PADD-ON: Peg-interferon ADDed to an Ongoing Nucleos(t)Ide Based Treatment in Patients With Chronic Hepatitis B to Induce Decrease of HBs-Antigen

• Sponsor: Johannes Gutenberg University Mainz (Other)
• Overall Status: Completed
• CT.gov ID: NCT01524679
• Collaborator: Roche Pharma AG (Industry)
• Enrollment: 170
• Locations: 24
• Arms: 2
• Duration (Months): 60.9
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A prospective, randomised, open-label phase IIb clinical trial assessing the effect of pegylated interferon alfa-2a(Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B

The primary objective of the trial is to investigate whether the add-on of pegylated interferon alfa-2a to a continued treatment with nucleos(t)ide analogues increases the percentage of patients who have significant decrease (≥ 1log10) of HBs antigen after 48 weeks.

170 Patients with chronic hepatitis B, HBe antigen negative, already being treated with an oral antiviral regimen and having a nondetectable viral load for at least 12 months are included.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis B	Drug: Pegylated interferon alfa-2a plus nucleos(t)ide(s)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 170 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomised, Open-label Phase IIb Clinical Trial Assessing the Effect of Pegylated Interferon Alfa-2a (Pegasys®)180 μg Once Weekly for 48 Weeks in Addition to an Ongoing Nucelos(t)Ide Based Treatment on Quantitative HBsAg Levels in Patients With Chronic HBeAg-negative Hepatitis B
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Aug 28, 2017
• Actual Study Completion Date: Aug 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment group pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B	Drug: Pegylated interferon alfa-2a plus nucleos(t)ide(s); Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s); Other Names: Pegasys®
No Intervention: Control group ongoing nucleos(t)ide based treatment alone

Outcome Measures

Primary Outcome Measures

1. Difference in Percentage of Patients Between Treatment and Comparator Arm Reaching a ≥ 1log10 Decline of Quantitative HBsAg After 48 Weeks [48 weeks]

   Difference in percentage of patients between treatment and comparator arm reaching a ≥ 1log10 decline (tenfold reduction) of quantitative HBsAg after 48 weeks

Secondary Outcome Measures

1. Change in Quantitative HBs Antigen at Week 12 [week 12]

   Change in quantitative HBs antigen at week 12. The data were log transformed before analysis and the changes to baseline were analysed. Therefore, the reported values might be interpreted as percentage changes. Lower scores mean a better outcome.

2. Change in Quantitative HBs Antigen at Week 24 [week 24]

   Change in quantitative HBs antigen at week 24. The data were log transformed before analysis and the changes to baseline were analysed. Therefore, the reported values might be interpreted as percentage changes. Lower scores mean a better outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Chronic hepatitis B, HBe antigen negative

• treatment with a stable oral antiviral treatment (not containing telbivudine) and a fully suppressed viral load for at least 12 months (below limit of detection in conventional HBV-PCR assays, i.e. <116 IU / ml).

• 18-70 ys

• willingness and ability to give informed consent and to follow study procedures

• willingness to use adequate contraception

Exclusion Criteria:

• contraindications against treatment with pegylated interferon, e.g. depression, uncontrolled epilepsy, autoimmune diseases, pregnancy, leukocytopenia or thrombocytopenia at screening, etc.

