Pegylated Interferon Alfa-2a Plus Low Dose Ribavirin for Treatment-Naïve Hemodialysis Patients With Chronic Hepatitis C

• ClinicalTrials.gov Identifier: NCT00491244
• Recruitment Status: Completed
• First Posted: June 26, 2007
• Results First Posted: December 13, 2013
• Last Update Posted: February 10, 2014
• Sponsor: National Taiwan University Hospital
• Collaborators: National Science Council, Taiwan; Department of Health, Executive Yuan, R.O.C. (Taiwan)
• Information provided by (Responsible Party): National Taiwan University Hospital

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Chronic Hepatitis C
• Interventions: Drug: Peginterferon alfa-2a and ribavirin; Drug: Peginterferon alfa-2a
• Enrollment: 377

Participant Flow

Recruitment Details	Recruitment from 1 June, 2007 to 9 May, 2012 Location: 8 academic centers in Taiwan
Pre-assignment Details

Arm/Group Title	Peginterferon and Ribavirin	Peginterferon
Arm/Group Description	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)
Period Title: Overall Study
Started	189	188
Completed	162	168
Not Completed	27	20

Baseline Characteristics

Arm/Group Title		Peginterferon and Ribavirin	Peginterferon	Total
Arm/Group Description		Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)	Total of all reporting groups
Overall Number of Baseline Participants		189	188	377
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	189 participants	188 participants	377 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	189 100.0%	188 100.0%	377 100.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	189 participants	188 participants	377 participants
		51 (10)	51 (11)	51 (10)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	189 participants	188 participants	377 participants
	Female	76 40.2%	76 40.4%	152 40.3%
	Male	113 59.8%	112 59.6%	225 59.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Taiwan	Number Analyzed	189 participants	188 participants	377 participants
		189	188	377

Outcome Measures

1. Primary Outcome

Title	Sustained Virologic Response (SVR)Rate
Description	[Not Specified]
Time Frame	1.5 year

Outcome Measure Data

Analysis Population Description

All participants were analyzed if they received at least one dose of the study medication

Arm/Group Title	Peginterferon and Ribavirin	Peginterferon
Arm/Group Description:	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)
Overall Number of Participants Analyzed	189	188
Measure Type: Number; Unit of Measure: participants
	130	72

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peginterferon and Ribavirin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.80
	Confidence Interval	(2-Sided) 95%; 1.46 to 2.21
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Adverse Event (AE)-Related Withdrawal Rate
Description	[Not Specified]
Time Frame	1.5 year

Outcome Measure Data

Analysis Population Description

All patients were analyzed if they received at least one dose of the study medication; monitoring the events until the last visit

Arm/Group Title	Peginterferon and Ribavirin	Peginterferon
Arm/Group Description:	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)
Overall Number of Participants Analyzed	189	188
Measure Type: Number; Unit of Measure: participants
Advese event related withdrawal rate	12	7
Non withdrawal	177	171

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peginterferon and Ribavirin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.35
	Comments	[Not Specified]
	Method	Chi-squared
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.61
	Confidence Interval	(2-Sided) 95%; 0.65 to 4.01
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	18 months
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Peginterferon and Ribavirin		Peginterferon
Arm/Group Description	Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week plus ribavirin (Copegus, F. Hoffman-LaRoche) 200 mg/day for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)		Pegylated interferon alfa-2a (Pegasys, F. Hoffman-LaRoche) 135 ug/week for 24 to 48 weeks (genotype 1: 48 weeks, genotype 2: 24 weeks)
All-Cause Mortality
	Peginterferon and Ribavirin		Peginterferon
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Peginterferon and Ribavirin		Peginterferon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/189 (4.23%)		7/188 (3.72%)
Cardiac disorders
Postural dizziness † 1	2/189 (1.06%)	2	0/188 (0.00%)	0
Gastrointestinal disorders
Intractable diarrhea † 1	1/189 (0.53%)	1	0/188 (0.00%)	0
Peptic ulcer bleeding † 1	0/189 (0.00%)	0	1/188 (0.53%)	1
Infections and infestations
Cholangitis † 1	0/189 (0.00%)	0	1/188 (0.53%)	1
Peritonitis † 1	1/189 (0.53%)	1	0/188 (0.00%)	0
Pneumonia † 1	2/189 (1.06%)	2	3/188 (1.60%)	3
Salmonella gastroenteritis † 1	0/189 (0.00%)	0	1/188 (0.53%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma † 1	1/189 (0.53%)	1	0/188 (0.00%)	0
Psychiatric disorders
Major depression † 1	0/189 (0.00%)	0	1/188 (0.53%)	1
Skin and subcutaneous tissue disorders
Stevens-Johnson sybdrome † 1	1/189 (0.53%)	1	0/188 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, DAIDS AE grade table
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Peginterferon and Ribavirin		Peginterferon
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	170/189 (89.95%)		154/188 (81.91%)
Blood and lymphatic system disorders
Anemia † 1 [1]	134/189 (70.90%)	134	13/188 (6.91%)	13
Neutropenia † 1 [2]	30/189 (15.87%)	30	26/188 (13.83%)	26
Thrombocytopenia † 1 [3]	19/189 (10.05%)	19	21/188 (11.17%)	21
Gastrointestinal disorders
Anorexia † 1	44/189 (23.28%)	44	38/188 (20.21%)	38
Diarrhea † 1	22/189 (11.64%)	22	20/188 (10.64%)	20
Constipation † 1	16/189 (8.47%)	16	15/188 (7.98%)	15
Immune system disorders
Flu-like syndrome † 1	47/189 (24.87%)	47	50/188 (26.60%)	50
Nervous system disorders
Fatigue † 1	106/189 (56.08%)	106	97/188 (51.60%)	97
Headache † 1	51/189 (26.98%)	51	48/188 (25.53%)	48
Insomnia † 1	62/189 (32.80%)	62	66/188 (35.11%)	66
Psychiatric disorders
Irritability † 1	21/189 (11.11%)	21	19/188 (10.11%)	19
Depression † 1	25/189 (13.23%)	25	23/188 (12.23%)	23
Respiratory, thoracic and mediastinal disorders
Cough † 1	26/189 (13.76%)	26	10/188 (5.32%)	10
Skin and subcutaneous tissue disorders
Dermatitis † 1	43/189 (22.75%)	43	38/188 (20.21%)	38
Injection site reaction † 1	27/189 (14.29%)	27	27/188 (14.36%)	27
Hair loss † 1	47/189 (24.87%)	47	43/188 (22.87%)	43
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, DAIDS AE grade table; [1] Hemoglobin level < 8.5 g/dL; [2] Absolute neutrophil count < 750 x 10^9 cells/L; [3] Platelet count < 50 x 10^9 cells/L

