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Clinical Trial Results:
A Randomized, Active-Controlled, Dose-Ranging Estimation Study to Evaluate the Safety, Tolerability, and Efficacy of Different Regimens of MK-5172 When Administered Concomitantly with Peginterferon alfa-2b and Ribavirin in Treatment-Naïve Patients with Chronic Genotype 1 Hepatitis C Virus Infection

Summary
EudraCT number	2011-000759-18
Trial protocol	DE BE IT
Global end of trial date	10 Mar 2015

Results information
Results version number	v1(current)
This version publication date	26 Feb 2016
First version publication date	26 Feb 2016
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

5172-003

ISRCTN number

US NCT number

NCT01353911

WHO universal trial number (UTN)

Other trial identifiers

Merck Registration: MK-5172-003

Sponsor organisation name

Merck Sharp & Dohme Corp.

Sponsor organisation address

2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com

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

10 Mar 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

10 Mar 2015

Was the trial ended prematurely?

Main objective of the trial

This study will evaluate the safety, tolerability, and antiviral activity of grazoprevir (MK-5172) when administered in combination with peginterferon (Peg-IFN) and ribavirin (RBV) in treatment-naïve (TN) participants with chronic hepatitis C.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Jun 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 10

Country: Number of subjects enrolled

Canada: 17

Country: Number of subjects enrolled

France: 21

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Israel: 29

Country: Number of subjects enrolled

Italy: 19

Country: Number of subjects enrolled

United States: 255

Worldwide total number of subjects

368

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)

353

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

368 participants enrolled on study. 36 cirrhotic participants received open-label (OL) grazoprevir + peginterferon (Peg-IFN) + ribavirin (RBV), and 332 non-cirrhotic participants were randomized to receive 100, 200, 400, or 800 mg grazoprevir + Peg-IFN + RBV. 43 in the 400 mg group and 36 in the 800 mg group were down-dosed to 100 mg grazoprevir.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor

Are arms mutually exclusive

Yes

OL Grazoprevir 100 mg

Arm description

Treatment-naïve (TN) cirrhotic participants received open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Grazoprevir 100 mg

Arm description

TN non-cirrhotic (NC) participants received Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Grazoprevir 200 mg

Arm description

TN NC participants received Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Grazoprevir 400 mg

Arm description

TN NC participants received Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Grazoprevir 800 mg

Arm description

TN NC participants received Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Grazoprevir 400 mg/100 mg

Arm description

TN NC participants initially were randomized to receive Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy. As the result of an interim analysis, these participants were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Grazoprevir 800 mg/100 mg

Arm description

TN NC participants initially were randomized to receive Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy. As the result of an interim analysis, these participants were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Experimental

Investigational medicinal product name

Grazoprevir

Investigational medicinal product code

Other name

MK-5172

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM. Blinded or open-label depending on treatment arm.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four capsules orally three times daily.

Boceprevir 800 mg

Arm description

TN NC participants started a 4 week lead-in with Peg-IFN + RBV, then received Boceprevir 800 mg + Peg-IFN + RBV for 24 weeks followed by 0 or 20 weeks of Peg-IFN + RBV, based on response guided therapy.

Arm type

Active comparator

Investigational medicinal product name

Boceprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Four 200 mg capsules orally three times daily.

Investigational medicinal product name

Peg-interferon alfa-2b

Investigational medicinal product code

Other name

PegIntron™

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.5 μg/kg/week subcutaneous injection.

Investigational medicinal product name

Ribavirin

Investigational medicinal product code

Other name

Rebetol™

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

300 mg to 700 mg orally twice daily.

Investigational medicinal product name

Placebo for Grazoprevir

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Orally once daily in AM.

Number of subjects in period 1	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Started	36	66	68	24	29	43	36	66
Completed	28	57	59	22	23	36	30	51
Not completed	8	9	9	2	6	7	6	15
Status Not Recorded	4	-	1	-	-	-	-	-
Consent withdrawn by subject	2	3	4	2	2	3	3	9
Lost to follow-up	2	6	4	-	4	4	3	6

Baseline characteristics

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Reporting group title

OL Grazoprevir 100 mg

Reporting group description

Treatment-naïve (TN) cirrhotic participants received open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 100 mg

Reporting group description

TN non-cirrhotic (NC) participants received Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 200 mg

Reporting group description

TN NC participants received Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg

Reporting group description

TN NC participants received Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 800 mg

Reporting group description

TN NC participants received Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg/100 mg

Reporting group description

Reporting group title

Grazoprevir 800 mg/100 mg

Reporting group description

Reporting group title

Boceprevir 800 mg

Reporting group description

Reporting group values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg	Total
Number of subjects	36	66	68	24	29	43	36	66	302
Age categorical
Units: Subjects
Age Continuous \|
Units: years
arithmetic mean (standard deviation)	54.4 ( 6.9 )	46.4 ( 11.3 )	48.3 ( 10.6 )	44.6 ( 12.5 )	50.4 ( 13.4 )	48.3 ( 11.4 )	50.3 ( 11.2 )	48.3 ( 11.2 )	-
Gender, Male/Female
Units: participants
Female	14	25	32	12	15	15	13	29	155
Male	22	41	36	12	14	28	23	37	213

End points

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Reporting group title

OL Grazoprevir 100 mg

Reporting group description

Treatment-naïve (TN) cirrhotic participants received open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 100 mg

Reporting group description

TN non-cirrhotic (NC) participants received Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 200 mg

Reporting group description

TN NC participants received Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg

Reporting group description

TN NC participants received Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 800 mg

Reporting group description

TN NC participants received Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg/100 mg

Reporting group description

Reporting group title

Grazoprevir 800 mg/100 mg

Reporting group description

Reporting group title

Boceprevir 800 mg

Reporting group description

Primary: Percentage of Participants Achieving Complete Early Viral Response (cEVR)

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End point title

Percentage of Participants Achieving Complete Early Viral Response (cEVR) ^[1]

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). cEVR was defined as undetectable HCV RNA (target not detected [TND]) at Week 12. 95% confidence intervals provided based on the Clopper-Pearson method. A Missing = Failure approach was used for missing data. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Primary

End point timeframe

After 12 weeks of treatment with grazoprevir/boceprevir

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no formal efficacy hypothesis testing planned for this endpoint, and there were no between-group statistical comparisons performed.

