Clinical trial NCT01937806: Phase 3 and Extensional Study of Besifovir
Official title: A Phase Ⅲ, Multi-center, Randomized, Double-blinded, Parallel Study to Assess the Antiviral Activity and Safety of Besifovir 150 mg Compared to Tenofovir 300 mg in Chronic Hepatitis B Patients for 48 Weeks
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Chronic Hepatitis B
Keywords: Chronic hepatitis B
Lead sponsor: IlDong Pharmaceutical Co Ltd
Sponsor class: INDUSTRY
First posted: 2013-09-10
Enrollment: 197
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To prove that a study drug is noninferior to a control drug with a proportion of subjects who showed HBV DNA undetected (less than 400 copies/mL (69 IU/mL)) at the 48th week after 48-week administration of Besifovir 150 mg, or Tenofovir 300 mg as a control drug to chronic hepatitis B patients

Detailed description: * Screening Period Subject registration is conducted with confirming selection and exclusion criteria after a written consent form is obtained within 28 days before clinical trial drug administration.
* Wash-out Period Subjects who had been treated with antiviral agents within 12 weeks should complete a 4-week wash-out period from the stage of stopping antiviral agent treatment before a baseline visit and subjects who have no experience of antiviral agent treatment start a baseline visit without a wash-out period.
* Baseline Subjects who visit on the date of starting clinical trial drug administration are randomized to a test group or a control group at a ratio of 1:1. Double blindness is applied for both groups.
* Treatment period Subjects are orally administered with a clinical trial drug q.ds.i.d. for 48 weeks and visit at the 0, 4th, 12th, 24th, 36th, and 48th week for an HBV DNA test, laboratory tests, a physical test, vital signs, and adverse events.
* Follow-up period Subjects are provided with appropriate treatment after completing the 48-week trial or dropping out. Subjects visit once at the 60th week for follow-up of adverse events, such as acute deterioration of hepatitis B, and HBV DNA test results. If any treatment is not conducted after 48-week administration, subjects visit at intervals of four weeks until a follow-up visit (60th week) and the same tests with the 24th week visit (Visit 5) are conducted. However, subjects who participate in a 48-week separate extended trial conducted after 48-week administration in this clinical trial do not have a follow-up period.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients over the age of 20 years old
2. Patients who show positive HBsAg or has a history of chronic hepatitis B for the last six months or more before screening
3. Patients who have not received interferon (including Pegylation formulation) to treat chronic hepatitis and antiviral agents for more than 12 weeks.
4. Patients who showed positive HBsAg during screening
5. Patients who showed HBV DNA measured by COBAS TaqManTM HBV Test more than 1x105 copies/mL (17,241 IU/mL) in case of positive HBeAg during screening, or who showed HBV DNA measured by COBAS TaqManTM HBV Test more than 1x104 copies/mL (1,724 IU/mL) in case of negative HBeAg
6. Patients who showed ALT more than 1.2 times, or less than 10 times of the upper limit in the normal range during screening
7. Patients who were explained about the purpose, methods and effects of the clinical trial and then, signed a written consent form.
8. Male and female patients of childbearing age who can use double contraception acknowledged\* during a trial period \* Double contraception acknowledged means combination of barrier contraception (condom, diaphragm, etc.) and other contraception (sterilization operation, intrauterine contraceptive device, oral contraceptive drug, other hormone delivery system, contraceptive cream, jelly or foam, etc.).

Exclusion Criteria:

1. Patients who have hepatitis C (HCV), hepatitis D (HDV), or human immunodeficiency virus (HIV)
2. Patients with a uncompensated liver disease who have at least one of the following values or signs during screening

   * Total bilirubin \> 2 x ULN
   * Prothrombin time delayed more than three seconds compared to the normal value
   * Serum Albumin \< 30 g/L (3 g/dL)
   * A medical history of ascites, jaundice, hemorrhage by varix, hepatic encephalopathy, or other signs of liver function loss
3. At least one of the following laboratory values during screening

   * Hemoglobin \< 9.0 g/dL
   * Absolute neutrophil count (ANC) \< 1.5 x 109 /L (1500 /mm3)
   * Platelet count \< 100 x 109 /L (100 x 103 /mm3)
   * Serum creatinine \> 1.5 mg/dL
   * Serum amylase \> 2 x ULN and Lipase \> 2 x ULN
4. Patients who showed GFR less than 50 mL/min by calculating MDRD (Modification of Diet in Renal Disease: 1.86 x PCr -1.154 x AGE -0.203 (x 0.742 for women)) during screening
5. Patients who showed alpha-fetoprotein(AFP) more than 50 ng/mL during screening and are estimated to have hepatocellular carcinoma (HCC) through liver/abdomen CT scans
6. Patients who had received the following drugs for the last two months before screening (however, short-term use (less than consecutive 14 days) of these drugs and low-dose aspirin (100 mg, maximally, 300 mg/day) are allowed.)