• active alcohol or drug abuse

• preexisting polyneuropathy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Facharztpraxis Prof. Löhr	Wiesbaden	Hessen	Germany	65185
2	Universitätsklinikum Aachen, Medizinische Klinik III	Aachen		Germany	52074
3	Leber- und Studienzentrum am Checkpoint	Berlin		Germany	10969
4	Charité Campus Virchow Klinikum, Universitätsmedizin Berlin	Berlin		Germany	13353
5	Medizinische Klinik und Poliklinik I, Universitätsklinik Bonn	Bonn		Germany	53105
6	Medizinisches Versorgungszentrum Dr. Mauss, Schmutz, Dr. Athmann, Dr. Hegener	Düsseldorf		Germany	40237
7	Medizinische Klinik I, Klinik der J.W. Goethe Universität	Frankfurt		Germany	60590
8	Teuber Consulting & Research KG	Frankfurt		Germany	60594
9	Universitätsklinikum Freiburg Innere Medizin II	Freiburg		Germany	79106
10	Universitätsklinikum Gießen und Marburg GmbH	Gießen		Germany	35392
11	Universitätsklinikum Hamburg-Eppendorf, I. Med. Klinik und Poliklinik	Hamburg		Germany	20246
12	Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie	Hannover		Germany	30625
13	Universitätsklinikum Heidelberg, Medizinische Klinik IV	Heidelberg		Germany	69120
14	Universitätsklinikum des Saarlandes	Homburg		Germany	66421
15	Universitätsklinik Schleswig-Holstein Campus Kiel Klinik für Allgemeine Innere Medizin	Kiel		Germany	24105
16	Klinik für Gastroenterologie und Hepatologie am Abdominalzentrum Universitätsklinikum Köln	Köln		Germany	50937
17	Universitätsklinikum Leipzig AöR	Leipzig		Germany	04103
18	Universitätsmedizin Mainz, I. Med. Klinik und Poliklinik	Mainz		Germany	55131
19	Universitätsklinikum Mannheim	Mannheim		Germany	68167
20	Klinikum rechts der Isar der Technischen Universität München	München		Germany	81675
21	Universitätsklinikum Regensburg	Regensburg		Germany	93053
22	Uniklinik Tübingen Innere Medizin Abt. I	Tübingen		Germany	72076
23	Universitätsklinikum Ulm, Zentrum für Innere Medizin	Ulm		Germany	89081
24	Klinikum der Universität Würzburg Zentrum für Innere Medizin (ZIM) Medizinische Klinik und Poliklinik II Leber- und Infektionsambulanz	Würzburg		Germany	97080

Sponsors and Collaborators

• Johannes Gutenberg University Mainz
• Roche Pharma AG

Investigators

• Principal Investigator: Peter R. Galle, Univ.-Prof. Dr. med., I. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz

Study Documents (Full-Text)

• Study Protocol - Apr 19, 2013
• Statistical Analysis Plan - Sep 22, 2017

More Information

Publications

• Sprinzl MF, Grambihler A, Kittner JM, Wachtlin D, Ruckes C, et al. (2015) Prospective Randomized Open-label Trial Protocol Investigating the Addition of Pegylated Interferon-alpha to an Ongoing Nucleos(t)ide Treatment Regimen of HBeAg Negative Chronic Hepatitis B Patients (PADD-ON). J Clin Trials 5: 226. doi:10.4172/2167-0870.1000226

• Responsible Party: Peter R. Galle, Univ.-Prof. Dr. med., Johannes Gutenberg University Mainz
• ClinicalTrials.gov Identifier: NCT01524679
• Other Study ID Numbers: ML 27787
• First Posted: Feb 2, 2012
• Last Update Posted: Feb 18, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Peter R. Galle, Univ.-Prof. Dr. med., Johannes Gutenberg University Mainz: chronic hepatitis B
• Additional relevant MeSH terms: Hepatitis A; Hepatitis B; Hepatitis B, Chronic; Hepatitis; Hepatitis, Chronic; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a

Study Results

Participant Flow

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)	ongoing nucleos(t)ide based treatment alone
Period Title: Overall Study
STARTED	112	58
COMPLETED	89	49
NOT COMPLETED	23	9

Baseline Characteristics

Arm/Group Title	Treatment Group	Control Group	Total
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)	ongoing nucleos(t)ide based treatment alone	Total of all reporting groups
Overall Participants	110	55	165
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.8 (9.6)	45.1 (9.7)	44.3 (9.6)
Sex: Female, Male (Count of Participants)
Female	26 23.6%	16 29.1%	42 25.5%
Male	84 76.4%	39 70.9%	123 74.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	15 13.6%	6 10.9%	21 12.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	7 6.4%	6 10.9%	13 7.9%
White	85 77.3%	39 70.9%	124 75.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 2.7%	4 7.3%	7 4.2%
Region of Enrollment (participants) [Number]
Germany	110 100%	55 100%	165 100%
Virology: HBV DNA quant. negative? (Count of Participants)
Yes	109 99.1%	54 98.2%	163 98.8%
No	1 0.9%	1 1.8%	2 1.2%
Virology: Anti-HBs (Count of Participants)
Positive	7 6.4%	2 3.6%	9 5.5%
Negative	103 93.6%	53 96.4%	156 94.5%
Virology: HBeAg (Count of Participants)
Positive	0 0%	0 0%	0 0%
Negative	110 100%	55 100%	165 100%
Virology: Anti-HBe (Count of Participants)
Positive	96 87.3%	45 81.8%	141 85.5%
Negative	11 10%	10 18.2%	21 12.7%
Virology: Anti-HBc (Count of Participants)
Positive	94 85.5%	48 87.3%	142 86.1%
Negative	15 13.6%	7 12.7%	22 13.3%
Virology: HCV (Count of Participants)
Positive	0 0%	0 0%	0 0%
Negative	110 100%	55 100%	165 100%
Virology: HDV (Count of Participants)
Positive	0 0%	0 0%	0 0%
Negative	110 100%	55 100%	165 100%
Virology: HIV (Count of Participants)
Positive	0 0%	0 0%	0 0%
Negative	109 99.1%	55 100%	164 99.4%
HBV Genotype known? (Count of Participants)
Yes	22 20%	12 21.8%	34 20.6%
No	88 80%	43 78.2%	131 79.4%
HBV Genotype (Count of Participants)
Genotype A	2 1.8%	1 1.8%	3 1.8%
Genotype C	1 0.9%	0 0%	1 0.6%
Genotype D	16 14.5%	11 20%	27 16.4%
Genotype E	1 0.9%	0 0%	1 0.6%
Wildtype	1 0.9%	0 0%	1 0.6%
Not specified	1 0.9%	0 0%	1 0.6%
HBsAG Concentration (IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [IU/mL]	6547.5 (10326.2)	8434.9 (12660.1)	7180.6 (11159.5)