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[2]	66 ^[3]	68 ^[4]	24 ^[5]	29 ^[6]	43 ^[7]	36 ^[8]	66 ^[9]
Units: percentage of participants
number (confidence interval 95%)	94.4 (81.3 to 99.9)	80.3 (68.7 to 89.1)	85.3 (74.6 to 92.7)	87.5 (67.6 to 97.3)	75.9 (56.5 to 89.7)	86 (72.1 to 94.7)	86.1 (70.5 to 95.3)	69.7 (57.1 to 80.4)

Notes
[2] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[3] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[4] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[5] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[6] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[7] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[8] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.
[9] - Full Analysis Set (FAS); all randomized/enrolled participants receiving ≥1 dose of study treatment.

No statistical analyses for this end point

Primary: Percentage of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days

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End point title

Percentage of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days

End point description

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR’s product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR’s product, was also an AE. Participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Primary

End point timeframe

Treatment period plus the first 14 days of follow-up (up to 50 weeks)

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[10]	66 ^[11]	68 ^[12]	24 ^[13]	29 ^[14]	43 ^[15]	36 ^[16]	66 ^[17]
Units: percentage of participants
number (not applicable)	94.4	98.5	97.1	95.8	96.6	97.7	97.2	97

Notes
[10] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[11] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[12] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[13] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[14] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[15] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[16] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.
[17] - All Participants as Treated (APaT); all randomized/enrolled receiving ≥1 dose of study treatment.

Grazoprevir 100 mg vs. Boceprevir 800 mg

Statistical analysis description

The percentage of participants with at least one AE was evaluated for each grazoprevir arm in combination with Peg-IFN and RBV relative to the control boceprevir regimen. 95% confidence intervals for between-treatment differences in the percentage of participants with events were calculated using the Miettinen and Nurminen method.

Comparison groups

Grazoprevir 100 mg v Boceprevir 800 mg

Number of subjects included in analysis

132

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5.4

upper limit

9.1

Grazoprevir 200 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 200 mg v Boceprevir 800 mg

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.5

upper limit

7.9

Grazoprevir 400 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 400 mg v Boceprevir 800 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

7.2

Grazoprevir 800 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 800 mg v Boceprevir 800 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-14.5

upper limit

7.7

Grazoprevir 400 mg/100 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 400 mg/100 mg v Boceprevir 800 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-9.4

upper limit

8.5

Grazoprevir 800 mg/100 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 800 mg/100 mg v Boceprevir 800 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-11.5

upper limit

8.1

Primary: Percentage of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days

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End point title

Percentage of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days

End point description

End point type

Primary

End point timeframe

Treatment period plus the first 14 days of follow-up (up to 50 weeks)

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[18]	66 ^[19]	68 ^[20]	24 ^[21]	29 ^[22]	43 ^[23]	36 ^[24]	66 ^[25]
Units: percentage of participants
number (not applicable)	5.6	4.5	5.9	8.3	10.3	9.3	5.6	13.6

Notes
[18] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[19] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[20] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[21] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[22] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[23] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[24] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.
[25] - APaT; all randomized/enrolled receiving ≥1 dose of study treatment.

Grazoprevir 100 mg vs. Boceprevir 800 mg

Statistical analysis description

The percentage of participants that discontinued study medication due to an AE was evaluated for each grazoprevir arm in combination with Peg-IFN and RBV relative to the control boceprevir regimen. 95% confidence intervals for between-treatment differences in the percentage of participants with events were calculated using the Miettinen and Nurminen method.

Comparison groups

Grazoprevir 100 mg v Boceprevir 800 mg

Number of subjects included in analysis

132

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-20.1

upper limit

0.9

Grazoprevir 200 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 200 mg v Boceprevir 800 mg

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-7.8

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

2.5

Grazoprevir 400 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 400 mg v Boceprevir 800 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-17.9

upper limit

13.5

Grazoprevir 800 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 800 mg v Boceprevir 800 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-16.1

upper limit

14.1

Grazoprevir 400 mg/100 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 400 mg/100 mg v Boceprevir 800 mg

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-4.3

Confidence interval

level

95%

sides

2-sided

lower limit

-16.5

upper limit

9.6

Grazoprevir 800 mg/100 mg vs. Boceprevir 800 mg

Statistical analysis description

Comparison groups

Grazoprevir 800 mg/100 mg v Boceprevir 800 mg

Number of subjects included in analysis

102

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

-8.1

Confidence interval

level

95%

sides

2-sided

lower limit

-19.6

upper limit

5.9

Secondary: Median Time to First Achievement of Undetectable HCV RNA During Treatment

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End point title

Median Time to First Achievement of Undetectable HCV RNA During Treatment

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. Kaplan Meier summary statistics were calculated for each treatment arm. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens. Participants in the FAS not achieving TND were censored.