Limitations and Caveats

1. Open-label trial
2. Results may not be generalizable to peritoneal dialysis patients
3. Higher percentages of favorable IL28B genotypes
4. Secondary endpoint may not be powered to detect the differences

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Chen-Hua Liu
• Organization: National Taiwan University Hospital
• Phone: +886-2-23123456 ext 63572
• EMail: jacque_liu@mail2000.com.tw

Publications:

Fabrizi F, Poordad FF, Martin P. Hepatitis C infection and the patient with end-stage renal disease. Hepatology. 2002 Jul;36(1):3-10. Review.

Kao JH, Huang CH, Chen W, Tsai TJ, Lee SH, Hung KY, Chen DS. GB virus C infection in hemodialysis patients: molecular evidence for nosocomial transmission. J Infect Dis. 1999 Jul;180(1):191-4.

Hou CH, Chen WY, Kao JH, Chen DS, Yang Y, Chen JJ, Lee SH, Wu DJ, Yang SC. Intrafamilial transmission of hepatitis C virus in hemodialysis patients. J Med Virol. 1995 Apr;45(4):381-5.

Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs D, McCredie M, Boyle P. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet. 1999 Jul 10;354(9173):93-9.

Nakayama E, Akiba T, Marumo F, Sato C. Prognosis of anti-hepatitis C virus antibody-positive patients on regular hemodialysis therapy. J Am Soc Nephrol. 2000 Oct;11(10):1896-902.

Stehman-Breen CO, Emerson S, Gretch D, Johnson RJ. Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis. 1998 Oct;32(4):629-34.

Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R, Schmid CH, Levey AS. Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int. 1998 May;53(5):1374-81.

Mathurin P, Mouquet C, Poynard T, Sylla C, Benalia H, Fretz C, Thibault V, Cadranel JF, Bernard B, Opolon P, Coriat P, Bitker MO. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology. 1999 Jan;29(1):257-63.

Legendre C, Garrigue V, Le Bihan C, Mamzer-Bruneel MF, Chaix ML, Landais P, Kreis H, Pol S. Harmful long-term impact of hepatitis C virus infection in kidney transplant recipients. Transplantation. 1998 Mar 15;65(5):667-70.

Vosnides GG. Hepatitis C in renal transplantation. Kidney Int. 1997 Sep;52(3):843-61.

Izopet J, Rostaing L, Sandres K, Cisterne JM, Pasquier C, Rumeau JL, Duffaut M, Durand D, Puel J. Longitudinal analysis of hepatitis C virus replication and liver fibrosis progression in renal transplant recipients. J Infect Dis. 2000 Mar;181(3):852-8.

Zylberberg H, Nalpas B, Carnot F, Skhiri H, Fontaine H, Legendre C, Kreis H, Bréchot C, Pol S. Severe evolution of chronic hepatitis C in renal transplantation: a case control study. Nephrol Dial Transplant. 2002 Jan;17(1):129-33.

Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients. Aliment Pharmacol Ther. 2003 Dec;18(11-12):1071-81. Review.

Russo MW, Goldsweig CD, Jacobson IM, Brown RS Jr. Interferon monotherapy for dialysis patients with chronic hepatitis C: an analysis of the literature on efficacy and safety. Am J Gastroenterol. 2003 Jul;98(7):1610-5. Review.

