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Clinical Trial Results:
Comparison of effectiveness of hepatitis B revaccination schemes in healthy non-responders

Summary
EudraCT number	2011-005627-40
Trial protocol	NL
Global end of trial date	31 Jan 2018

Results information
Results version number	v1(current)
This version publication date	16 Jun 2023
First version publication date	16 Jun 2023
Other versions

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

P12.130

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Nederlands Trial register: NL3011

Sponsor organisation name

LUMC

Sponsor organisation address

Albinusdreef 2, Leiden, Netherlands, 2333 ZA Leiden

Public contact

Department of infectious diseases, LUMC, Department of infectious diseases, LUMC, 0031 71 526 91 11, research@lumc.nl

Scientific contact

Department of infectious diseases, LUMC, Department of infectious diseases, LUMC, 0031 715262613, research@lumc.nl

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

02 Apr 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

31 Jan 2018

Global end of trial reached?

Yes

Global end of trial date

31 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

Study the efficacy of mounting a protective immunological response against hepatitis B infection in previous hepatitis B vaccine non-responders. In this trial 4 different Hepatitis B vaccines are investigated.

Protection of trial subjects

Ethics Committee Opinion of the trial application was favourable. Active safety follow up for 7 days post vaccination and passively for 30 days for any events post vaccination.

Background therapy

Non-protective immunity after a hepatitis B vaccination series occurs in 5–30% of healthy adults, depending on age, and it has major implications for individuals at high risk of hepatitis B. We searched PubMed using the following keywords in different combinations: “vaccination”, “vaccine”, “recombinant vaccine”, “hepatitis b virus”, “HBV”, “hepatitis B infection”, “nonresponders”, “non-responders” and “non responders” for clinical trials comparing immunogenicity for hepatitis B vaccines in healthy non-responding adults between Jan 1, 1986, and May 1, 2018. We updated the search between May 1, 2018, and Oct 1, 2019; we can confirm that with these search items no similar study has been published in the past year. Previous clinical trials compared different administration routes, vaccines with different antigen doses or additional adjuvants, and additional doses given to non-responders after hepatitis B vaccination. However, these studies show great diversity; they had design limitations, and in general they had a small sample sizes that limited the evidence-based rationale for recommendations in guidelines regarding healthy non-responders

Evidence for comparator

The exact immunological mechanisms of non-response have not yet been elucidated. Guidelines recommend revaccinating non-responders with additional vaccine doses. Dutch guidelines recommend three revaccinations of a standard vaccine administered at months 0, 1, and 2, which induces a seroconversion rate of 50–70%. In a proof-of-principle trial, increasing the cumulative antigen dose achieved by increasing the number of administered doses of a standard vaccine, all the participants eventually reached antibody concentrations greater than 10 IU/L.11 Additional strategies to increase the immune response in healthy non-responders are vaccination with higher doses of HBsAg, combining HBsAg with other antigens, and use of more potent adjuvants or alternative routes of administration. A meta-analysis comparing revaccination regimens by dosage and route of administration suggests a higher seroconversion rate after the first additional dose, regardless of the revaccination regimen chosen. This growing body of evidence strengthens the expectations that alternative vaccine schedules will overcome non-responsiveness. However, these trials generally had small sample sizes, deviating vaccine dosages or vaccination intervals or retrospective study designs, or both, and did not all report on antibody titres in non-responders. This is important as the nearly complete absence of an anti-HBs titre is associated with lower seroconversion rates after revaccination than an anti-HBs titre above the cutoff limit of detection. In some studies, the interval between final vaccine dose and anti-HBs testing was more than 6 months or unknown, the number of previous vaccinations was variable, or a vaccine had been used that was withdrawn from the market.5,18,19 We have done the current trial to overcome these limitations.