End point type

Secondary

End point timeframe

From first dose of study medication until first achievement of undetectable HCV RNA (up to 48 weeks of treatment)

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[26]	66 ^[27]	68 ^[28]	24 ^[29]	29 ^[30]	43 ^[31]	36 ^[32]	66 ^[33]
Units: days
median (confidence interval 95%)	22 (21 to 29)	15 (15 to 18)	28 (23 to 29)	16 (14 to 29)	16.5 (14 to 28)	27 (15 to 29)	29 (15 to 29)	57 (57 to 59)

Notes
[26] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[27] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[28] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[29] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[30] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[31] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[32] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[33] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Rapid Viral Response (RVR)

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End point title

Percentage of Participants Achieving Rapid Viral Response (RVR)

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). RVR was defined as undetectable (TND) HCV RNA at Week 4 of study therapy. 95% confidence intervals provided based on the Clopper-Pearson method. A Missing = Failure approach was used for missing data. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Secondary

End point timeframe

After 4 weeks of treatment with grazoprevir/boceprevir

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[34]	66 ^[35]	68 ^[36]	24 ^[37]	29 ^[38]	43 ^[39]	36 ^[40]	66 ^[41]
Units: percentage of participants
number (confidence interval 95%)	72.2 (54.8 to 85.8)	90.9 (81.3 to 96.6)	91.2 (81.8 to 96.7)	87.5 (67.6 to 97.3)	86.2 (68.3 to 96.1)	81.4 (66.6 to 91.6)	83.3 (67.2 to 93.6)	59.1 (46.3 to 71)

Notes
[34] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[35] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[36] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[37] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[38] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[39] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[40] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[41] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)

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End point title

Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). SVR12 was defined as undetectable (TND) HCV RNA at 12 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method. A Missing = Failure approach was used for missing data. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Secondary

End point timeframe

12 weeks after the end of all treatment (up to 60 weeks)

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[42]	66 ^[43]	68 ^[44]	24 ^[45]	29 ^[46]	43 ^[47]	36 ^[48]	66 ^[49]
Units: percentage of participants
number (confidence interval 95%)	72.2 (54.8 to 85.8)	89.4 (79.4 to 95.6)	91.2 (81.8 to 96.7)	87.5 (67.6 to 97.3)	79.3 (60.3 to 92)	93 (80.9 to 98.5)	91.7 (77.5 to 98.2)	60.6 (47.8 to 72.4)

Notes
[42] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[43] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[44] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[45] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[46] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[47] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[48] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[49] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)

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End point title

Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). SVR24 was defined as undetectable (TND) HCV RNA at 24 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method. A Missing = Failure approach was used for missing data. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Secondary

End point timeframe

24 weeks after the end of all treatment (up to 72 weeks)

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[50]	66 ^[51]	68 ^[52]	24 ^[53]	29 ^[54]	43 ^[55]	36 ^[56]	66 ^[57]
Units: percentage of participants
number (confidence interval 95%)	72.2 (54.8 to 85.8)	86.4 (75.7 to 93.6)	92.6 (83.7 to 97.6)	87.5 (67.6 to 97.3)	79.3 (60.3 to 92)	93 (80.9 to 98.5)	91.7 (77.5 to 98.2)	57.6 (44.8 to 69.7)

Notes
[50] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[51] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[52] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[53] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[54] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[55] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[56] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[57] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Undetectable HCV RNA at Week 72

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End point title

Percentage of Participants Achieving Undetectable HCV RNA at Week 72

End point description

Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. 95% confidence intervals provided based on the Clopper-Pearson method. A Missing = Failure approach was used for missing data. Results for participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

End point type

Secondary

End point timeframe

Week 72

End point values	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Number of subjects analysed	36 ^[58]	66 ^[59]	68 ^[60]	24 ^[61]	29 ^[62]	43 ^[63]	36 ^[64]	66 ^[65]
Units: percentage of participants
number (confidence interval 95%)	69.4 (51.9 to 83.7)	80.3 (68.7 to 89.1)	86.8 (76.4 to 93.8)	87.5 (67.6 to 97.3)	75.9 (56.5 to 89.7)	79.1 (64 to 90)	83.3 (67.2 to 93.6)	54.5 (41.8 to 66.9)

Notes
[58] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[59] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[60] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[61] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[62] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[63] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[64] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.
[65] - FAS; all randomized/enrolled participants who received ≥1 dose of study treatment.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study medication up to 72 weeks

Adverse event reporting additional description

APaT population; all randomized/enrolled who received ≥1 dose of study treatment according to treatment actually received. Participants who received grazoprevir 400 or 800 mg and were then down-dosed to receive grazoprevir 100 mg are reported separately from participants who completed the 400 mg and 800 mg regimens.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

OL Grazoprevir 100 mg

Reporting group description

TN cirrhotic participants received open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 100 mg

Reporting group description

TN NC participants received Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 200 mg

Reporting group description

TN NC participants received Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg

Reporting group description

TN NC participants received Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 800 mg

Reporting group description

TN NC participants received Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.

