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Trial registered on ANZCTR


Registration number
ACTRN12612001189819
Ethics application status
Approved
Date submitted
9/11/2012
Date registered
12/11/2012
Date last updated
1/07/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the safety of BIT225 in combination with pegylated interferon and ribavirin in patients with hepatitis C virus and human immunodeficiency virus co-infection, who are naive to treatment with pegylated interferon and ribavirin, and whose HIV is currently well controlled by standard antiretroviral therapy.
Scientific title
A Phase 2, Open Label Study of the Safety, Pharmacokinetics and Antiviral Activity of BIT225 in Combination with Pegylated Interferon and Ribavirin in Patients Co-infected with Hepatitis C Virus and Human Immunodeficiency Virus-1.
Secondary ID [1] 281498 0
BIT225-006
Universal Trial Number (UTN)
U1111-1136-7284
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hepatitis C Virus infection in patients co-infected with human immunodeficiency virus-1 287768 0
Condition category
Condition code
Infection 288114 288114 0 0
Other infectious diseases
Oral and Gastrointestinal 288115 288115 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Infection 288143 288143 0 0
Acquired immune deficiency syndrome (AIDS / HIV)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
BIT225 300mg, once daily on Days 7 and 35, and twice daily on Days 8 to 34. BIT225 is supplied as a powder to be suspended immediately before use in water (25mL). All participants will also receive standard of care therapy for hepatitis C virus of pegylated interferon alfa-2b 80-120ug/week by subcutaneous injection (weight based) and oral ribavirin 1000-1200mg/day (weight based) for 48 weeks.
Intervention code [1] 286011 0
Treatment: Drugs
Comparator / control treatment
Not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288319 0
Evaluate the safety and tolerability of 300mg BIT225 twice daily in combination with pegylated interferon alfa-2b (IFN), ribavirin (RBV) and anti-retroviral therapy (ART) in patients with chronic hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1) co-infection.
Timepoint [1] 288319 0
Medical changes, clinical laboratory assessments, vital signs and ECG parameters will be assessed on the first, second, and fourth day, as well as weekly over the 28 days of BIT225 dosing, and up to 7 weeks after ceasing BIT225.
Secondary outcome [1] 299839 0
Evaluate the pharmacokinetics of BIT225 300mg administered daily on Days 7 and 35 and twice daily on Days 8 to 34 in combination with IFN, RBV and ART in patients with chronic HCV and HIV-1 co-infection.
Timepoint [1] 299839 0
Pharmacokinetic samples will be collected on Day 7, pre-dose and 30, 60, 90, 120 minutes, 3, 4, 6, 8 10, 12 and 24 hours post-dose; on Days 10, 14, 21 and 28 pre-dose; and Day 35 pre-dose and 30, 60, 90, 120 minutes, 3 and 4 hours post-dose. The concentration of BIT225 in the plasma will be measured using a validated liquid chromatography tandem mass spectrometry method.
Secondary outcome [2] 299840 0
Evaluate the antiviral activity of BIT225 administered for 28 consecutive days in combination with IFN and RBV in patients with chronic HCV and HIV-1 infection that are treatment naive to anti-HCV treatment with IFN and/or RBV and are virologically suppressed on ART.
Timepoint [2] 299840 0
Blood samples for HCV RNA assays will be collected at screening, Days 0, 7, 8, 10, 14, 21, 28, 35, weeks 8, 12, 24, 48, 60 and 72. Quantitative HCV RNA measurements will be determined by the COBAS Ampliprep/COBAS TaqMan HCV test (Roche).

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

2. Chronic hepatitis C infection (defined as persistent HCV infection as diagnosed by detection of HCV RNA in the blood at least 6 months from initial detection).

3. Serologic evidence of HCV infection by anti-HCV antibody test.

4. Documentation of HCV genotype 1, 2, or 3 at any time prior to entry. (Enrolment will be limited to 4 patients with genotype 1 and 8 patients with genotype 2 or 3).