Actual start date of recruitment

01 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 480

Worldwide total number of subjects

480

EEA total number of subjects

480

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)

454

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The participants were recruited between Nov 1, 2012, and Sept 1, 2017. Healthy adults (aged 18–80 years) from 16 Dutch centres (13 public health services, two university hospitals, and one travel clinic) were included in this multicentre, parallel group, randomised, controlled, superiority trial. The inclusion criterion was HBV vaccine non-response

Screening details

Non-response was defined as an anti-HBs titre of less than 10 IU/L, measured in serum 4 weeks to 3 months after last vaccination and assessed according to the local laboratory serology. To rule out chronic or hidden HBV infection as a cause of vaccine non-response and to exclude people with a previous HBV infection, seropositivity for HBsAg.

Number of subjects started

640 ^[1]

Number of subjects completed

480

Reason: Number of subjects

Consent withdrawn by subject: 160

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The participants were only screened for being eligible to participate in this study. We do not consider them as part of the included participants.

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind ^[2]

Roles blinded

Investigator, Data analyst, Assessor ^[3]

Blinding implementation details

After the participant's informed consent was obtained, a staff-member of that centre uploaded a limited patient-specific dataset in the randomisation programme that enabled the allocation to one of the vaccine groups. Participants and staff of the participating centres were unmasked to assignment after randomisation. The central laboratory staff (LUMC) who analysed the samples were masked to vaccine-group assignment. Investigators were masked to assignment for analysing data and assessing outcom

Are arms mutually exclusive

Yes

Control

Arm description

Participants were individually randomly assigned in this open-label trial with an allocation ratio of 1:1:1:1 to one of the following groups: repeating initial series for the control group (HBVaxPro 10 μg or Engerix-B 20 μg),

Arm type

Active comparator

Investigational medicinal product name

Engerix / HBVaxPro-10

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

HBVaxPro 10 μg or Engerix-B 20 μg

Twinrix

Arm description

Participants were individually randomly assigned in this open-label trial with an allocation ratio of 1:1:1:1 to one of the following groups: a combined vaccine against hepatitis A and hepatitis B (Twinrix 20 μg)

Arm type

Experimental

Investigational medicinal product name

Twinrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Twinrix 20 μg

HBVaxPRO40

Arm description

Participants were individually randomly assigned in this open-label trial with an allocation ratio of 1:1:1:1 to one of the following groups: or a vaccine with a higher antigen dose (HBVaxPro 40 μg).

Arm type

Experimental

Investigational medicinal product name

HBVaxPro 40

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

HBVaxPro 40 μg

Fendrix

Arm description

Participants were individually randomly assigned in this open-label trial with an allocation ratio of 1:1:1:1 to one of the following groups: r a vaccine with an AS04 adjuvant containing 3ʹ-deacylated monophosphoryl lipid A and aluminium salt (Fendrix 20 μg

Arm type

Experimental

Investigational medicinal product name

Fendrix

Investigational medicinal product code

Other name

Pharmaceutical forms

Suspension for injection

Routes of administration

Intramuscular use

Dosage and administration details

Fendrix 20 μg

Notes
[2] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial.
Justification: After the participant's informed consent was obtained, a staff-member of that centre uploaded a limited patient-specific dataset in the randomisation programme that enabled the allocation to one of the vaccine groups. Participants and staff of the participating centres were unmasked to assignment after randomisation. The central laboratory staff (LUMC) who analysed the samples were masked to vaccine-group assignment. Investigators were masked to assignment for analysing data and assessing outcom
[3] - The roles blinded appear inconsistent with a simple blinded trial.
Justification: After the participant's informed consent was obtained, a staff-member of that centre uploaded a limited patient-specific dataset in the randomisation programme that enabled the allocation to one of the vaccine groups. Participants and staff of the participating centres were unmasked to assignment after randomisation. The central laboratory staff (LUMC) who analysed the samples were masked to vaccine-group assignment. Investigators were masked to assignment for analysing data and assessing outcom

Number of subjects in period 1	Control	Twinrix	HBVaxPRO40	Fendrix
Started	124	118	114	124
Completed	117	114	109	119
Not completed	7	4	5	5
Consent withdrawn by subject	5	3	5	2
inclusion criteria not met	2	-	-	3
Protocol deviation	-	1	-	-