Reporting group title

Grazoprevir 400 mg/100 mg

Reporting group description

Reporting group title

Grazoprevir 800 mg/100 mg

Reporting group description

Reporting group title

Boceprevir 800 mg

Reporting group description

Serious adverse events	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 36 (8.33%)	6 / 66 (9.09%)	9 / 68 (13.24%)	2 / 24 (8.33%)	2 / 29 (6.90%)	5 / 43 (11.63%)	4 / 36 (11.11%)	5 / 66 (7.58%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intermittent claudication
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vocal cord polyp
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Schizoaffective disorder
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial paresis
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Normochromic normocytic anaemia
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids thrombosed
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Segmented hyalinising vasculitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast abscess
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	2 / 24 (8.33%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	OL Grazoprevir 100 mg	Grazoprevir 100 mg	Grazoprevir 200 mg	Grazoprevir 400 mg	Grazoprevir 800 mg	Grazoprevir 400 mg/100 mg	Grazoprevir 800 mg/100 mg	Boceprevir 800 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	34 / 36 (94.44%)	64 / 66 (96.97%)	65 / 68 (95.59%)	23 / 24 (95.83%)	27 / 29 (93.10%)	42 / 43 (97.67%)	36 / 36 (100.00%)	64 / 66 (96.97%)
Vascular disorders
Hypertension
subjects affected / exposed	3 / 36 (8.33%)	1 / 66 (1.52%)	1 / 68 (1.47%)	1 / 24 (4.17%)	1 / 29 (3.45%)	4 / 43 (9.30%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	3	1	1	1	1	4	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	8 / 36 (22.22%)	14 / 66 (21.21%)	9 / 68 (13.24%)	5 / 24 (20.83%)	3 / 29 (10.34%)	7 / 43 (16.28%)	8 / 36 (22.22%)	12 / 66 (18.18%)
occurrences all number	9	19	9	5	4	8	8	13
Chest pain
subjects affected / exposed	4 / 36 (11.11%)	2 / 66 (3.03%)	2 / 68 (2.94%)	1 / 24 (4.17%)	0 / 29 (0.00%)	1 / 43 (2.33%)	2 / 36 (5.56%)	2 / 66 (3.03%)
occurrences all number	4	2	3	1	0	1	2	2
Chills
subjects affected / exposed	10 / 36 (27.78%)	20 / 66 (30.30%)	19 / 68 (27.94%)	6 / 24 (25.00%)	10 / 29 (34.48%)	12 / 43 (27.91%)	11 / 36 (30.56%)	15 / 66 (22.73%)
occurrences all number	11	22	20	7	10	12	12	16
Fatigue
subjects affected / exposed	18 / 36 (50.00%)	27 / 66 (40.91%)	31 / 68 (45.59%)	11 / 24 (45.83%)	16 / 29 (55.17%)	17 / 43 (39.53%)	15 / 36 (41.67%)	27 / 66 (40.91%)
occurrences all number	19	30	38	12	19	17	16	30
Influenza like illness
subjects affected / exposed	9 / 36 (25.00%)	14 / 66 (21.21%)	20 / 68 (29.41%)	7 / 24 (29.17%)	5 / 29 (17.24%)	15 / 43 (34.88%)	7 / 36 (19.44%)	23 / 66 (34.85%)
occurrences all number	9	15	22	7	5	15	7	24
Injection site erythema
subjects affected / exposed	2 / 36 (5.56%)	12 / 66 (18.18%)	10 / 68 (14.71%)	1 / 24 (4.17%)	8 / 29 (27.59%)	2 / 43 (4.65%)	3 / 36 (8.33%)	8 / 66 (12.12%)
occurrences all number	2	12	10	1	8	2	3	9
Injection site irritation
subjects affected / exposed	3 / 36 (8.33%)	1 / 66 (1.52%)	0 / 68 (0.00%)	1 / 24 (4.17%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	3	1	0	1	1	0	0	0
Injection site rash
subjects affected / exposed	1 / 36 (2.78%)	3 / 66 (4.55%)	6 / 68 (8.82%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	4 / 66 (6.06%)
occurrences all number	1	3	6	0	0	1	0	4
Injection site reaction
subjects affected / exposed	2 / 36 (5.56%)	3 / 66 (4.55%)	5 / 68 (7.35%)	1 / 24 (4.17%)	0 / 29 (0.00%)	2 / 43 (4.65%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	2	3	5	1	0	2	1	2
Oedema peripheral
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	3	0	0	0	1	0	0	1
Pain
subjects affected / exposed	8 / 36 (22.22%)	12 / 66 (18.18%)	12 / 68 (17.65%)	3 / 24 (12.50%)	11 / 29 (37.93%)	8 / 43 (18.60%)	4 / 36 (11.11%)	12 / 66 (18.18%)
occurrences all number	8	13	12	3	11	8	4	13
Pyrexia
subjects affected / exposed	9 / 36 (25.00%)	20 / 66 (30.30%)	24 / 68 (35.29%)	12 / 24 (50.00%)	8 / 29 (27.59%)	12 / 43 (27.91%)	6 / 36 (16.67%)	20 / 66 (30.30%)
occurrences all number	9	23	27	12	10	18	22	21
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 36 (19.44%)	5 / 66 (7.58%)	9 / 68 (13.24%)	1 / 24 (4.17%)	4 / 29 (13.79%)	9 / 43 (20.93%)	6 / 36 (16.67%)	7 / 66 (10.61%)
occurrences all number	7	5	9	1	5	10	6	8
Dyspnoea
subjects affected / exposed	9 / 36 (25.00%)	6 / 66 (9.09%)	10 / 68 (14.71%)	1 / 24 (4.17%)	3 / 29 (10.34%)	2 / 43 (4.65%)	4 / 36 (11.11%)	7 / 66 (10.61%)
occurrences all number	10	8	12	1	5	2	4	7
Dyspnoea exertional
subjects affected / exposed	0 / 36 (0.00%)	3 / 66 (4.55%)	6 / 68 (8.82%)	0 / 24 (0.00%)	6 / 29 (20.69%)	6 / 43 (13.95%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	0	3	7	0	6	6	1	2
Epistaxis
subjects affected / exposed	3 / 36 (8.33%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	1 / 29 (3.45%)	2 / 43 (4.65%)	0 / 36 (0.00%)	2 / 66 (3.03%)
occurrences all number	3	0	1	0	1	2	0	2
