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Clinical Trial Results:
Direct acting antiviral therapy of hepatitis C in Denmark: treatment response, adverse events and resistance associated variants

Summary
EudraCT number	2015-001956-31
Trial protocol	DK
Global end of trial date	01 Jun 2018

Results information
Results version number	v1(current)
This version publication date	09 Nov 2019
First version publication date	09 Nov 2019
Other versions
Summary report(s)	Published article

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

2015-001956-31

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre.

Sponsor organisation address

Kettegaard Alle´30, Hvidovre, Denmark, 2650

Public contact

Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre., 0045 38623514, ninaweis@dadlnet.dk

Scientific contact

Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre., 0045 38623514, ninaweis@dadlnet.dk

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

01 Mar 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Dec 2017

Global end of trial reached?

Yes

Global end of trial date

01 Jun 2018

Was the trial ended prematurely?

Main objective of the trial

To study the rate of adverse events and sustanied viral response in a randomized study of patients with chronic hepatitis C, genotype 1 patients, treated for 12 weeks with Viekira PAK® and ribavirin versus Harvoni® and ribavirin. Compare the adverse events- and sustanied viral response rates between the two groups of patients in each treatment arm in relation to demographic, biological and genetic factors.

Protection of trial subjects

Close monitoring during treatment to address any adverse events. Reduction of ribavirin if patient experienced severe anemia. To reduce distress during blood sampling were ultra sound used if the patient had experienced difficulties during previous blood sampling.

Background therapy

None.

Evidence for comparator

Clinical trials with direct acting antivirals (DAA) have shown improved cure rates ≥90% with good tolerability, including difficult to treat patient groups (liver cirrhosis and liver transplantation and previous treatment failure) However, this rapid development has led to few systematic comparisons of different DAA regimens, usually evaluated in cohorts of patients randomized with respect to dosage, addition of ribavirin or treatment duration. This design provides limited information about the rate of adverse events across different DAA regimens. Minimizing adverse events is crucial in relation to adherence to treatment and prevention of prematurely treatment termination due to poor tolerability. The chosen DAA drugs in the study were the DAAs available and approved at the time of initiation of the study.

Actual start date of recruitment

01 Jul 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Denmark: 72

Worldwide total number of subjects

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients were screened from July 1st 2015 to 1st of April 2017 at six screening sites (departments of infectious diseases and department of hepatology) which covered 4 out of 5 regions in Denmark.

Screening details

Eligible patients were 18-70 years and registered with chronic hepatitis C, genotype 1 in the Danish Database for Hepatitis B and C . The patients had to fulfil inclusion criteria defined as: liver biopsy (Metavir score ≥F2), liver stiffness measurement ≥10 kPa, clinical cirrhosis or extra-hepatic manifestations of importance to treat.

Period 1 title

overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

The study was conducted as non-blinded with randomization lists produced electronically in blocks of 4.

Are arms mutually exclusive

Yes

Arm 1, genotype 1.

Arm description

Sofosbuvir/ledipasvir/ribavirin

Arm type

Active comparator

Investigational medicinal product name

Harvoni

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1 tablet ledipasvir 90 mg/sofosbuvir 400 mg and tablets ribavirin (according to weight) in the morning. Tablets ribavirin (according to weight) in the evening.

Investigational medicinal product name

Rebetol

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

800-1200 mg depending on weight. Half dose is taken in the morning and half dose is taken in the evening.

Arm 2, genotype 1

Arm description

Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

Arm type

Active comparator

Investigational medicinal product name

viekira PAK

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 tablets of paritaprevir/ombitasvir/ritonavir and 1 tablet of dasabuvir and tablet ribavirin (according to weight) in the morning with food. 1 tablet of dasabuvir tablet ribavirin (according to weight) in the evening with food.

Investigational medicinal product name

Rebetol

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

800 - 1400 mg depending on weight. Half dose in the morning and half dose in the evening.

