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Clinical Trial Results:
A multicentre randomized controlled trial evaluating the rate of sustained remission and the safety when stopping nucleos(t)ide analogue treatment in non-cirrhotic HBeAg-negative chronic Hepatitis B patients with long-term virologic response

Summary
EudraCT number	2013-004882-15
Trial protocol	DE
Global end of trial date	26 Jan 2022

Results information
Results version number	v1(current)
This version publication date	20 Apr 2023
First version publication date	20 Apr 2023
Other versions
Summary report(s)	Ergebnisbericht

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

STOP-NUC

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Deutsches Register für Klinische Studien: DRKS00006240

Sponsor organisation name

Leipzig University

Sponsor organisation address

Ritterstr. 26, Leipzig, Germany,

Public contact

Florian van Bömmel, authorized representative of the sponsor, 49 34197 12200, Florian.vanBoemmel@medizin.uni-leipzig.de

Scientific contact

Florian van Bömmel, authorized representative of the sponsor, 49 34197 12200, Florian.vanBoemmel@medizin.uni-leipzig.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

17 Jan 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Jan 2022

Global end of trial reached?

Yes

Global end of trial date

26 Jan 2022

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the STOP-NUC trial is to assess the potential of treatment cessation of nucleos(t)ide analogue treatment to induce complete and definitive remission in patients showing complete treatment response for at least 4 years. According to the EASL Clinical Practice Guidelines, sustained HBsAg loss will be used as marker for complete remission. We hypothesize that after treatment discontinuation, the rate of complete remissions will be significantly higher than under continued nucleos(t)ide analogue treatment.

Protection of trial subjects

not applicable

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Nov 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 166

Worldwide total number of subjects

166

EEA total number of subjects

166

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

150

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

From 2014-11-18 to 2018-01-11 a total of 201 patients were registered to the trial, from which 166 were randomised. The first patient was randomised on 2014-11-27, the last patient on 2018-02-01

Screening details

From 2014-11-18 to 2018-01-11 a total of 201 patients were registered to the trial, from which 166 were randomised.

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Stop NUC therapy

Arm description

Arm type

experimental

Investigational medicinal product name

No investigational medicinal product assigned in this arm

NUC therapy

Arm description

Arm type

Active comparator

Investigational medicinal product name

Lamivudine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

100 mg per day

Investigational medicinal product name

Adefovir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg per day

Investigational medicinal product name

Telbivudine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

600 mg per day

Investigational medicinal product name

Entecavir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg per day

Investigational medicinal product name

Tenofovir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

245 mg per day

Number of subjects in period 1	Stop NUC therapy	NUC therapy
Started	83	83
Completed	79	79
Not completed	4	4
Consent withdrawn by subject	3	4
medical personnel	1	-

Baseline characteristics

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Reporting group title

Stop NUC therapy

Reporting group description

Reporting group title

NUC therapy

Reporting group description

Reporting group values	Stop NUC therapy	NUC therapy	Total
Number of subjects	83	83	166
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	51.6 ( 8.4 )	52.0 ( 10.2 )	-
Gender categorical
Units: Subjects
Female	31	29	60
Male	52	54	106

End points

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Reporting group title

Stop NUC therapy

Reporting group description

Reporting group title

NUC therapy

Reporting group description

Primary: sustained HBsAg loss up to week 96

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End point title

sustained HBsAg loss up to week 96

End point description

HBsAg will be quantified in a central laboratory at every scheduled visit until week 96. HBsAg loss is defined as not detectable HBsAg in all subsequent assessments after HBsAg became undetectable for the first time. If at week 96, HBsAg is for the first time not detectable, a further measurement will be performed at week 108 in order to confirm the HBsAg loss.

End point type

Primary

End point timeframe

96 weeks

End point values	Stop NUC therapy	NUC therapy
Number of subjects analysed	79 ^[1]	79 ^[2]
Units: number	8	0

Notes
[1] - 4 drop-outs directly after randomisation are excluded
[2] - 4 drop-outs directly after randomisation are excluded

HBsAg loss primary analysis

Statistical analysis description

Fisher’s exact test will be used to compare the two treatment groups with respect to the primary endpoint. Wilson’s score interval method will be used to provide 95% confidence intervals for the efficacy rates and their difference. Primary analysis will be based on the intent to treat principle (ITT).

Comparison groups

Stop NUC therapy v NUC therapy

Number of subjects included in analysis

158

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.006

Method

Fisher exact

Parameter type

rate difference

Point estimate

10.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.2

upper limit

Adverse events

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Timeframe for reporting adverse events

96 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Stop NUC therapy

Reporting group description

Reporting group title

Continue NUC therapy

Reporting group description

Serious adverse events	Stop NUC therapy	Continue NUC therapy
Total subjects affected by serious adverse events
subjects affected / exposed	11 / 79 (13.92%)	3 / 79 (3.80%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Schwannoma
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Joint injury
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney rupture
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Stent placement
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Inflammation
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Enteritis
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 79 (0.00%)	1 / 79 (1.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Panic attack
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Influenza
subjects affected / exposed	1 / 79 (1.27%)	0 / 79 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Stop NUC therapy	Continue NUC therapy
Total subjects affected by non serious adverse events
subjects affected / exposed	54 / 79 (68.35%)	48 / 79 (60.76%)
Nervous system disorders
Headache
subjects affected / exposed	9 / 79 (11.39%)	9 / 79 (11.39%)
occurrences all number	10	11
General disorders and administration site conditions
Fatigue
subjects affected / exposed	6 / 79 (7.59%)	4 / 79 (5.06%)
occurrences all number	7	4
Influenza like illness
subjects affected / exposed	3 / 79 (3.80%)	9 / 79 (11.39%)
occurrences all number	6	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 79 (8.86%)	3 / 79 (3.80%)
occurrences all number	9	4
Back pain
subjects affected / exposed	5 / 79 (6.33%)	8 / 79 (10.13%)
occurrences all number	5	8
Infections and infestations
Nasopharyngitis
subjects affected / exposed	24 / 79 (30.38%)	15 / 79 (18.99%)
occurrences all number	29	19

More information

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Were there any global substantial amendments to the protocol? Yes

19 Mar 2015

Relevant changes at trial protocol with amendment01: Changes in different Inclusion criteria

23 Mar 2015

with amendment02: Change in one exclusion criterion

23 Mar 2020

with amendment03: Additional objectives of the prolonged observation period Further long-term endpoints Duration of Trial: prolonged observation period

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A multicentre randomized controlled trial evaluating the rate of sustained remission and the safety when stopping nucleos(t)ide analogue treatment in non-cirrhotic HBeAg-negative chronic Hepatitis B patients with long-term virologic response

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: sustained HBsAg loss up to week 96

Primary: sustained HBsAg loss up to week 96

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A multicentre randomized controlled trial evaluating the rate of sustained remission and the safety when stopping nucleos(t)ide analogue treatment in non-cirrhotic HBeAg-negative chronic Hepatitis B patients with long-term virologic response

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: sustained HBsAg loss up to week 96

Primary: sustained HBsAg loss up to week 96

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicentre randomized controlled trial evaluating the rate of sustained remission and the safety when stopping nucleos(t)ide analogue treatment in non-cirrhotic HBeAg-negative chronic Hepatitis B patients with long-term virologic response