Nasal congestion
subjects affected / exposed	2 / 36 (5.56%)	2 / 66 (3.03%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	2 / 66 (3.03%)
occurrences all number	2	2	1	0	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 36 (0.00%)	4 / 66 (6.06%)	6 / 68 (8.82%)	2 / 24 (8.33%)	4 / 29 (13.79%)	1 / 43 (2.33%)	3 / 36 (8.33%)	6 / 66 (9.09%)
occurrences all number	0	4	7	2	4	1	3	7
Productive cough
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	1 / 68 (1.47%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	1	1	0	2	1	0	1
Respiratory tract congestion
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	2 / 68 (2.94%)	0 / 24 (0.00%)	1 / 29 (3.45%)	1 / 43 (2.33%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	2	0	2	0	1	1	1	2
Sinus congestion
subjects affected / exposed	1 / 36 (2.78%)	3 / 66 (4.55%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	2 / 43 (4.65%)	2 / 36 (5.56%)	3 / 66 (4.55%)
occurrences all number	1	3	1	0	0	2	3	3
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 36 (11.11%)	5 / 66 (7.58%)	10 / 68 (14.71%)	0 / 24 (0.00%)	0 / 29 (0.00%)	3 / 43 (6.98%)	3 / 36 (8.33%)	3 / 66 (4.55%)
occurrences all number	4	5	10	0	0	3	3	3
Apathy
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	3 / 29 (10.34%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	0	1	0	0	3	1	0	0
Depression
subjects affected / exposed	4 / 36 (11.11%)	7 / 66 (10.61%)	11 / 68 (16.18%)	1 / 24 (4.17%)	5 / 29 (17.24%)	6 / 43 (13.95%)	8 / 36 (22.22%)	7 / 66 (10.61%)
occurrences all number	4	7	11	1	5	6	8	7
Insomnia
subjects affected / exposed	8 / 36 (22.22%)	15 / 66 (22.73%)	10 / 68 (14.71%)	3 / 24 (12.50%)	6 / 29 (20.69%)	7 / 43 (16.28%)	8 / 36 (22.22%)	21 / 66 (31.82%)
occurrences all number	10	15	10	3	7	7	10	22
Irritability
subjects affected / exposed	10 / 36 (27.78%)	16 / 66 (24.24%)	9 / 68 (13.24%)	1 / 24 (4.17%)	3 / 29 (10.34%)	7 / 43 (16.28%)	5 / 36 (13.89%)	12 / 66 (18.18%)
occurrences all number	10	16	11	1	3	7	7	14
Mood swings
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	2	0	1	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 36 (2.78%)	1 / 66 (1.52%)	3 / 68 (4.41%)	1 / 24 (4.17%)	4 / 29 (13.79%)	4 / 43 (9.30%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences all number	1	1	3	1	4	4	1	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	3 / 29 (10.34%)	2 / 43 (4.65%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences all number	1	0	1	0	3	2	1	0
Blood bilirubin increased
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	2 / 68 (2.94%)	2 / 24 (8.33%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	0	2	2	1	0	0	1
Haemoglobin decreased
subjects affected / exposed	3 / 36 (8.33%)	2 / 66 (3.03%)	4 / 68 (5.88%)	1 / 24 (4.17%)	0 / 29 (0.00%)	1 / 43 (2.33%)	1 / 36 (2.78%)	5 / 66 (7.58%)
occurrences all number	3	2	4	1	0	1	1	8
Spleen palpable
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Weight decreased
subjects affected / exposed	1 / 36 (2.78%)	1 / 66 (1.52%)	2 / 68 (2.94%)	1 / 24 (4.17%)	3 / 29 (10.34%)	0 / 43 (0.00%)	5 / 36 (13.89%)	3 / 66 (4.55%)
occurrences all number	1	1	2	1	3	0	5	3
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 36 (2.78%)	4 / 66 (6.06%)	8 / 68 (11.76%)	3 / 24 (12.50%)	6 / 29 (20.69%)	3 / 43 (6.98%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	1	6	8	3	6	5	1	2
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	4 / 43 (9.30%)	0 / 36 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	1	0	0	0	4	0	2
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 36 (0.00%)	4 / 66 (6.06%)	8 / 68 (11.76%)	1 / 24 (4.17%)	0 / 29 (0.00%)	2 / 43 (4.65%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	0	4	9	1	0	3	2	1
Dizziness
subjects affected / exposed	7 / 36 (19.44%)	6 / 66 (9.09%)	10 / 68 (14.71%)	2 / 24 (8.33%)	6 / 29 (20.69%)	5 / 43 (11.63%)	5 / 36 (13.89%)	9 / 66 (13.64%)
occurrences all number	8	6	10	2	6	6	6	9
Dysgeusia
subjects affected / exposed	1 / 36 (2.78%)	5 / 66 (7.58%)	7 / 68 (10.29%)	3 / 24 (12.50%)	3 / 29 (10.34%)	1 / 43 (2.33%)	4 / 36 (11.11%)	19 / 66 (28.79%)
occurrences all number	1	5	7	3	3	1	4	19
Headache
subjects affected / exposed	12 / 36 (33.33%)	28 / 66 (42.42%)	31 / 68 (45.59%)	8 / 24 (33.33%)	12 / 29 (41.38%)	12 / 43 (27.91%)	17 / 36 (47.22%)	35 / 66 (53.03%)
occurrences all number	16	39	35	8	16	13	19	44
Hypoaesthesia
subjects affected / exposed	3 / 36 (8.33%)	1 / 66 (1.52%)	6 / 68 (8.82%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	3	1	6	0	1	0	2	4
Migraine
subjects affected / exposed	0 / 36 (0.00%)	2 / 66 (3.03%)	1 / 68 (1.47%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	0 / 36 (0.00%)	3 / 66 (4.55%)
occurrences all number	0	2	1	0	3	1	0	4
Paraesthesia
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	2 / 36 (5.56%)	1 / 66 (1.52%)
occurrences all number	0	0	0	0	0	1	2	1
Poor quality sleep
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	13 / 36 (36.11%)	11 / 66 (16.67%)	17 / 68 (25.00%)	2 / 24 (8.33%)	7 / 29 (24.14%)	5 / 43 (11.63%)	7 / 36 (19.44%)	18 / 66 (27.27%)