Outcome Measures

1. Primary Outcome

Title	Difference in Percentage of Patients Between Treatment and Comparator Arm Reaching a ≥ 1log10 Decline of Quantitative HBsAg After 48 Weeks
Description	Difference in percentage of patients between treatment and comparator arm reaching a ≥ 1log10 decline (tenfold reduction) of quantitative HBsAg after 48 weeks
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

mITT population consisting of all randomized patients with at least one post-baseline measurement

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)	ongoing nucleos(t)ide based treatment alone
Measure Participants	106	54
Yes	26 23.6%	1 1.8%
Missing	80 72.7%	53 96.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group, Control Group
	Comments	Nullhypothesis was the equality of response rates of the treatment group and the control group. Treatments were compared by a two-sided Fisher test on a level of significance of 0.05. The study was appropriately powered (80%) for this analysis.
	Type of Statistical Test	Superiority
	Comments	The Fisher Test with asymptotic test statistic provided by the analysis software was used.
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This was the only a priori defined primary endpoint. There was no adjustment for multiple comparisons.
	Method	Fisher Exact
	Comments	There was no adjustment for other variables intended for the primary analysis. Confounding variables were analysed in subsequent analyses.

2. Secondary Outcome

Title	Change in Quantitative HBs Antigen at Week 12
Description	Change in quantitative HBs antigen at week 12. The data were log transformed before analysis and the changes to baseline were analysed. Therefore, the reported values might be interpreted as percentage changes. Lower scores mean a better outcome.
Time Frame	week 12

Outcome Measure Data

Analysis Population Description

Values were only available in 154 patients.

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)	ongoing nucleos(t)ide based treatment alone
Measure Participants	101	53
Geometric Least Squares Mean (95% Confidence Interval) [IU/ml]	0.7058	0.9380

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group, Control Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0957
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.7525
	Confidence Interval	(2-Sided) 95%; 0.5382 to 1.0521
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Quantitative HBs Antigen at Week 24
Description	Change in quantitative HBs antigen at week 24. The data were log transformed before analysis and the changes to baseline were analysed. Therefore, the reported values might be interpreted as percentage changes. Lower scores mean a better outcome.
Time Frame	week 24

Outcome Measure Data

Analysis Population Description

Values were only available in 151 patients.

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)	ongoing nucleos(t)ide based treatment alone
Measure Participants	99	52
Geometric Least Squares Mean (95% Confidence Interval) [IU/ml]	0.3694	0.7995

