Clinical trial NCT02982837: To Study the Effect of Adding on Pegylated Interferon (PEG-INF) Therapy for Patients Diagnosed With Chronic Hepatitis B
Official title: Randomized, Multicenter, Open -Label Clinical Trial to Study the Effect of Adding on Pegylated Interferon Therapy for Patients Diagnosed With Chronic Hepatitis B Showing Maintained Response While Receiving Ongoing Nucleotide Analogues
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hepatitis B
Lead sponsor: King Abdullah International Medical Research Center
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2016-12-06
Enrollment: 214
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To assess whether PEG-INF (Peglyated - interferon) Add-on therapy in patients of CHB who have achieved a maintained viral suppression (HBV DNA PCR( polymerase chain reaction) \<200 for last 3-6 month) with NA's can result in increased rate of HBV infection eradication (HbsAg is undetectable by serological blood testing with or without seroconversion to HBs antibody).

Detailed description: Hepatitis B virus (HBV) infection remains a global health care problem with more than one third of world's population having serological evidence of been exposed to the virus and about 5% of global population ( 350-400 million) being chronically infected. About 15-40% of Patients with chronic hepatitis B (CHB) infection develop complications of liver cirrhosis, liver failure and hepatocellular carcinoma(HCC) in their life time , resulting in an estimated of 500,000 to 1.2 million deaths each year. In Saudi Arabia, chronic hepatitis B remains a serious medical problem, despite the implementation of mandatory HBV vaccination of children since 1989. According to a recent study conducted in Saudi hospital, HBV accounts for 49% of the hepatitis cases . Persistent viral replication is associated with disease progression to liver fibrosis, cirrhosis and development of HCC. Currently two classes of drugs are available for treatment of CHB namely immunomodulatory therapy (conventional \& pegylated interferon (Pegasys) PEG-IFN) and nucleoside/nucleotide analogues(NA). Interferon(IFN)-α with its dual immunomodulatory and antiviral effects was the first drug (recombinant standard IFN- α) licensed for Chronic hepatitis B treatment in the 1990's followed by introduction of nucleos(t)ide analogues(NA) in 1998 that directly inhibit HBV polymerase and provide an effective on treatment maintained viral suppression . With the introduction of pegylated interferon- α (PEG-IFN) in 2005 that allows a convenient once a week dosing interval and of equal or superior treatment efficacy than conventional (IFN), the interferon based therapy has markedly improved its utility. Due to its predominant immunomodulatory effect peginterferon (PEG-IFN) offers the advantage of higher sustained off treatment response rate compared to NA thus allowing a finite duration of treatment. The NA act by directly inhibiting HBV polymerase resulting in effective on treatment maintained viral suppression (HBV DNA PCR \<200 for last 3-6 month)). However, long term NA therapy has the problems of emergence of viral resistance, long -term safety, cost and patient compliance.

Eligibility criteria: Inclusion Criteria:

* Adults ≥18 \& \< 70 years of both genders.
* CHB on NA's in maintained viral suppression (HBV DNA PCR \<200 for last 3-6 month)
* Patients with measurable HBsAg quantitative levels
* Patients with any HBV genotypes.
* Patients with either CHB e Ag positive or eAg negative
* Patients who sign an informed consent for inclusion into the study.
* Patients with hepatitis Delta co-infection.
* only patients with a negative pregnancy test who are of child bearing potential and agree to utilize a strict birth control method will be enrolled

Exclusion Criteria:

* Patients with following characteristics will not be considered for the trial:
* Decompensated liver Cirrhosis
* HCV (hepatitis C virus) or HIV co infection.
* Autoimmune disorders like SLE (Systemic lupus erythematosus), RA (Rheumatoid Arthritis ), AIH (Autoimmune Hemolytic Anemia), ITP (Immune thrombocytopenic purpura), psoriasis etc.
* Untreated psychiatric conditions like depression and alcohol or drug abuse.
* Comorbid conditions like chronic renal failure or post renal/liver transplantation on immunosuppressive therapy.
* Complicated diabetes mellitus and advanced heart failure.
* Pregnancy or not willing to practice contraception.
* Known allergy to Interferons.
* Concomitant treatment with Telbivudine
* Evidence of portal hypertension by Biochemical (Low Platelets less than 100), imaging or UGI (upper gastrointestinal)endoscopy