occurrences all number	16	16	21	2	7	7	7	25
Leukopenia
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	2 / 68 (2.94%)	1 / 24 (4.17%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	5 / 66 (7.58%)
occurrences all number	0	3	3	1	2	0	0	9
Neutropenia
subjects affected / exposed	7 / 36 (19.44%)	6 / 66 (9.09%)	7 / 68 (10.29%)	2 / 24 (8.33%)	1 / 29 (3.45%)	2 / 43 (4.65%)	0 / 36 (0.00%)	11 / 66 (16.67%)
occurrences all number	7	12	8	3	2	3	0	13
Thrombocytopenia
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	0 / 36 (0.00%)	3 / 66 (4.55%)
occurrences all number	4	0	0	0	0	0	0	3
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	1 / 68 (1.47%)	2 / 24 (8.33%)	1 / 29 (3.45%)	1 / 43 (2.33%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	2	0	1	2	1	1	0	1
Eye disorders
Dry eye
subjects affected / exposed	0 / 36 (0.00%)	2 / 66 (3.03%)	1 / 68 (1.47%)	2 / 24 (8.33%)	2 / 29 (6.90%)	3 / 43 (6.98%)	2 / 36 (5.56%)	2 / 66 (3.03%)
occurrences all number	0	2	1	2	2	3	2	2
Eye irritation
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	1 / 24 (4.17%)	0 / 29 (0.00%)	0 / 43 (0.00%)	2 / 36 (5.56%)	0 / 66 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0
Visual acuity reduced
subjects affected / exposed	2 / 36 (5.56%)	2 / 66 (3.03%)	0 / 68 (0.00%)	0 / 24 (0.00%)	0 / 29 (0.00%)	0 / 43 (0.00%)	2 / 36 (5.56%)	1 / 66 (1.52%)
occurrences all number	2	2	0	0	0	0	2	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	3 / 43 (6.98%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	0	1	1	0	0	3	1	2
Abdominal pain
subjects affected / exposed	4 / 36 (11.11%)	3 / 66 (4.55%)	7 / 68 (10.29%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	1 / 36 (2.78%)	4 / 66 (6.06%)
occurrences all number	5	3	8	0	2	1	1	4
Abdominal pain upper
subjects affected / exposed	2 / 36 (5.56%)	7 / 66 (10.61%)	5 / 68 (7.35%)	2 / 24 (8.33%)	2 / 29 (6.90%)	0 / 43 (0.00%)	5 / 36 (13.89%)	4 / 66 (6.06%)
occurrences all number	2	7	6	2	2	0	5	4
Constipation
subjects affected / exposed	3 / 36 (8.33%)	2 / 66 (3.03%)	3 / 68 (4.41%)	2 / 24 (8.33%)	0 / 29 (0.00%)	1 / 43 (2.33%)	3 / 36 (8.33%)	4 / 66 (6.06%)
occurrences all number	3	2	3	2	0	1	4	4
Diarrhoea
subjects affected / exposed	5 / 36 (13.89%)	11 / 66 (16.67%)	11 / 68 (16.18%)	5 / 24 (20.83%)	11 / 29 (37.93%)	5 / 43 (11.63%)	12 / 36 (33.33%)	16 / 66 (24.24%)
occurrences all number	7	13	13	6	14	5	13	19
Dry mouth
subjects affected / exposed	2 / 36 (5.56%)	2 / 66 (3.03%)	5 / 68 (7.35%)	2 / 24 (8.33%)	1 / 29 (3.45%)	2 / 43 (4.65%)	2 / 36 (5.56%)	1 / 66 (1.52%)
occurrences all number	2	2	5	2	1	2	2	1
Dyspepsia
subjects affected / exposed	2 / 36 (5.56%)	2 / 66 (3.03%)	7 / 68 (10.29%)	3 / 24 (12.50%)	2 / 29 (6.90%)	2 / 43 (4.65%)	4 / 36 (11.11%)	3 / 66 (4.55%)
occurrences all number	2	2	7	3	2	2	4	3
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	0 / 36 (0.00%)	5 / 66 (7.58%)
occurrences all number	2	0	1	0	3	1	0	5
Nausea
subjects affected / exposed	9 / 36 (25.00%)	25 / 66 (37.88%)	25 / 68 (36.76%)	6 / 24 (25.00%)	16 / 29 (55.17%)	15 / 43 (34.88%)	19 / 36 (52.78%)	31 / 66 (46.97%)
occurrences all number	10	29	28	8	21	17	29	37
Stomatitis
subjects affected / exposed	0 / 36 (0.00%)	2 / 66 (3.03%)	2 / 68 (2.94%)	2 / 24 (8.33%)	1 / 29 (3.45%)	1 / 43 (2.33%)	0 / 36 (0.00%)	6 / 66 (9.09%)
occurrences all number	0	2	2	2	1	1	0	6
Toothache
subjects affected / exposed	1 / 36 (2.78%)	4 / 66 (6.06%)	1 / 68 (1.47%)	1 / 24 (4.17%)	0 / 29 (0.00%)	1 / 43 (2.33%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	1	5	1	1	0	1	1	1
Vomiting
subjects affected / exposed	4 / 36 (11.11%)	8 / 66 (12.12%)	8 / 68 (11.76%)	6 / 24 (25.00%)	5 / 29 (17.24%)	4 / 43 (9.30%)	6 / 36 (16.67%)	16 / 66 (24.24%)
occurrences all number	4	13	10	8	7	9	7	20
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	2 / 68 (2.94%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	2 / 36 (5.56%)	0 / 66 (0.00%)
occurrences all number	0	0	2	0	3	0	2	0
Jaundice
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	8 / 36 (22.22%)	17 / 66 (25.76%)	19 / 68 (27.94%)	7 / 24 (29.17%)	9 / 29 (31.03%)	8 / 43 (18.60%)	10 / 36 (27.78%)	8 / 66 (12.12%)
occurrences all number	8	17	20	7	10	8	10	8
Dry skin
subjects affected / exposed	4 / 36 (11.11%)	6 / 66 (9.09%)	9 / 68 (13.24%)	1 / 24 (4.17%)	2 / 29 (6.90%)	7 / 43 (16.28%)	5 / 36 (13.89%)	8 / 66 (12.12%)
occurrences all number	4	6	10	1	2	7	5	8
Eczema
subjects affected / exposed	1 / 36 (2.78%)	4 / 66 (6.06%)	0 / 68 (0.00%)	1 / 24 (4.17%)	1 / 29 (3.45%)	1 / 43 (2.33%)	2 / 36 (5.56%)	1 / 66 (1.52%)
occurrences all number	2	4	0	1	1	1	2	1
Erythema
subjects affected / exposed	2 / 36 (5.56%)	4 / 66 (6.06%)	4 / 68 (5.88%)	1 / 24 (4.17%)	2 / 29 (6.90%)	3 / 43 (6.98%)	0 / 36 (0.00%)	2 / 66 (3.03%)
occurrences all number	2	4	5	1	2	3	0	2
Hyperhidrosis
subjects affected / exposed	0 / 36 (0.00%)	7 / 66 (10.61%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	2 / 43 (4.65%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	0	9	0	0	2	2	0	0