Baseline characteristics

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Reporting group title

Control

Reporting group description

Reporting group title

Twinrix

Reporting group description

Reporting group title

HBVaxPRO40

Reporting group description

Reporting group title

Fendrix

Reporting group description

Reporting group values	Control	Twinrix	HBVaxPRO40	Fendrix	Total
Number of subjects	124	118	114	124	480
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
Age in years at the start of the trial inclusion.
Units: years
arithmetic mean (standard deviation)	45.3 ± 14.4	44.8 ± 14.2	46.1 ± 15.9	45.6 ± 13.3	-
Gender categorical
Gender categories.
Units: Subjects
Female	48	62	43	59	212
Male	76	56	71	65	268
anti-HBs < 1 IU/l
anti-HBs < 1 IU/l in the baseline sample (T=0)
Units: Subjects
anti-HBs < 1IU/l	54	53	50	62	219
anti-HBs 1 or >1 IU/l	70	65	64	62	261
active smoking
active smoking was defined of smoking at least 5 or more cigarettes a day.
Units: Subjects
active smoking	31	40	31	30	132
non smoking	82	71	74	88	315
not recorded	11	7	9	6	33
Diabetes +
Self reported diabetes type 1 and 2
Units: Subjects
diabetes	5	7	7	8	27
no diabetes	113	105	99	113	430
not recorded	6	6	8	3	23

Subject analysis set title

primary analysis

Subject analysis set type

Intention-to-treat

Subject analysis set description

The primary analysis of this superiority trial was an intention-to-treat analysis with the last observation carried forward (LOCF) for participants with any missing anti-HBs titre measurements.

Subject analysis sets values	primary analysis
Number of subjects	480
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Age in years at the start of the trial inclusion.
Units: years
arithmetic mean (standard deviation)	45.3 ± 14.4
Gender categorical
Gender categories.
Units: Subjects
Female	212
Male	268
anti-HBs < 1 IU/l
anti-HBs < 1 IU/l in the baseline sample (T=0)
Units: Subjects
anti-HBs < 1IU/l	219
anti-HBs 1 or >1 IU/l	261
active smoking
active smoking was defined of smoking at least 5 or more cigarettes a day.
Units: Subjects
active smoking	132
non smoking	315
not recorded	33
Diabetes +
Self reported diabetes type 1 and 2
Units: Subjects
diabetes	27
no diabetes	430
not recorded	23

End points

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Reporting group title

Control

Reporting group description

Reporting group title

Twinrix

Reporting group description

Reporting group title

HBVaxPRO40

Reporting group description

Reporting group title

Fendrix

Reporting group description

Subject analysis set title

primary analysis

Subject analysis set type

Intention-to-treat

Subject analysis set description

The primary analysis of this superiority trial was an intention-to-treat analysis with the last observation carried forward (LOCF) for participants with any missing anti-HBs titre measurements.

Primary: percentage responders

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End point title

percentage responders

End point description

As an anti-HBs titre of 10 IU/L or more is a correlate of protection against clinically relevant hepatitis B infections, our primary endpoint was the proportion of responders with an anti-HBs titre of 10 IU/L or more, 4 weeks to 3 months after completion of the revaccination series given at months 0, 1, and 2.

End point type

Primary

End point timeframe

Between 1 Nov 2012, and 1 Sept 2017

End point values	Control	Twinrix	HBVaxPRO40	Fendrix	primary analysis
Number of subjects analysed	124	118	114	124	480
Units: numbers
percentage responders	83	94	95	108	380

Attachments

reverse cumulative distribution curve

difference proportion

Statistical analysis description

The proportion of responders (antiHBs ≥10 IU/L) in each vaccination group was calculated. The outcome variable (anti-HBs titre) was transformed to a log 10 variable to compute the geometric mean titre. Its sample mean per study group was back-transformed to express the geometric mean titre and 95% CI in terms of anti-HBs titres, which, at least in an approximate sense, refer to the median anti-HBs titres.