Kokoglu OF, Uçmak H, Hosoglu S, Cetinkaya A, Kantarceken B, Buyukbese MA, Isik IO. Efficacy and tolerability of pegylated-interferon alpha-2a in hemodialysis patients with chronic hepatitis C. J Gastroenterol Hepatol. 2006 Mar;21(3):575-80.

Sporea I, Popescu A, Sirli R, Golea O, Totolici C, Danila M, Vernic C. Pegylated-interferon alpha 2a treatment for chronic hepatitis C in patients on chronic haemodialysis. World J Gastroenterol. 2006 Jul 14;12(26):4191-4.

Chan TM, Ho SK, Tang CS, Tse KC, Lam MF, Lai KN, Yung S. Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection. Nephrology (Carlton). 2007 Feb;12(1):11-7.

Russo MW, Ghalib R, Sigal S, Joshi V. Randomized trial of pegylated interferon alpha-2b monotherapy in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transplant. 2006 Feb;21(2):437-43. Epub 2005 Oct 18.

Annicchiarico BE, Siciliano M. Pegylated interferon-alpha 2b monotherapy for haemodialysis patients with chronic hepatitis C. Aliment Pharmacol Ther. 2004 Jul 1;20(1):123-4; author reply 124.

Potthoff A, Wiegand J, Lüth JB, Wedemeyer H, Manns MP, Tillmann HL. Superiority of standard interferon-alpha2b compared to pegylated interferon-alpha2b (12 kDa) in a hemodialysis patient with chronic hepatitis C? Clin Nephrol. 2005 Mar;63(3):232-5.

Magnone M, Holley JL, Shapiro R, Scantlebury V, McCauley J, Jordan M, Vivas C, Starzl T, Johnson JP. Interferon-alpha-induced acute renal allograft rejection. Transplantation. 1995 Apr 15;59(7):1068-70.

Morales JM. Hepatitis C virus infection and renal disease after renal transplantation. Transplant Proc. 2004 Apr;36(3):760-2. Review.

Rostaing L, Izopet J, Baron E, Duffaut M, Puel J, Durand D. Treatment of chronic hepatitis C with recombinant alpha 2b interferon in kidney transplant recipients: preliminary results and side effects. Transplant Proc. 1995 Feb;27(1):948-50.

Casanovas-Taltavull T, Baliellas C, Benasco C, Serrano TT, Casanova A, Pérez JL, Guerrero L, González MT, Andres E, Gil-Vernet S, Casais LA. Efficacy of interferon for chronic hepatitis C virus-related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation. Am J Gastroenterol. 2001 Apr;96(4):1170-7.

Mousa DH, Abdalla AH, Al-Shoail G, Al-Sulaiman MH, Al-Hawas FA, Al-Khader AA. Alpha-interferon with ribavirin in the treatment of hemodialysis patients with hepatitis C. Transplant Proc. 2004 Jul-Aug;36(6):1831-4.

Bruchfeld A, Ståhle L, Andersson J, Schvarcz R. Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection--a pilot study. J Viral Hepat. 2001 Jul;8(4):287-92.

Bruchfeld A, Ståhle L, Andersson J, Schvarcz R. Interferon and ribavirin therapy in dialysis patients with chronic hepatitis C. Nephrol Dial Transplant. 2001 Aug;16(8):1729.

Bruchfeld A, Lindahl K, Reichard O, Carlsson T, Schvarcz R. Pegylated interferon and ribavirin treatment for hepatitis C in haemodialysis patients. J Viral Hepat. 2006 May;13(5):316-21.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Liu CH, Liu CJ, Huang CF, Lin JW, Dai CY, Liang CC, Huang JF, Hung PH, Tsai HB, Tsai MK, Lee CY, Chen SI, Yang SS, Su TH, Yang HC, Chen PJ, Chen DS, Chuang WL, Yu ML, Kao JH. Peginterferon alfa-2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 2 receiving haemodialysis: a randomised trial. Gut. 2015 Feb;64(2):303-11. doi: 10.1136/gutjnl-2014-307080. Epub 2014 Apr 19.

Liu CH, Huang CF, Liu CJ, Dai CY, Liang CC, Huang JF, Hung PH, Tsai HB, Tsai MK, Chen SI, Lin JW, Yang SS, Su TH, Yang HC, Chen PJ, Chen DS, Chuang WL, Yu ML, Kao JH. Pegylated interferon-α2a with or without low-dose ribavirin for treatment-naive patients with hepatitis C virus genotype 1 receiving hemodialysis: a randomized trial. Ann Intern Med. 2013 Dec 3;159(11):729-38. doi: 10.7326/0003-4819-159-11-201312030-00005.

• Responsible Party: National Taiwan University Hospital
• ClinicalTrials.gov Identifier: NCT00491244 History of Changes
• Other Study ID Numbers: 200703010M
• First Submitted: June 23, 2007
• First Posted: June 26, 2007
• Results First Submitted: September 29, 2013
• Results First Posted: December 13, 2013
• Last Update Posted: February 10, 2014