Photosensitivity reaction
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	0	0	1	0	2	0	0	0
Pruritus
subjects affected / exposed	6 / 36 (16.67%)	12 / 66 (18.18%)	15 / 68 (22.06%)	6 / 24 (25.00%)	7 / 29 (24.14%)	4 / 43 (9.30%)	10 / 36 (27.78%)	10 / 66 (15.15%)
occurrences all number	7	16	17	6	7	4	11	12
Pruritus generalised
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	3 / 68 (4.41%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences all number	0	0	3	0	2	1	1	0
Rash
subjects affected / exposed	8 / 36 (22.22%)	15 / 66 (22.73%)	13 / 68 (19.12%)	3 / 24 (12.50%)	6 / 29 (20.69%)	7 / 43 (16.28%)	9 / 36 (25.00%)	17 / 66 (25.76%)
occurrences all number	9	17	14	7	7	12	10	22
Rash erythematous
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	1 / 68 (1.47%)	2 / 24 (8.33%)	2 / 29 (6.90%)	2 / 43 (4.65%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	0	0	1	3	4	7	3	3
Rash pruritic
subjects affected / exposed	1 / 36 (2.78%)	1 / 66 (1.52%)	1 / 68 (1.47%)	0 / 24 (0.00%)	0 / 29 (0.00%)	2 / 43 (4.65%)	0 / 36 (0.00%)	4 / 66 (6.06%)
occurrences all number	1	1	1	0	0	2	0	4
Scab
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Skin exfoliation
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	0 / 68 (0.00%)	1 / 24 (4.17%)	1 / 29 (3.45%)	1 / 43 (2.33%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	2	0	0	1	1	1	0	0
Xeroderma
subjects affected / exposed	2 / 36 (5.56%)	2 / 66 (3.03%)	1 / 68 (1.47%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	0 / 66 (0.00%)
occurrences all number	2	2	1	0	1	0	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	2 / 36 (5.56%)	1 / 66 (1.52%)	1 / 68 (1.47%)	1 / 24 (4.17%)	1 / 29 (3.45%)	0 / 43 (0.00%)	1 / 36 (2.78%)	0 / 66 (0.00%)
occurrences all number	2	1	1	1	1	0	1	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	1 / 68 (1.47%)	1 / 24 (4.17%)	1 / 29 (3.45%)	0 / 43 (0.00%)	1 / 36 (2.78%)	5 / 66 (7.58%)
occurrences all number	0	1	1	1	1	0	1	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 36 (16.67%)	11 / 66 (16.67%)	9 / 68 (13.24%)	7 / 24 (29.17%)	4 / 29 (13.79%)	3 / 43 (6.98%)	7 / 36 (19.44%)	12 / 66 (18.18%)
occurrences all number	7	11	13	8	7	3	7	15
Back pain
subjects affected / exposed	7 / 36 (19.44%)	5 / 66 (7.58%)	4 / 68 (5.88%)	0 / 24 (0.00%)	2 / 29 (6.90%)	2 / 43 (4.65%)	5 / 36 (13.89%)	3 / 66 (4.55%)
occurrences all number	7	5	4	0	3	2	7	3
Muscle spasms
subjects affected / exposed	4 / 36 (11.11%)	1 / 66 (1.52%)	1 / 68 (1.47%)	1 / 24 (4.17%)	0 / 29 (0.00%)	1 / 43 (2.33%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	4	1	1	1	0	1	1	2
Myalgia
subjects affected / exposed	6 / 36 (16.67%)	12 / 66 (18.18%)	9 / 68 (13.24%)	6 / 24 (25.00%)	4 / 29 (13.79%)	7 / 43 (16.28%)	5 / 36 (13.89%)	13 / 66 (19.70%)
occurrences all number	6	13	11	9	5	7	6	15
Neck pain
subjects affected / exposed	1 / 36 (2.78%)	2 / 66 (3.03%)	1 / 68 (1.47%)	0 / 24 (0.00%)	2 / 29 (6.90%)	1 / 43 (2.33%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	2	1	0	2	1	0	1
Pain in extremity
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	4 / 68 (5.88%)	2 / 24 (8.33%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	2 / 66 (3.03%)
occurrences all number	0	0	5	2	0	2	0	2
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 36 (5.56%)	0 / 66 (0.00%)	3 / 68 (4.41%)	0 / 24 (0.00%)	0 / 29 (0.00%)	2 / 43 (4.65%)	2 / 36 (5.56%)	2 / 66 (3.03%)
occurrences all number	2	0	3	0	0	2	2	3
Ear infection
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	1 / 36 (2.78%)	2 / 66 (3.03%)
occurrences all number	0	1	0	0	2	0	1	2
Influenza
subjects affected / exposed	1 / 36 (2.78%)	0 / 66 (0.00%)	1 / 68 (1.47%)	2 / 24 (8.33%)	0 / 29 (0.00%)	1 / 43 (2.33%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	1	0	1	2	0	1	0	1
Nasopharyngitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	4 / 68 (5.88%)	1 / 24 (4.17%)	1 / 29 (3.45%)	0 / 43 (0.00%)	0 / 36 (0.00%)	1 / 66 (1.52%)
occurrences all number	0	2	4	1	1	0	0	1
Pneumonia
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	2 / 29 (6.90%)	0 / 43 (0.00%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	0	0	0	0	2	0	1	1
Sinusitis
subjects affected / exposed	0 / 36 (0.00%)	1 / 66 (1.52%)	2 / 68 (2.94%)	0 / 24 (0.00%)	1 / 29 (3.45%)	3 / 43 (6.98%)	0 / 36 (0.00%)	5 / 66 (7.58%)
occurrences all number	0	1	2	0	1	4	0	5
Upper respiratory tract infection
subjects affected / exposed	0 / 36 (0.00%)	3 / 66 (4.55%)	6 / 68 (8.82%)	0 / 24 (0.00%)	0 / 29 (0.00%)	1 / 43 (2.33%)	1 / 36 (2.78%)	1 / 66 (1.52%)
occurrences all number	0	3	6	0	0	1	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 36 (11.11%)	16 / 66 (24.24%)	11 / 68 (16.18%)	4 / 24 (16.67%)	9 / 29 (31.03%)	10 / 43 (23.26%)	14 / 36 (38.89%)	15 / 66 (22.73%)
occurrences all number	4	17	11	5	9	10	14	16
Dehydration
subjects affected / exposed	0 / 36 (0.00%)	0 / 66 (0.00%)	0 / 68 (0.00%)	0 / 24 (0.00%)	1 / 29 (3.45%)	0 / 43 (0.00%)	3 / 36 (8.33%)	0 / 66 (0.00%)
occurrences all number	0	0	0	0	1	0	3	0