Comparison groups

Control v Twinrix v primary analysis

Number of subjects included in analysis

722

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

difference proportion

Comparison groups

Control v HBVaxPRO40

Number of subjects included in analysis

238

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

10.4

upper limit

32.7

difference proportion

Comparison groups

Control v Fendrix v primary analysis

Number of subjects included in analysis

728

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Mantel-Haenszel

Parameter type

Mean difference (final values)

Point estimate

26.3

Confidence interval

level

95%

sides

2-sided

lower limit

15.4

upper limit

37.3

Primary: Difference proportion of responders

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End point title

Difference proportion of responders ^[1]

End point description

We used the permutation version of the test based on the so-called sum statistic to compare differences between vaccine groups regarding the proportion of responders and geometric mean titres. The sum statistic is equivalent to the Mantel–Haenszel test for a binary—our primary—outcome; it can be seen as a generalisation of Fisher’s exact test for the situation in which the various pairs of samples come from different strata or blocks (the centres in our case) In the case of a continuous outcome (our secondary outcome), the sum statistic is the sum of the within-stratum differences between average responses in the two vaccine groups being compared. To estimate the p values we have used 1 million permutations. The Bonferroni method was used to correct for multiple testing separately for the two endpoints; in each case, the probability of at least one type 1 error among a set of three tests was kept at 0·05.

End point type

Primary

End point timeframe

Between 1 Nov 2012, and 1 Sept 2017

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: As the end point is a difference in proportion between the control group and one of the other arms the control group has been taken into account in this end point.

End point values	Twinrix	HBVaxPRO40	Fendrix
Number of subjects analysed	118	114	124
Units: percentage protection
number (confidence interval 95%)
difference in proportion responders	25 (13 to 37)	22 (10 to 33)	26 (15 to 37)

difference proportion 1

Comparison groups

Twinrix v HBVaxPRO40 v Fendrix

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05 ^[2]

Method

Fisher exact

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[2] - The Bonferroni method was used to correct for multiple testing separately for the two endpoints; in each case, the probability of at least one type 1 error among a set of three tests was kept at 0·05.

Adverse events

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Timeframe for reporting adverse events

7 days after vaccination, 30 days for SAE The participants classified the severity of the local and general reactions on a four-point scale (absent–mild–moderate–severe).

Assessment type

Systematic

Dictionary name

self defined

Dictionary version

Reporting group title

dose 1 all arms

Reporting group description

Reporting group title

dose 2 all arms

Reporting group description

Reporting group title

dose 3 all arms

Reporting group description

Serious adverse events	dose 1 all arms	dose 2 all arms	dose 3 all arms
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 480 (0.00%)	1 / 480 (0.21%)	0 / 480 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Infections and infestations
SAE
Additional description: herpes zoster ophtalmicus
subjects affected / exposed	0 / 480 (0.00%)	1 / 480 (0.21%)	0 / 480 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	dose 1 all arms	dose 2 all arms	dose 3 all arms
Total subjects affected by non serious adverse events
subjects affected / exposed	222 / 480 (46.25%)	174 / 480 (36.25%)	145 / 480 (30.21%)
Investigations
General symptom
Additional description: The diary card consisted of three items regarding a local reaction after vaccination (pain, erythema, and oedema), two items for systemic reactions (fever and myalgia), and free text fields for other possible reactions.
subjects affected / exposed	222 / 480 (46.25%)	174 / 480 (36.25%)	145 / 480 (30.21%)
occurrences all number	222	174	145

More information

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Were there any global substantial amendments to the protocol? No

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

http://www.ncbi.nlm.nih.gov/pubmed/31629649

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Clinical Trial Results:
Comparison of effectiveness of hepatitis B revaccination schemes in healthy non-responders

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Baseline characteristics

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Primary: percentage responders

Primary: percentage responders

Primary: Difference proportion of responders

Primary: Difference proportion of responders

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Clinical Trial Results: Comparison of effectiveness of hepatitis B revaccination schemes in healthy non-responders

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: percentage responders

Primary: percentage responders

Primary: Difference proportion of responders

Primary: Difference proportion of responders

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Comparison of effectiveness of hepatitis B revaccination schemes in healthy non-responders