   * Nephrotoxic drugs (e.g. Aminoglycosides, Amphotericin B, NSAIDs)
   * Hepatotoxic drugs (e.g. Erythromycin, Ketoconazole, Rifampin, Fluconazole, Dapsone)
   * Anticoagulant (e.g. Warfarin)
7. Patients who are suspected by an investigator to have the level of immunity decreased among patients who had been administered with immunosuppressants within six months before screening
8. Patients who had been administered with long-term general corticosteroids (more than consecutive 14 days) at a high dose (more than prednisolone 20 mg daily\*) within three months before screening (In case of local corticosteroids, an investigator decides it.)

   \* It is equal to cortisone 125 mg, hydrocortisone 100 mg, prednisone 20 mg, methylprednisolone 16 mg, triamcinolone 16 mg, dexamethasone 3 mg, betamethasone 2.4 mg.
9. Patients who were diagnosed as a malignant tumor within five years before screening or have a relapse of a malignant tumor (In case of a benign tumor, if an investigator decides that it does not affect the progress of the clinical trial during a trial period, the patients can be registered.)
10. Patients who are scheduled to participate in other clinical trial after registered in this clinical trial, or had been participated in other clinical trial within three months before registered in this clinical trial
11. Pregnant women, lactating women, or patients who planned pregnancy during a trial period
12. Patients who have hypersensitivity to the clinical trial drug in this clinical trial
13. Patients who have a past medical history of clinical alcohol or drug abuse within a year before screening or now are abusers
14. Patients who have a severe disease, such as liver diseases, heart failure, renal failure, and pancreatitis, decided by an investigator to have an effect on this clinical trial
15. Patients who have other hepatic diseases (hematochromatosis, Wilson's disease, alcoholic liver diseases, nonalcoholic steatohepatitis, α1-antitrypsin deficiency) except hepatitis B
16. Patients who received an organ transplant
17. Persons who are possible to decline daily function due to a mental disease or patients who are not able to understand the purpose and methods of this clinical trial
18. Patients who are decided by an investigator as unsuitable for conducting this clinical trial