Number of subjects in period 1	Arm 1, genotype 1.	Arm 2, genotype 1
Started	34	38
Completed	32	37
Not completed	2	1
Adverse event, serious fatal	-	1
Adverse event, non-fatal	1	-
Lost to follow-up	1	-

Baseline characteristics

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Reporting group title

Arm 1, genotype 1.

Reporting group description

Sofosbuvir/ledipasvir/ribavirin

Reporting group title

Arm 2, genotype 1

Reporting group description

Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

Reporting group values	Arm 1, genotype 1.	Arm 2, genotype 1	Total
Number of subjects	34	38	72
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	31	35	66
From 65-84 years	3	3	6
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (full range (min-max))	54 (41 to 66)	51 (27 to 68)	-
Gender categorical
Units: Subjects
Female	10	9	19
Male	24	29	53
Hepatitis C virus subtype
Units: Subjects
1b	9	10	19
1a	25	27	52
unknown	0	1	1
Ethnicity
Units: Subjects
Caucasian	33	37	70
Non-Caucasian	1	1	2
Route of infection
Units: Subjects
Intravenous drug use	20	25	45
Non-intravenous drug use	7	10	17
Unknown	7	3	10
Liver fibrosis
Units: Subjects
Cirrhosis F4, >17 kPa, clinical diagnosed	13	13	26
Severe fibrosis F3/12-16.9 kPa	10	4	14
Mild-moderate fibrosis F1-F2/<11.9 kPa	11	21	32
HIV status
Units: Subjects
Negative	29	31	60
Positive	5	7	12
Hepatitis B status
Units: Subjects
Negative	34	38	72
Previous treatment
Units: Subjects
No	27	31	58
Yes	7	7	14
Previous response to treatment
Units: Subjects
Non-response	1	1	2
Relapse	3	3	6
Viral breakthrough	1	0	1
Termination due to adverse event	2	3	5
No previous treatment	27	31	58
Fatigue at baseline
The intensity of fatigue was recorded according to the common terminology criteria for adverse events (CTCAE)
Units: Subjects
Grade 1	11	5	16
Grade 2	0	2	2
None	23	31	54
Body-mass index
Units: numbers
arithmetic mean (standard deviation)	25.7 ± 3.16	25.6 ± 4.27	-
HCV RNA level
Units: IU/ml
log mean (standard deviation)	2.77 ± 3.39	2.35 ± 2.75	-
Alanine transaminase
Units: U/L
median (inter-quartile range (Q1-Q3))	74 (49 to 124)	86.5 (49 to 137)	-
Platelet count
x 10^9/liter
Units: x 10^9/liter
median (inter-quartile range (Q1-Q3))	187.5 (126 to 227)	206 (161 to 237)	-
serum albumin
Units: g/liter
median (inter-quartile range (Q1-Q3))	39 (37 to 41)	39 (36 to 42)	-

End points

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Reporting group title

Arm 1, genotype 1.

Reporting group description

Sofosbuvir/ledipasvir/ribavirin

Reporting group title

Arm 2, genotype 1

Reporting group description

Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

Primary: Adverse events

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End point title

Adverse events

End point description

End point type

Primary

End point timeframe

1 July 2015 - 1 December 2018

End point values	Arm 1, genotype 1.	Arm 2, genotype 1
Number of subjects analysed	34	38
Units: number of persons
Experienced Adverse events	33	37

Attachments

Statistic analysis

Adverse events overall

Comparison groups

Arm 2, genotype 1 v Arm 1, genotype 1.

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

≤ 0.05

Method

Fisher exact

Confidence interval

Notes
[1] - A sample size of 50 patients per group with 80% power using 2-sample test for proportions with a 2.sided significance level of 0.05 and the treatment-arm with Viekira PAk/ribavirin set to 30% would detect a difference of 22% giving a proportion of 8% in the other treatment arm. Fisher's exact Test was used.