Primary outcomes:
measure: The loss of HbsAg between groups (NA) group and NA +Peg_INF group assessed by HbsAg test
timeFrame: 48 weeks
Secondary outcomes:
measure: The seroconversion to HBs antibody between groups (NA) group and NA +Peg_INF group assessed by Hbe Ab test
timeFrame: 6 ,12 months & 48 weeks
measure: The HBeAg (Hepatitis B e-Antigen) loss in CHRONIC HBV eAg positive patient between groups (NA) group and NA +Peg_INF group assessed by HbeAg test
timeFrame: 6,12 months & 48 weeks
measure: The conversion of HBeAg to HBe-antibody in CHRONIC HBV eAg (eAntigen) positive patient between groups (NA) group and NA +Peg_INF group assessed by HBe-antibody test
timeFrame: 6,12 months & 48 weeks
measure: The correlation between HBsAg ( Hepatitis B Surface Antigen) levels while on therapy at the a defined interval ie 8,12.24,36,48 weeks and rate of HBsAg loss at end of therapy assessed by measuring HBV s Ag during the period 8,12.24,36 and 48 weeks
timeFrame: 8,12,24 and 48 weeks
measure: The relationship between HBV genotype and HBsAg loss at the end of the study assessed by measuring HBV genotype only at base line and see if any particular genotype have more HBV sAg loss at the end of the study
timeFrame: At base line & 48 weeks
measure: The relationship between IL28B (Interleukin 28B) genotypes ( polymorphism) and HBsAg loss with or without seroconversion to HBs antibody
timeFrame: At base line & 48 weeks
measure: The relationship between vitamin D deficiency and (HbsAg loss with or without seroconversion to HBs antibody) assess by measuring Vitamin D level at base line And correlate the baseline level of Vitamin with HBV sAg loss at the end of the study
timeFrame: At base line & 48 weeks
Other outcomes:
Locations:
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Jeddah
country: Saudi Arabia
facility: King Abdulaziz Hospital
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
Study officials:
affiliation: National Guards Health Affairs-Riyadh
name: Abduljaleel Alalwan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol. 2005 Dec;34(6):1329-39. doi: 10.1093/ije/dyi206. Epub 2005 Oct 25.
citation: Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer. 1988 May 15;61(10):1942-56. doi: 10.1002/1097-0142(19880515)61:103.0.co;2-j. No abstract available.
citation: Bosch FX, Ribes J, Cleries R, Diaz M. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005 May;9(2):191-211, v. doi: 10.1016/j.cld.2004.12.009.
citation: Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009 Feb 14;373(9663):582-92. doi: 10.1016/S0140-6736(09)60207-5.
citation: Al-Tawfiq JA, Anani A. Profile of viral hepatitis A, B, and C in a Saudi Arabian hospital. Med Sci Monit. 2008 Jan;14(1):CR52-56.
citation: Memish ZA, Knawy BA, El-Saed A. Incidence trends of viral hepatitis A, B, and C seropositivity over eight years of surveillance in Saudi Arabia. Int J Infect Dis. 2010 Feb;14(2):e115-20. doi: 10.1016/j.ijid.2009.03.027. Epub 2009 Jun 21.
citation: Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65.
citation: Chan HL, Tse CH, Mo F, Koh J, Wong VW, Wong GL, Lam Chan S, Yeo W, Sung JJ, Mok TS. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol. 2008 Jan 10;26(2):177-82. doi: 10.1200/JCO.2007.13.2043.
citation: Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology. 2009 Nov;137(5):1593-608.e1-2. doi: 10.1053/j.gastro.2009.08.063. Epub 2009 Sep 6.
citation: Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, Chutaputti A, Chang WY, Zahm FE, Pluck N. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003 Jul;10(4):298-305. doi: 10.1046/j.1365-2893.2003.00450.x.
citation: Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007 Feb;45(2):507-39. doi: 10.1002/hep.21513. No abstract available.
citation: Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GK, Locarnini S; Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the Liver. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008 Sep;2(3):263-83. doi: 10.1007/s12072-008-9080-3. Epub 2008 May 10.
citation: Lee A. Prevention of Helicobacter pylori infection. Scand J Gastroenterol Suppl. 1996;215:11-5.