Primary outcomes:
measure: The rate of subjects who showed HBV DNA undetected (less than 400 copies/mL (69 IU/mL)) at the 48th week
timeFrame: at the 48th week
Secondary outcomes:
measure: The rate of subjects who showed HBV DNA less than 116 copies/mL (20 IU/mL, LOQ of COBAS TaqManTM) at the 48th week
timeFrame: at the 48th week
measure: Average amount of change in an HBV DNA common logarithm value at the 48th week to a base value
timeFrame: at the 48th week
measure: The rate of subjects who showed ALT normalized at the 48th week
timeFrame: at the 48th week
measure: The rate of subjects who showed HBV DNA undetected (less than 400 copies/mL (69 IU/mL)) and ALT normalized at the 48th week
timeFrame: at the 48th week
measure: The rate of subjects who showed HBsAg serum loss and/or seroconversion (HBsAg loss and Anti-HBs formation) at the 48th week
timeFrame: at the 48th week
measure: The rate of subjects who showed HBeAg serum loss and/or seroconversion (HBeAg loss and Anti-HBe formation) at the 48th week among subjects with positive HBeAg
timeFrame: at the 48th week
measure: The rate of subjects who showed HBV DNA undetected (less than 400 copies/mL (69 IU/mL)) and HBeAg loss at the 48th week among subjects with positive HBeAg
timeFrame: at the 48th week
measure: The rate of subjects who showed HBV DNA undetected (less than 400 copies/mL (69 IU/mL)) and HBeAg seroconversion at the 48th week among subjects with positive HBeAg
timeFrame: at the 48th week
measure: Changes in antiviral drug resistant mutation according to HBV DNA sequencing results at the 48th week
timeFrame: at the 48th week
measure: The rate of subjects who showed virologic breakthrough according to serum HBV DNA at the 48th week
timeFrame: at the 48th week
Other outcomes:
Locations:
city: Cheonan
country: Korea, Republic of
facility: Soonchunhyang University Hospital
state: Chungchoengnam-do
city: ChunCheon
country: Korea, Republic of
facility: Hallym University Medical Center
state: Kangwon-do
city: Wonju
country: Korea, Republic of
facility: Wonju Sevrerance Christian Hospital
state: Kangwon-do
city: Ansan
country: Korea, Republic of
facility: Korea University Medical Center
state: Kyounggi-do
city: Guri
country: Korea, Republic of
facility: Hanyang University Guri Hospital
state: Kyunggi-do
city: Suwon,
country: Korea, Republic of
facility: Ajou University Medical Center
state: Kyunggi-do
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Pusan
country: Korea, Republic of
facility: Inje University Busan Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Boramae medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital of Yonsei University
city: Seoul
country: Korea, Republic of
facility: Soonchunhyang University Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea, Seoul St. Vincent's Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital,
Study officials:
affiliation: Kangnam Severance Hospital, Yonsei University, Seoul, Korea
name: Kwan Sik Lee, M.d., Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Kyungpook National University Hospital, Seoul, Korea
name: Young Oh Kweon, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University Medical Center, Ansan, Kyunggi-do, Korea
name: Hyung Joon Yim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Korea University Medical Center, Seoul, Korea
name: Soon Ho Um, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Boramae medical Center, Seoul, Korea
name: Won Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Inje University Busan Paik Hospital, Pusan, Korea
name: Sung Jae Park, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Seoul National University Hospital, Seoul, Korea
name: Yoon Jun Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Korea
name: Yoon Jun Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Asan Medical Center, Seoul, Korea
name: Young-Suk Lim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: The Catholic University of Korea, Seoul St. Vincent's Hospital, Seoul, Korea
name: JinMo Yang, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Soonchunhyang University Hospital, Seoul, Korea
name: Jang, Jae Young, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ajou University Medical Center, Suwon, Kyunggi-do, Korea
name: Jae-Youn Cheong, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Ulsan University Hospital, Ulsan, Korea
name: Neung Hwa Park, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Wonju Sevrerance Christian Hospital, Wonju, Kangwon-do, Korea
name: Moon Young Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Inha University Hospital, Incheon, Inchen, Korea
name: Jin-Woo Lee, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hallym University Medical Center, ChunCheon, Kangwon-do, Korea
name: Dong Joon Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Chungnam National University Hospital
name: Byung Seok Lee, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Hanyang University Guri Hospital, Guri, Kyunggi-do, Korea
name: Joo Hyun Sohn, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Severance Hospital of Yonsei University, Seoul, Korea
name: Kwang-Hyub Han, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Soonchunhyang University Hospital, Choenan, Chungchoengnam-do, Korea
name: Hong Soo Kim, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Song DS, Kim W, Ahn SH, Yim HJ, Jang JY, Kweon YO, Cho YK, Kim YJ, Hong GY, Kim DJ, Jung YK, Sohn JH, Lee JW, Park SJ, Lee BS, Kim JH, Kim HS, Yoon SK, Kim MY, Lee KS, Lim YS, Lee WS, Yang JM, Kim KH, Han KH, Um SH. Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial. Clin Mol Hepatol. 2021 Apr;27(2):346-359. doi: 10.3350/cmh.2020.0307. Epub 2021 Jan 25.
citation: Yim HJ, Kim W, Ahn SH, Yang JM, Jang JY, Kweon YO, Cho YK, Kim YJ, Hong GY, Kim DJ, Jung YK, Um SH, Sohn JH, Lee JW, Park SJ, Lee BS, Kim JH, Kim HS, Yoon SK, Kim MY, Lee KS, Lim YS, Lee WS, Han KH. Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial. Am J Gastroenterol. 2020 Aug;115(8):1217-1225. doi: 10.14309/ajg.0000000000000605.
citation: Ahn SH, Kim W, Jung YK, Yang JM, Jang JY, Kweon YO, Cho YK, Kim YJ, Hong GY, Kim DJ, Um SH, Sohn JH, Lee JW, Park SJ, Lee BS, Kim JH, Kim HS, Yoon SK, Kim MY, Yim HJ, Lee KS, Lim YS, Lee WS, Park NH, Jin SY, Kim KH, Choi W, Han KH. Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection. Clin Gastroenterol Hepatol. 2019 Aug;17(9):1850-1859.e4. doi: 10.1016/j.cgh.2018.11.001. Epub 2018 Nov 15.