Changes in laboratory results and liver stiffness

Statistical analysis description

The Wilcoxon signed-rank and rank-sum tests were applied to estimate changes in laboratory results and liver stiffness measurement from baseline to the end of treatment for all patients and the comparison of treatment groups, respectively.

Comparison groups

Arm 2, genotype 1 v Arm 1, genotype 1.

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (net)

Confidence interval

Secondary: Proportion of patients with sustanied virologic response after end of treatment

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End point title

Proportion of patients with sustanied virologic response after end of treatment

End point description

Hepatitis C virus RNA level measured in a blood sample

End point type

Secondary

End point timeframe

1 January 2016 - 1 August 2017.

End point values	Arm 1, genotype 1.	Arm 2, genotype 1
Number of subjects analysed	34	38
Units: numbers
Sustanied viral response	33	37

Attachments

Flowchart Genotype 1

Sustanied viral response

Comparison groups

Arm 2, genotype 1 v Arm 1, genotype 1.

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Fisher exact

Confidence interval

Adverse events

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Timeframe for reporting adverse events

1 July 2015 - 1 December 2018. Adverse events were recorded at baseline and for all patients at weeks 1, 2, 3, 4, 8 and 12 of the study period, and in the post-treatment period at weeks 4, 12 and 24.

Adverse event reporting additional description

For all adverse events, start- and end date, intensity (mild, moderate or severe), severity (is recovering, has recovered, recovered with sequelae, still affected), relation to study drug and action taken with study drug was recorded. The severity of adverse events and their relationship to treatment were assessed by the investigator.

Assessment type

Systematic

Dictionary name

CTCAE

Dictionary version

4.0

Reporting group title

Arm 1, genotype 1.

Reporting group description

Sofosbuvir/ledipasvir/ribavirin

Reporting group title

Arm 2, genotype 1

Reporting group description

Paritaprevir/dasabuvir/ombitasvir/ritonavir and ribavirin

Serious adverse events	Arm 1, genotype 1.	Arm 2, genotype 1
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 34 (17.65%)	3 / 38 (7.89%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	1
Cardiac disorders
Chest pain
Additional description: Occurred during treatment
subjects affected / exposed	1 / 34 (2.94%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Weakened general condition
Additional description: Did not occur during treatment.
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
gastro-intestinal bleeding
Additional description: Did not occur during treatment
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Severe stomach pain
Additional description: Occurred during treatment
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
Additional description: Occurred during treatment
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
decompensated liver cirrhosis with ascites
Additional description: Occurred during treatment
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver failure
Additional description: Suspected Unexpected serious Adverse Reaction (SUSAR).
subjects affected / exposed	0 / 34 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Shotness of breath
Additional description: Occurred during treatment
subjects affected / exposed	0 / 34 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foreign object in throat
Additional description: Occurred during treatment
subjects affected / exposed	0 / 34 (0.00%)	1 / 38 (2.63%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back- and hip pain
Additional description: Did not occur during treatment.
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
Additional description: Did not occur during treatment
subjects affected / exposed	1 / 34 (2.94%)	0 / 38 (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: 1%