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Group, Control Group
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.4621
	Confidence Interval	(2-Sided) 95%; 0.4621 to 0.7106
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	48 weeks
Arm/Group Title	Treatment Group		Control Group
Arm/Group Description	pegylated interferon alfa-2a (Pegasys®) 180 μg once weekly for 48 weeks added to an ongoing nucleos(t)ide based treatment in patients with chronic HBeAg-negative hepatitis B Pegylated interferon alfa-2a plus nucleos(t)ide(s): Pegylated interferon alfa-2a, s.c. 180 μg 1x/wk in addition to nucleos(t)ide(s)		ongoing nucleos(t)ide based treatment alone
All Cause Mortality
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/112 (0%)		0/58 (0%)
Serious Adverse Events
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/112 (11.6%)		4/58 (6.9%)
Blood and lymphatic system disorders
lymphadenopathy	1/112 (0.9%)	1	0/58 (0%)	0
Cardiac disorders
Aortic valve stenosis	1/112 (0.9%)	1	0/58 (0%)	0
coronary artery disease	1/112 (0.9%)	1	0/58 (0%)	0
Endocrine disorders
hyperthyroidism	1/112 (0.9%)	1	0/58 (0%)	0
Eye disorders
retinal haemorrhage	1/112 (0.9%)	1	0/58 (0%)	0
General disorders
pain	1/112 (0.9%)	1	0/58 (0%)	0
Infections and infestations
chlamydial infection	1/112 (0.9%)	1	0/58 (0%)	0
pyelonephritis	0/112 (0%)	0	1/58 (1.7%)	1
urinary tract infection	0/112 (0%)	0	1/58 (1.7%)	1
Injury, poisoning and procedural complications
Contusion	1/112 (0.9%)	1	0/58 (0%)	0
Meniscus injury	1/112 (0.9%)	1	0/58 (0%)	0
forearm fracture	1/112 (0.9%)	1	0/58 (0%)	0
facial bones fracture	1/112 (0.9%)	1	0/58 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia	1/112 (0.9%)	1	0/58 (0%)	0
osteoarthritis	1/112 (0.9%)	1	0/58 (0%)	0
foot deformity	0/112 (0%)	0	1/58 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
hepatocellular lymphoma	1/112 (0.9%)	1	0/58 (0%)	0
Renal and urinary disorders
renal colic	1/112 (0.9%)	1	0/58 (0%)	0
Reproductive system and breast disorders
endometrial hyperplasia	0/112 (0%)	0	1/58 (1.7%)	1
vaginal haemorrhage	0/112 (0%)	0	1/58 (1.7%)	1
Respiratory, thoracic and mediastinal disorders
nasal tubinate hypertrophy	0/112 (0%)	0	1/58 (1.7%)	1
Skin and subcutaneous tissue disorders
skin hyperpigmentation	0/112 (0%)	0	1/58 (1.7%)	1
Surgical and medical procedures
internal fixation of fracture	1/112 (0.9%)	1	0/58 (0%)	0
Other (Not Including Serious) Adverse Events
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/112 (94.6%)		20/58 (34.5%)
Blood and lymphatic system disorders
thrombocytopenia	8/112 (7.1%)	11	0/58 (0%)	0
Gastrointestinal disorders
abdominal pain upper	11/112 (9.8%)	11	6/58 (10.3%)	10
diarrhoea	9/112 (8%)	12	1/58 (1.7%)	1
nausea	12/112 (10.7%)	13	1/58 (1.7%)	1
General disorders
chills	11/112 (9.8%)	19	0/58 (0%)	0
fatigue	48/112 (42.9%)	52	2/58 (3.4%)	2
influenza like illness	13/112 (11.6%)	21	2/58 (3.4%)	2
injection site erythema	11/112 (9.8%)	12	0/58 (0%)	0
pyrexia	25/112 (22.3%)	28	0/58 (0%)	0
Infections and infestations
nasopharyngitis	28/112 (25%)	31	3/58 (5.2%)	3
Investigations
transaminases increased	6/112 (5.4%)	9	0/58 (0%)	0
weight decreased	8/112 (7.1%)	8	1/58 (1.7%)	1
Metabolism and nutrition disorders
decreased appetite	6/112 (5.4%)	9	0/58 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia	31/112 (27.7%)	45	0/58 (0%)	0
back pain	15/112 (13.4%)	17	2/58 (3.4%)	3
myalgia	19/112 (17%)	21	0/58 (0%)	0
Nervous system disorders
dizziness	11/112 (9.8%)	18	0/58 (0%)	0
headache	40/112 (35.7%)	48	0/58 (0%)	0
Psychiatric disorders
insomnia	9/112 (8%)	10	0/58 (0%)	0
Reproductive system and breast disorders
erectile dysfunction	6/112 (5.4%)	6	0/58 (0%)	0
Respiratory, thoracic and mediastinal disorders
cough	9/112 (8%)	10	2/58 (3.4%)	2
oropharyngeal pain	7/112 (6.3%)	8	0/58 (0%)	0
Skin and subcutaneous tissue disorders
alopecia	17/112 (15.2%)	17	0/58 (0%)	0
dry skin	7/112 (6.3%)	7	0/58 (0%)	0
pruritus	15/112 (13.4%)	17	0/58 (0%)	0
rash	8/112 (7.1%)	10	0/58 (0%)	0

Limitations/Caveats

[Not Specified]

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.