5. HCV RNA of >/=100,000 IU/mL within 60 days of Entry.

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

7. Currently receiving stable antiretroviral therapy (ART) for at least 6 months (defined as at least 2 nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI) boosted or un-boosted with ritonavir, or integrase inhibitors in combination). The same ART regimen will be continued for the duration of study treatment.

8. HIV-1 RNA less than 200 copies/mL within 60 days before Day 0.

9. CD4+ count >/= 350 cells/mm3 within 30 days before Day 0.

10. ALT (SGOT) and AST (SGPT) less than or equal to 10 times the upper limit of normal (ULN) and stable for at least one month; alkaline phosphatase (ALP) less than or equal to 5 times ULN within 60 days of Day 0.

11. For 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), must have a negative serum or urine pregnancy test at Screening and within 24 hours of starting HCV standard of care treatment (IFN and RBV) on Day 0.
A negative serum or urine pregnancy test result is also required within 24 hours prior to the initiation of BIT225 treatment (Day 7).

12. All subjects 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 subject 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.

13. Subjects 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.

14. Provide written informed consent to participate in the study and be willing to comply with the study procedures.

15. Naive to therapy for HCV, including any IFN or RBV.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients who have received an investigational drug for HCV or HIV, HIV vaccine, immunomodulators (e.g. interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy, or other investigational therapy within 30 days prior to Day 0.

2. Positive results for Hepatitis B (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)) at Screening.

3. Currently have any active AIDS defining illness (according to the CDC Surveillance Case Definition for HIV infection, AIDS-Defining Conditions, updated December 5, 2008).

4. History or presence of other evidence of a medical condition associated with chronic liver disease (e.g., chronic or acute hepatitis B, acute hepatitis A, hemochromatosis, autoimmune hepatitis, Wilson’s disease, Gilbert’s syndrome, homozygote alpha1-antitrypsin deficiency, alcoholic liver disease, and toxin exposures).

5. Bridging cirrhosis or cirrhosis confirmed on a liver biopsy obtained within the past 36 months as judged by a local pathologist.
Note: Patients with Metavir (or equivalent index) stage 3 fibrosis on a previous biopsy will require an abdominal ultrasound within 6 months of first dose showing no evidence of cirrhosis.

6. History or signs of decompensated liver disease manifested by presence of Child-Pugh class B or C, ascites, variceal bleeding, or hepatic encephalopathy, spontaneous bacterial peritonitis, or other clinical signs of portal hypertension or hepatic insufficiency.

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

8. Abnormal haematological and biochemical parameters within 60 days of Entry:
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 normalized ratio (INR) >1.5.
e. Total bilirubin outside of normal reference range
f. Creatinine > 1.5 mg/dL
Estimated creatinine clearance < 60 mL/minute at Screening, calculated using the Cockcroft-Gault formula.

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

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

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 which in the opinion of the Investigator should preclude them from participation in the study.

13. History of severe psychiatric disease, or depression which in the opinion of the Investigator could be exacerbated by IFN therapy. Uncontrolled or active depression or other psychiatric disorder such as untreated Grade >/=3 psychiatric disorder, Grade >/=3 disorder not amenable to medical intervention, or any hospitalization within the past 52 weeks that in the opinion of the site Investigator might preclude tolerability of study requirements.

14. Any prior suicide attempt.

15. 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.) that may be exacerbated by interferon use.

16. History or other evidence of chronic pulmonary disease associated with functional limitation.

17. History of active coronary artery disease or cardiovascular disease, clinically significant arrhythmia.

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

19. History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies or elevated serum alpha-fetoprotein >50 ng/mL.

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

21. History of having received any systemic anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) within 6 months prior to Day 0 or the expectation that such treatment will be needed at any time during the study.

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

23. Any patient with a baseline increased risk for anaemia (e.g. thalassemia, spherocytosis, history of gastrointestinal bleeding, etc) or for whom anaemia would be medically problematic.

24. History or other evidence of severe retinopathy.

25. 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.