Non-serious adverse events	Arm 1, genotype 1.	Arm 2, genotype 1
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 34 (97.06%)	37 / 38 (97.37%)
Cardiac disorders
Chest pain
subjects affected / exposed	1 / 34 (2.94%)	1 / 38 (2.63%)
occurrences all number	1	1
Nervous system disorders
Headache
subjects affected / exposed	14 / 34 (41.18%)	19 / 38 (50.00%)
occurrences all number	14	19
Insomnia
subjects affected / exposed	8 / 34 (23.53%)	9 / 38 (23.68%)
occurrences all number	8	9
Dizziness
subjects affected / exposed	3 / 34 (8.82%)	5 / 38 (13.16%)
occurrences all number	3	5
Memory impairment/absent minded
subjects affected / exposed	3 / 34 (8.82%)	1 / 38 (2.63%)
occurrences all number	3	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	27 / 34 (79.41%)	29 / 38 (76.32%)
occurrences all number	27	29
General disorders and administration site conditions
Fatigue
subjects affected / exposed	26 / 34 (76.47%)	27 / 38 (71.05%)
occurrences all number	26	27
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 34 (0.00%)	3 / 38 (7.89%)
occurrences all number	0	3
Eye disorders
Affected vision
subjects affected / exposed	1 / 34 (2.94%)	3 / 38 (7.89%)
occurrences all number	1	3
Gastrointestinal disorders
Heartburn/abdominal pain/abdominal distention
subjects affected / exposed	11 / 34 (32.35%)	16 / 38 (42.11%)
occurrences all number	11	16
Nausea/vomiting
subjects affected / exposed	11 / 34 (32.35%)	14 / 38 (36.84%)
occurrences all number	11	14
Decreased appetite
subjects affected / exposed	4 / 34 (11.76%)	11 / 38 (28.95%)
occurrences all number	4	11
Diarrhoea
subjects affected / exposed	6 / 34 (17.65%)	8 / 38 (21.05%)
occurrences all number	6	8
Increased appetite
subjects affected / exposed	3 / 34 (8.82%)	1 / 38 (2.63%)
occurrences all number	3	1
Constipation
subjects affected / exposed	1 / 34 (2.94%)	2 / 38 (5.26%)
occurrences all number	1	2
Respiratory, thoracic and mediastinal disorders
Dyspnea
subjects affected / exposed	10 / 34 (29.41%)	11 / 38 (28.95%)
occurrences all number	10	11
Skin and subcutaneous tissue disorders
Pruritus, dry skin or eczema
subjects affected / exposed	13 / 34 (38.24%)	20 / 38 (52.63%)
occurrences all number	13	20
Psychiatric disorders
Irritability/mood swings/depression
subjects affected / exposed	12 / 34 (35.29%)	8 / 38 (21.05%)
occurrences all number	12	8
Musculoskeletal and connective tissue disorders
Asthenia/malaise/tremor
subjects affected / exposed	9 / 34 (26.47%)	13 / 38 (34.21%)
occurrences all number	9	13
Arthralgia
subjects affected / exposed	4 / 34 (11.76%)	3 / 38 (7.89%)
occurrences all number	4	3
muscle spams
subjects affected / exposed	2 / 34 (5.88%)	3 / 38 (7.89%)
occurrences all number	2	3
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	11 / 34 (32.35%)	13 / 38 (34.21%)
occurrences all number	11	13
Herpes outbreak
subjects affected / exposed	1 / 34 (2.94%)	2 / 38 (5.26%)
occurrences all number	1	2
Fungal infection
subjects affected / exposed	0 / 34 (0.00%)	2 / 38 (5.26%)
occurrences all number	0	2

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.

The treatment-arm, enrolling patients with genotype 3 , was prematurely terminated because national treatment guidelines for genotype 3 patients were altered after approval of Epclusa (velpatasvir/sofosbuvir) in Europe.

http://www.ncbi.nlm.nih.gov/pubmed/29994874

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Clinical trials

Clinical Trial Results:
Direct acting antiviral therapy of hepatitis C in Denmark: treatment response, adverse events and resistance associated variants

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Adverse events

Primary: Adverse events

Secondary: Proportion of patients with sustanied virologic response after end of treatment

Secondary: Proportion of patients with sustanied virologic response after end of treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: Direct acting antiviral therapy of hepatitis C in Denmark: treatment response, adverse events and resistance associated variants

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Adverse events

Primary: Adverse events

Secondary: Proportion of patients with sustanied virologic response after end of treatment

Secondary: Proportion of patients with sustanied virologic response after end of treatment

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Direct acting antiviral therapy of hepatitis C in Denmark: treatment response, adverse events and resistance associated variants