (PK) of 100 mg BIT225 QD administered for 12 consecutive weeks in combination with cART:Atripla 'Registered Trademark' in patients infected with HIV-1.
Timepoint [2] 330409 0
A sub-group of 9 participants in the BIT225 100mg cohort will participate in the intensive PK sub-study.
PK samples will be collected at pre-Atripla dose on Day 1 and Week 12, and at 0.5 hour post Atripla dose as well as 0.5, 1, 2.5, 4, 6, 8, 12 and 24 hours after BIT225 dosing on both days, as well as a 48 and 96 hour sample after the Week 12 dose. Pharmacokinetic parameters assessed will include; Cmax, Tmax, AUC and T1/2.
PK samples will also be collected from all participants pre-dose on Days 4, 10 and 21, Weeks 4, 9, and 12. These samples will be used to determine the trough plasma concentration of BIT225, as well as tracking compliance to dosing.
The concentration of BIT225 in the plasma will be measured using a validated liquid chromatography tandem mass spectrometry method.

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 defined cART regimen (defined as Atripla 'Registered Trademark': FDC tablet 300 mg TDF/ 200 mg FTC/ 600 mg EFV, once daily).

4. Antiretroviral therapy naive (defined as no previous cART).

5. Plasma HIV-1 RNA > 5,000 copies/mL within 45 days before Entry (Day 1) by any FDA-approved test for quantifying HIV-1 RNA at any certified laboratory.

6. CD4+ count > 100 cells/mm3 within 45 days before Entry (Day 1).

7. Females of reproductive potential (defined as women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 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.

8. 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).
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 and for 6 months after stopping 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
NOTE: Pregnancy should be avoided in women receiving Atripla 'Registered Trademark', EFV, a component of Atripla 'Registered Trademark', may cause fetal harm when administered during the first trimester to a pregnant woman. Adequate contraceptive measures should continue for 12 weeks after discontinuation of cART: Atripla 'Registered Trademark'.

9. 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.

10. 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 any active AIDS defining illness (according to the CDC Surveillance Case Definition for HIV infection, AIDS-Defining Conditions, revised April 11, 2014, Appendix 1).

2. Patients 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 study entry (Day 1).

3. 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)

4. Confirmed or suspected active TB disease (confirmation determined by chest X-ray and if necessary, sputum smear)

5. History or other evidence of clinically significant renal disease.

6. Pregnancy or breast feeding, male partners of pregnant females.

7. Abnormal haematological and biochemical parameters within 45 days of Entry (Day 1):
a. Absolute neutrophil count <1000/mm3
b. Haemoglobin <12 g/dL in females or 13 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 >/=2.5 times upper limit of normal
f. Total bilirubin > 1.5 times the normal reference range
g. Creatinine > 1.5 mg/dL
Estimated creatinine clearance < 60 mL/minute at Screening. Value will be calculated using the Cockcroft-Gault formula.

8. Screening ECG QTcB value >/=450 ms.

9. The consumption / administration of concomitant medication (prescribed, over-the-counter or complementary) at the time of the Screening visit listed in Appendix 4. This list is not exhaustive and any medication taken from 30 days prior to first dose through to the end of the participation in the study must be approved by the Biotron Medical Monitor in consultation with the Investigator.

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 drugs of abuse at Screening or Day 1 which in the opinion of the Investigator should preclude them from participation in the study.

12. Any prior suicide attempt.

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 or cardiovascular disease, 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 the study.

17. History of having received any systemic anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) 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 by 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. Unable to refrain from smoking during the PK evaluation periods of the trial, if enrolled in the PK sub-study.

22. 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.

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

24. 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 a sequentially numbered 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
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
Allocation of treatment is in a ratio of 2:1, BIT225 to placebo
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
18/04/2017
Actual
19/04/2017
Date of last participant enrolment
Anticipated
Actual
20/07/2017
Date of last data collection
Anticipated
4/01/2018
Actual
3/01/2018
Sample size
Target
36
Accrual to date
Final
36
Recruitment outside Australia
Country [1] 8530 0
Thailand
State/province [1] 8530 0

Funding & Sponsors
Funding source category [1] 295241 0
Commercial sector/Industry
Name [1] 295241 0
Biotron Limited
Country [1] 295241 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Biotron Limited
Address
Suite 1.9
56 Delhi Road
North Ryde NSW 2113
Country
Australia
Secondary sponsor category [1] 294068 0
None
Name [1] 294068 0
Address [1] 294068 0
Country [1] 294068 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296580 0
lnstitutional Review Board, Faculty of Medicine, Chulalongkorn University
Ethics committee address [1] 296580 0
Ethics committee country [1] 296580 0
Thailand
Date submitted for ethics approval [1] 296580 0
28/11/2016
Approval date [1] 296580 0
09/02/2017
Ethics approval number [1] 296580 0
Ethics committee name [2] 296871 0
Research Ethics Committee, Faculty of Medicine, Chiang Mai University
Ethics committee address [2] 296871 0
Ethics committee country [2] 296871 0
Thailand
Date submitted for ethics approval [2] 296871 0
20/12/2016
Approval date [2] 296871 0
13/03/2017
Ethics approval number [2] 296871 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71358 0
Dr Anchalee Avihingsanon
Address 71358 0
HIV-NAT, Thai Red Cross AIDS Research Centre
104 Ratchadamri Rd, Pathumwan,
Bangkok, 10330, Thailand
Country 71358 0
Thailand
Phone 71358 0
+66 2 652 6040 ext 107
Fax 71358 0
+66 2 252 5779
Email 71358 0
anchaleea2009@gmail.com
Contact person for public queries
Name 71359 0
Michelle Miller
Address 71359 0
Biotron Limited
Suite 1.9, 56 Delhi Rd
North Ryde NSW 2113
Australia
Country 71359 0
Australia
Phone 71359 0
+61 2 9805 0488
Fax 71359 0
+61 2 9805 0688
Email 71359 0
mmiller@biotron.com.au
Contact person for scientific queries
Name 71360 0
Michelle Miller
Address 71360 0
Biotron Limited
Suite 1.9, 56 Delhi Rd
North Ryde NSW 2113
Australia
Country 71360 0
Australia
Phone 71360 0
+61 2 9805 0488
Fax 71360 0
+61 2 9805 0688
Email 71360 0
mmiller@biotron.com.au

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