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

27. Unable to refrain from smoking during the PK evaluation periods of the trial.

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

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

30. 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)
Suitable patients will be identified through the hospital clinic, given a Participant Information Sheet and Consent Form and a full verbal explanation of the study by an Investigator. After signing the Informed Consent , the volunteers will undergo a screening evaluation to determine eligibility for the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This is an open-label study of BIT225 in patients with HCV and HIV-1 co-infection that are HCV treatment-naive and currently receiving HIV treatment. Participants must be on a stable regimen of ART for the last 6 months and throughout the study. One dose level of BIT225 (300 mg BID) will be studied in 4 patients with HCV genotype 1 and 8 patients with HCV genotypes 2 or 3, resulting in 12 patients enrolled in total. Patients will initiate standard of care (SOC) treatment with IFN and RBV on Day 0. On Day 7, BIT225 treatment will be added for 28 days (300 mg once daily on Day 7 and Day 35 and twice daily on Days 8 – 34). Patients will remain on ART and will continue IFN and RBV for up to 48 weeks.
If HCV RNA from baseline to 12 weeks decreases less than 2 logs, subjects will discontinue IFN and RBV treatment. In addition, subjects will discontinue IFN and RBV treatment at 25 weeks if there is detectable HCV RNA at repeat measurements at Weeks 24 and 25.
Phase
Phase 2
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
26/11/2012
Actual
26/02/2013
Date of last participant enrolment
Anticipated
Actual
30/07/2013
Date of last data collection
Anticipated
Actual
16/12/2014
Sample size
Target
12
Accrual to date
Final
12
Recruitment outside Australia
Country [1] 4670 0
Thailand
State/province [1] 4670 0
Bangkok

Funding & Sponsors
Funding source category [1] 286279 0
Commercial sector/Industry
Name [1] 286279 0
Biotron Limited
Country [1] 286279 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Biotron Limited
Address
Suite 1.09
56 Delhi Road
North Ryde NSW 2113
Country
Australia
Secondary sponsor category [1] 285072 0
None
Name [1] 285072 0
None
Address [1] 285072 0
Country [1] 285072 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288349 0
Siriraj Institutional Review Board, Faculty of Medicine, Mahidol University
Ethics committee address [1] 288349 0
2 Prannok Road
Bangkokonoi
Bangkok 10700
Ethics committee country [1] 288349 0
Thailand
Date submitted for ethics approval [1] 288349 0
02/10/2012
Approval date [1] 288349 0
26/10/2012
Ethics approval number [1] 288349 0
00005261

Summary
Brief summary
This study will assess the safety of BIT225 in combination with the standard of care therapy of IFNand RBV in patients with HCV, co-infected with HIV-1 who have not received any prior IFN or RBV therapy. The patients will be currently receiving therapy for HIV-1, and will be virologically suppressed. The study will also assess how well the BIT225 is tolerated in this patient group, the level of BIT225 in the blood following oral administration and how well BIT225 performs at reducing HCV levels in the blood. Patients with HCV, HIV-1 co-infection tend to have a lower response to IFN and RBV, and it is hoped that the addition of BIT225 will improve the response to treatment.
Trial website
Trial related presentations / publications
Not Applicable
Public notes

Contacts
Principal investigator
Name 34920 0
A/Prof Tawesak Tanwandee
Address 34920 0
Division of Gastroenterology
Department of Medicine
Faculty of Medicine
Siriraj Hospital
Mahidol University
Bangkok 10700 Thailand
Country 34920 0
Thailand
Phone 34920 0
+66 2 419 7283
Fax 34920 0
Email 34920 0
[email protected]
Contact person for public queries
Name 18167 0
Michelle Miller, PhD
Address 18167 0
Biotron Limited
Suite 1.09
56 Delhi Road
North Ryde NSW 2113
Country 18167 0
Australia
Phone 18167 0
+61 2 9805 0488
Fax 18167 0
+61 2 9805 0688
Email 18167 0
[email protected]
Contact person for scientific queries
Name 9095 0
Michelle Miller
Address 9095 0
Biotron Limited
Suite 1.09
56 Delhi Road
North Ryde NSW 2113
Country 9095 0
Australia
Phone 9095 0
+61 2 9805 0488
Fax 9095 0
+61 2 9805 0688
Email 9095 0
[email protected]

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