More information

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Were there any global substantial amendments to the protocol? Yes

08 Jul 2011

Protocol amendment 1 (AM1) added the response-guided therapy regimen for the boceprevir control arm, revised the criteria for virologic failure for all arms, included changes to the prohibited concomitant medications, and removed Area under the concentration-time curve as a pharmacokinetic (PK) endpoint.

29 Sep 2011

AM2 added a semen analysis substudy to the study flow chart, added exclusion criteria for the semen analysis substudy, changed the missing data approach, and updated guidance for missed doses of grazoprevir.

26 Jan 2012

AM3 revised protocol text, study diagram, flow chart, study objectives, eligibility criteria, and statistical analysis text to include a prior treatment failure and compensated cirrhotic patient cohort. AM3 also added a second planned interim analysis and modified AE and blood chemistry analysis.

10 Apr 2012

AM4 revised text throughout the protocol to remove the prior treatment failure and compensated cirrhotic patient cohort and added text throughout the protocol describing results and actions related to the first interim analysis including the down-dosing of patients in the 400 mg and 800 mg grazoprevir arms to 100 mg

04 Jan 2013

AM5 added a cohort to study 100 mg grazoprevir in combination with PEG-IFN and RBV in treatment-naïve cirrhotic patients and revised eligibility criteria for this new cohort accordingly.

29 Mar 2013

AM6 added a dosing duration modification for the cirrhotic cohort assigned to the 24-week treatment duration, and made revisions to the study flow chart, eligibility criteria, PK Analysis section, and HCV RNA analysis section in relation to the cirrhotic cohort.

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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Baseline characteristics

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End points

Primary: Percentage of Participants Achieving Complete Early Viral Response (cEVR)

Primary: Percentage of Participants Achieving Complete Early Viral Response (cEVR)

Primary: Percentage of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days

Primary: Percentage of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days

Primary: Percentage of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days

Primary: Percentage of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days

Secondary: Median Time to First Achievement of Undetectable HCV RNA During Treatment

Secondary: Median Time to First Achievement of Undetectable HCV RNA During Treatment

Secondary: Percentage of Participants Achieving Rapid Viral Response (RVR)

Secondary: Percentage of Participants Achieving Rapid Viral Response (RVR)

Secondary: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)

Secondary: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)

Secondary: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)

Secondary: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)

Secondary: Percentage of Participants Achieving Undetectable HCV RNA at Week 72

Secondary: Percentage of Participants Achieving Undetectable HCV RNA at Week 72

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
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Slovenia
Spain
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United Kingdom
Outside EU/EEA